Miller's Anesthesia [9 ed.]

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The Scope of Modern Anesthetic Practice KATE LESLIE, LARS I. ERIKSSON, JEANINE P. WIENER-KRONISH, NEAL H. COHEN, LEE A. FLEISHER, and MICHAEL A. GROPPER

KEY POINTS

□ The

scope of modern anesthesia practice includes preoperative evaluation and preparation; intraprocedural care; postoperative care including acute pain management; critical care, resuscitation, and retrieval; chronic pain management; and palliative care. Anesthesia plays a key role in health service delivery and has a significant impact on population health and the burden of disease. □ Global and national forces for change include changing patient populations, locations of care, workforce, costs, quality and safety initiatives, research capability, and the availability of data. These forces have major implications for the delivery of care, evaluation and organization of the anesthesia practice, and education and training of physician anesthesiologists. □ The volume of patients presenting for perioperative and obstetric care continues to grow. Increasingly more patients at extremes of age are requiring anesthesia services. Many of the patients are elderly and have significant comorbidities, including obesity and opioid use disorder. This has important implications for delivery of care and health system issues. □ Anesthesia care is shifting from the traditional surgical suite to other procedural areas, ambulatory sites, office-based facilities, and home environments. As anesthesia care expands, anesthesiologists must focus on maintaining the safety and quality of care in these diverse settings. □ Global and regional deficits in the availability of high-quality anesthesia care must be managed by improving the supply of both physician and non-physician anesthesia providers, by better use of technology, and by limiting demand through health promotion and disease prevention strategies. □ Internationally, the costs of health care continue to escalate; unfortunately the increased spending has not consistently translated into improved health outcomes. Health policy initiatives including alternative approaches to healthcare financing and payment systems are increasingly being implemented to encourage efficient and effective team-based anesthesia care. □ Anesthesiology was among the first medical specialties to focus on improving the safety of patient care. As anesthesia has become safer, attention has intensified on quality improvement, a process designed to improve patient experience and outcomes through systematic change and evaluation. □ Basic, translational, clinical, and implementation research is vital to continuous improvement in outcomes. Opportunities to optimize care are supported by the availability of large datasets generated using electronic health records as well as novel analytic techniques. These changes create new opportunities for anesthesiologists to collaborate with basic and translational scientists to better understand current practices and define better ways to deliver care. As always the provision of resources to support these research initiatives is a challenge. □ The scope of modern anesthetic practice is continually expanding and changing. The changes occurring in health care in the 21st century create opportunities for anesthesiologists to assume a broader role in clinical practice and health policy, providing exciting opportunities for the next generation of physicians in our specialty.

Introduction Anesthesia is fundamental to the overall practice of medicine worldwide. Hundreds of millions of patients receive anesthesia care each year in association with a wide range of medical, surgical, and obstetric procedures. In addition to direct delivery of anesthesia to patients undergoing a surgical procedure, the scope of anesthesia practice extends beyond the traditional surgical suite to include preoperative

evaluation and management of underlying clinical conditions (see Chapter 31); postoperative care including acute pain management (see Chapter 81); critical care, resuscitation, and retrieval (see Chapter 67); chronic pain management (see Chapter 51); and palliative care (see Chapter 52). Anesthesia therefore plays an essential role in health service delivery (see Chapter 3) and has a significant impact on global health and the burden of disease (see Chapter 2). The purpose of Miller’s Anesthesia is to cover the full scope of

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1 • The Scope of Modern Anesthetic Practice

contemporary anesthesia practice, from fundamental principles to advanced subspecialty procedures. Every edition of this textbook begins with comments about the novel diagnostic and therapeutic procedures that have been developed since the last edition and the increasing complexity of patients presenting for anesthesia and perioperative care, especially those at the extremes of life. Each edition also provides descriptions about advances in anesthesiology that have facilitated patient care, including improved understanding of the processes that underlie disease and injury, the increasing sophistication of the pharmacologic and technical resources available, and the improvements in systems designed to promote safety and quality in health care. The 9th edition is no exception: in the last decade the advances in anesthesia and surgical care, especially for patients receiving complex clinical care, have been truly remarkable. None of these advances would have been possible without the commitment of anesthesiologists to leadership, teaching, and research. Evidence of their contributions can be found in every chapter of the book, extending from improved understanding of the mechanisms of anesthesia and the processes that regulate organ function and drive organ failure; through new technologies, drugs, and systems of care and education; to improved understanding and acknowledgement of the critical role patients and their families play in decision making about healthcare and endof-life issues. The future of anesthesiology is filled with opportunities and challenges. Global and national forces will drive evidence-based, cost-effective perioperative and obstetric care by multiprofessional and multidisciplinary teams. These changes will be supported by integrated electronic medical records and large databases and registries of healthcare outputs and outcomes. Increasingly, anesthesia care has expanded outside the operating room, into preoperative clinics, intervention suites, extended postanesthesia care units, and even into patients’ homes. As is true for other medical specialties, anesthesiologists have adopted telehealth strategies to extend the care provided to patients and colleagues beyond face-to-face encounters. Technological advances have and will continue to facilitate less invasive interventions and improved anesthesia delivery and monitoring systems. As a result, seriously ill and injured patients and those at the extremes of age, often with associated comorbidities now have access to care previously not available to them. Care is also becoming more personalized, in large part because of the availability of genetic testing and an improved understanding of the unique needs of each patient based on disease severity and his or her probability of responding to specific treatment modalities. Partially as a result of these improvements in care, the costs of caring for an aging population with progressively sophisticated therapies challenge all nations. These forces will likely have a major effect on the scope of perioperative care in general and anesthesia services in particular. Therefore, anesthesiologists must be involved in health policy decisions about the distribution of resources and the need for high-quality evidence to guide practice. In the rest of this chapter we will deal with some of these forces in detail. 

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Forces That Will Change Practice (Fig. 1.1) CHANGING PATIENT POPULATIONS The volume of patients having surgical procedures each year is large and growing. In 2012, more than 300 million patients had surgery worldwide.1 This number probably underestimates the overall volume of patients requiring anesthesia services, in large part because much of anesthesia care is now provided outside of traditional surgical suite environments. Global initiatives aimed at delivering universal health coverage and safe and affordable surgery and anesthesia care will result in further increases in the number of patients requiring anesthesia care in coming decades (see Chapter 2). Increasingly many of the patients requiring anesthesia services will be older and have multiple health problems, including obesity and chronic pain associated with opioid use. The World Health Organization has estimated that by the year 2050 nearly one-quarter of the world’s population will be over 60 years of age.2 In the United States the number of people aged 65 years and over, and therefore eligible for treatment under Medicare, is expected to exceed 78 million by 2030. In high income countries the increase in the numbers of older patients will result from improved preventative care and management of chronic disease and injury. In low- and middle-income countries this change will result from improvements in maternal and child health and the eradication or control of infectious diseases. Concurrently, improvements in anesthetic and surgical care in many countries are increasing medical care options for older patients, who are now receiving more surgical services—many complicated procedures—than ever before. However, the accessibility of these additional options is presenting new challenges for both patients and providers. Aging is associated with a decline in physiologic reserve and organ function and an increase in the risk of disease, injury, and disability (both physical and cognitive). The aging process is highly variable, with significant influence from genetic, environmental, and societal factors. Aging is also associated with considerable changes in social and economic circumstances. Overall these factors lead the older adult to greater dependence on health and social care and challenges in the provision of safe surgery and anesthesia (see Chapters 65 and 82). One significant public health issue that is accelerating internationally is obesity. It has emerged as a global health epidemic. In 2016, 39% of adults and 18% of children and adolescents worldwide were overweight.3 In the United States the prevalence of overweight populations was 67.9% and 41.8% in adults and children, respectively. Although the rate of increase in the number of overweight and obese populations have slowed in some high-income nations, this is not the case in low- and middle-income countries. Poor access to healthy diets and limited exercise contribute to the problem. Obesity is associated with an increased burden of disease and injury, including diabetes and hypertension that result in the need for more interactions with the health system, high costs, and significant challenges in the provision of safe and high-quality surgical and anesthetic care (see Chapter 58).

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SECTION I  •  Introduction

A

D

C

B

E

F

G

Fig. 1.1  Changing scope and settings of anesthesia and perioperative medicine. (A) The Cure of Folly, by Hieronymus Bosch (c.1450–1516), depicting the removal of stones in the head, thought to be a cure for madness. (B) Friedrich Esmarch amputating with the use of anesthesia and antisepsis. (C) Harvey Cushing performing an operation. The Harvey Cushing Society is observing (1932). (D) Placement of a deep brain stimulator for the treatment of Parkinson disease using a real-time magnetic resonance (MR) imaging technology (MR fluoroscopy). The procedure occurs in the MR suite of the radiology department. The patient is anesthetized and (E) moved into the bore of the magnet. (F) A sterile field is created for intracranial instrumentation, and (G) electrodes are placed using real-time guidance. (A, Museo Nacional del Prado, Madrid. B, Woodcut from Esmarch’s Handbuch Der Kriegschirurgischen Technik [1877]; Jeremy Norman & Co. C, Photograph by Richard Upjohn Light (Boston Medical Library). D to G, Courtesy Paul Larson, University of California–San Francisco, San Francisco Veterans Administration Medical Center.)

Pain management strategies have also had impact on anesthesia practice and perioperative care. The current opioid epidemic arose from increased prescription of opioid drugs to treat all types of acute and chronic pain, including postoperative pain. This crisis has been exacerbated by diversion of prescribed medication (i.e., diverting a medication from its original licit medical purpose) and use of “street” drugs, including opioids. The consequences are significant for individual patients and society as a whole. Opioid use has resulted in addiction, overdoses, homelessness, excessive emergency room visits, increased infections, and neonatal abstinence syndrome. The Centers for Disease Control and Prevention (CDC) estimated that more than 191 million prescriptions (58.7 prescriptions per 100 persons) were filled in the United States in 2017, with marked regional variation characterized with adverse physical, economic, and social circumstances.4 Opioids were involved in 42,249 overdose deaths in 2016 (66.4% of all drug overdose deaths). The situation is similar in other nations, with the World Health Organization estimating that 27 million people worldwide suffered opioid use disorder in 2015.5 Recent government action has been substantial, particularly in the United States. The Department of Health and Human Services has implemented a five-point plan to combat the crisis including: (1) improved access to prevention, treatment, and recovery support services; (2) targeted availability and distribution of overdose-reversing (narcotic antagonist)

drugs; (3) strengthened public health data reporting and collection; (4) support for cutting-edge research on addiction and pain; and (5) advances in pain management practice.6 As experts in the pharmacology and clinical use of opioid drugs (see Chapters 24, 51, and 81), anesthesiologists and pain medicine specialists have and must continue their essential role in resolving this crisis. 

CHANGING LOCATIONS OF CARE Anesthesia practice has expanded to a variety of locations. A number of factors account for this shift in anesthesia and perioperative care (see Chapter 73). The costs of traditional operating room care are high and the services available may be unnecessarily comprehensive and complex for the planned episode of care. With advances in clinical care, the need for inpatient perioperative care is reduced for many surgical procedures. As a result more and more procedures are being performed in hospital outpatient settings, ambulatory surgery centers, and office-based practices. The focus of accrediting bodies and anesthesiology societies has been on maintaining the safety and quality of anesthesia care in outpatient settings, including providing for extended admission and escalation of care when clinically necessary to ensure patient safety.7 At the same time, the payment models have not necessarily kept pace with these advances in clinical care. In the United States, the growth in

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1 • The Scope of Modern Anesthetic Practice

nonhospital-based care has occurred despite curbs in reimbursement for ambulatory surgery by governmental and private payers. The clinical practice for surgical patients has also changed because of changes in sites of care and inpatient management. For most patients, many aspects of perioperative care have shifted from the hospital or other healthcare facility to outpatient or home settings. As one example, the elimination of preoperative hospital admission to day-of-surgery admission is virtually complete in high-income nations. Hospital lengths of stay are also much shorter. As a result, postoperative care is increasingly undertaken in the home as well, often as part of enhanced recovery after surgery programs.8 Advances in monitoring technology and pain management techniques create opportunities for anesthesiologists in which to not only participate, but also manage many aspects of postoperative care in the home. Although these changes have been beneficial to many patients with improved outcomes and reduced costs, for some families the transition to short hospital lengths of stay has created significant clinical and social problems. Anesthesiologists must have an understanding of patients perioperative and postoperative support needs and should be actively engaged in determining the most appropriate setting for a procedure and how to manage the transitions of care.9 In addition to the changes taking place for surgical patients, anesthesia care is also shifting outside the operating room as a result of the advances in minimally invasive techniques provided by cardiologists, radiologists, endoscopists, and pain medicine specialists (see Chapters 51, 55, 57, and 73). As the volume of these services increases, anesthesiologists may be asked to provide care in procedural areas that were not designed for delivery of anesthesia services, and often not properly equipped to support patient and provider needs. The locations are frequently remote from the operating suite and may lack the usual support available for the care of patients with complex cases and the management of crises. Anesthesiologists therefore must participate in planning for these services and provide leadership in defining and maintaining the same standards of operating room practice to other areas of the hospital.10,11 Another example of the advances in clinical care and implications is the remarkable increase in referrals for colonoscopy for colon cancer screening.12 Although the sedation provider for colonoscopy widely varies internationally and regionally within the United States, anesthesiologists are now more commonly participating in the care of these patients, in part due to medical needs related to comorbidities, but also because of documented complications associated with the use of sedation that have resulted in airway compromise or respiratory failure. These complications have caused providers and payers to reevaluate patient needs, the appropriate training of practitioners delivering procedural sedation, and when to optimize care by having an anesthesia practitioner monitor the patient and administer sedation. American11,13 and international14,15 sedation guidelines recognize that for many patients, nonanesthesiologist physicians and independent or semi-independent nonmedical practitioners can provide deep sedation for endoscopy; however, all guidelines emphasize that anesthesiologists should be involved in the care of high-risk patients or those with significant comorbidities. 

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CHANGES IN THE ANESTHESIA WORKFORCE As a result of advances in perioperative care and the many other changes that impact the need for anesthesia practitioners, global and regional workforce shortages have been identified in recent years and are expected to increase (see Chapter 2). There are a number of reasons for these deficits including an insufficient number of medical graduates (in some places exacerbated by outward migration and an aging workforce), duty hour restrictions for practicing physicians (due to regulation of work hours, changing lifestyle preferences, and desire for better work-life balance), and increased demand for medical services (due to population growth and on a per capita basis). In addition to the impact of these societal changes, demand for physician care in the United States has increased in part due to the Patient Protection and Affordable Care Act (Affordable Care Act) with more patients having medical insurance and seeking care. To respond to the shortages, many countries within the Organisation for Economic Co-operation and Development (there are 36 member countries, including the United States) have increased medical school admissions in recent years.16 Unfortunately, even this increase in number of trainees is insufficient to meet future needs. In 2017, the United States produced 7.55 medical graduates per 100,000 population, well below average (12 per 100,000 inhabitants). The Association of American Medical Colleges (AAMC) projects a shortage of up to 121,000 physicians by 2030.14 At the same time, despite the increases in medical student enrollment, in the United States, most residency positions are funded by the Medicare program. As the medical school intakes have increased, this federal funding for residency positions (including anesthesiology) has not kept pace resulting in a bottleneck in the training pipeline. Along with reconsidering the cap on federally-funded positions, the AAMC has proposed alternative ways to leverage the skills and experience of physicians to advance care with improved use of technology and more interdisciplinary, team-based care as potential solutions. Team-based care (anesthesia care team model) is already common in anesthesia practice, particularly in the United States. In the United States, the number of physician and nonphysician anesthesia providers are approaching parity, with the number of nurse anesthetists and anesthesia assistants increasing more rapidly than the number of physician anesthesiologists. In 2017, the American Society of Anesthesiologists (ASA) released a statement on the anesthesia care team that enunciated its vision for physicianled teams where anesthesiologists have a particular role in governance, planning, and oversight of anesthesia care, advanced airway management, and resuscitation.17 This oversight includes defining and monitoring sedation provided in non-operating room locations and other requirements for the credentialing of providers to optimize care of the patient who requires deep sedation. Similar team-based approaches to care associated with physician supervision are commonplace or emerging in other countries around the world. The number of women in medical schools has increased to over 50% of the student cohort in many countries. At the same time, until recently, United States anesthesiology training programs have recruited a smaller proportion of

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SECTION I  •  Introduction

women (37%). In academic departments, few women have reached the rank of professor, or become department chairs, or been elected to leadership positions in representative anesthesia organizations.18 Programs to improve recruitment and advancement of women in academic medicine and anesthesiology have gained traction in the last decade (e.g., Athena Scientific Women’s Academic Network19). In addition, all academic programs are paying more attention to diversity in the workforce, particularly among women and underrepresented minorities. With the increased understanding of the inequities, programs can be developed to more effectively address the disparities and broaden the diversity of the anesthesia workforce. It is essential that the anesthesia workforce reflect the diversity of the patient population that is served. 

INCREASING COSTS OF CARE The costs of health care continue to grow internationally, with health care consuming 8% of gross domestic product (GDP) on average in most countries, whereas in the United States the costs are as high as 18% of GDP.20 Unfortunately the increased healthcare expenditures have not translated into improved health outcomes, particularly for Americans. Despite the Affordable Care Act, the United States continues to have a large uninsured or underinsured population, lapses in quality and safety of care inside and outside the hospital, and high rates of drug abuse, violence, and use of firearms.21 The National Academy of Medicine concluded that healthcare funding in the United States needs to “reorient competition in the healthcare system around the value of services provided rather than the volume of services provided.” This transition from volume to value is creating many new challenges and opportunities for anesthesiologists. As the health system adopts practices that provide documented improved outcomes at reduced costs, anesthesiologists must both understand the implications of these changes in clinical practices and also take a leadership role in identifying opportunities to reengineer care if the specialty is to retain its leadership role in quality and safety (see Chapter 3). Payment for physician services is being modified to better align health systems, providers, and payers with respect to delivery of high-quality, patient-centered care. Compensation for clinical care continues to have a fee-forservice component, particularly in the United States; however, more compensation is becoming incentive-based to encourage changes in practice that improve efficiency and effectiveness. In contrast to fee-for-service models (which reward inputs), pay-for-performance models reward medical care that is consistent with published evidence and that improves the processes of care (e.g., timely administration of perioperative antibiotics), output (e.g., meeting targets for urgent surgery), or outcome (e.g., fewer centralline associated blood stream infections) measures. In the United States, recent pay-for-performance programs have included the Premier Hospital Quality Incentive Demonstration program of the Centers for Medicare and Medicaid Services (2003–2009) and the national Hospital ValueBased Purchasing Program, adopted after the passage of the Affordable Care Act (2011). This initial attempt to modify anesthesia practice has had limited impact on outcomes,

possibly because financial incentives are too small, payment is delayed, and/or the costs associated with implementing the programs is greater.22 Nonetheless, incentive-based pay-for-performance programs (which are widespread in other nations with high-cost healthcare systems) will continue to expand.23 In addition to paying for high-quality performance, in the United States and other high-income nations there has been increasing emphasis on not paying for poor outcomes of errors in care. For example, some payers withhold payment for “never” events (e.g., wrong-sided surgery, pressure ulcers, retained foreign objects, mismatched blood transfusion) unless they are present on admission to the hospital. This approach may be expanded to withhold payment associated with treatment of preventable complications. A number of anesthesia-specific activities have been identified that impact outcomes and, if these are not provided, the consequence could be either no payment or penalties. For example, monitoring and maintaining body temperature during surgery as promoted by the Surgical Care Improvement Project is but one example of an anesthesia metric that affects outcomes and costs of care.24 At the same time, identification of some of the interventions or monitoring techniques that impact outcome is challenging. As a result, it is critically important for anesthesiologists to continue to evaluate practices and do additional research to both optimize care and reduce costs. Other changes in payment for clinical care have and will continue to have significant impact on compensation for anesthesia services. Some payers are providing “bundled” payments to compensate providers for episodes of care. This approach to payment is an integral part of the reforms introduced under the Affordable Care Act, although some of the incentives may be redefined by subsequent legislation. The Bundled Payments for Care Improvement initiative introduced by the Centers for Medicare and Medicaid Services tested the ability of bundling payments as a method for improving quality and lowering costs. The program has been most successful for selected clinical services such as total joint arthroplasty for which participation by anesthesiologists through the continuum of care can be most significant.25 The ASA has proposed the Perioperative Surgical Home as an anesthesiologist-managed structure to coordinate perioperative team-based care. This model of coordinated care throughout the perioperative period should be amenable to bundled payments or other new approaches to compensating providers.26 

INCREASING FOCUS ON SAFETY AND QUALITY Anesthesiology was among the first medical specialties to focus on improving patient safety.27 A number of initiatives have had major impact on outcomes of care, including improved monitoring techniques, airway management options, and new improved drugs. Anesthesiologists have been actively assessing clinical care through the use of incident reporting systems, morbidity and mortality conferences, and “near-miss” reports. Incident reporting, which was initiated in the United States more than 50 years ago, has documented a decline in anesthesia-related mortality to less than 1 per 1 million population.28 In recent years national incident reporting programs have been initiated

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1 • The Scope of Modern Anesthetic Practice

by the Anesthesia Quality Institute (Anesthesia Incident Reporting System29) and the Society of Pediatric Anesthesia (Wake Up Safe30). In addition to helping identify areas in which to improve clinical care, these programs provide legal protection to practitioners under the Patient Safety and Quality Improvement Act (2005). A number of programs have developed based on the experiences identified through these reporting mechanisms. Recognition of the human factors associated with adverse events has spawned a national and international movement directed at improving situational awareness and team functioning through simulation training (see Chapter 6). More recently programs to encourage healthcare providers and consumers to speak up about traditional patient safety concerns (e.g., commencing a wrong-side procedure) and unsafe professional behaviors (e.g., bullying and sexual harassment) have been integrated into workplaces nationwide and internationally.31 Anesthesiologists also led the way in the development of practice standards and checklists to improve clinical care. In some cases, the implementation of checklists has become a requirement for accreditation. In the last decade anesthesiologists were pivotal in the development, implementation, and evaluation of the World Health Organization’s Surgical Safety Checklist.32 Although the uptake of the Checklist has been patchy and its effect on outcomes has been inconsistent, the Checklist is widely implemented in the United States and other countries (see Chapter 2) in the belief that it will enable effective communication and a culture of safety.33 As anesthesia has become more and more safe, our attention has increasingly been focused on quality improvement, a process designed to improve patient experience and outcomes through systematic change and evaluation. In the United States, the Anesthesia Quality Institute established the National Anesthesia Clinical Outcomes Registry to enable systematic collection of quality information for use in quality improvement processes both nationally and locally.34 Recently greater emphasis has been placed on longer-term and patient-centered or patient-reported outcomes. Many of these outcome measures have been incorporated into quality improvement programs and publicly reported metrics.35 Anesthesiologists have identified the importance of assessing outcomes beyond the immediate perioperative period. As anesthesiologists assume a greater role in overall periprocedural care and outcomes, they will undoubtedly continue to advance the safety and quality agenda in large part due to their longstanding history in safety and quality as well as their training and pivotal role in perioperative care. 

NEW OPPORTUNITIES AND CHALLENGES IN RESEARCH Academic anesthesia departments are committed to advancing the scientific underpinning of anesthesiology. Basic, translational, clinical, and implementation research is vital to the continuous improvement in patient and health service outcomes (see Chapter 89). Fortunately, overall funding for biomedical and health services research in the United States more than doubled between 1994 and 2012. Although overall research funding has increased,

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since 2004 the overall growth of NIH funding for medical research has declined by 1.8%.36 Private sources of funding have been important to supplement government-sponsored research support. Industry support is valuable and has been critical to the research agenda for academic departments. It also creates both real and perceived conflicts of interest that can be difficult to manage. Over the past decade, there has been a decline in early-stage research in favor of device development and clinical trials, poor mapping of research effort to the global burden of disease, and limited funding for critically important health services research.36 The implications of these changes in research support on anesthesia are significant. Academic anesthesia departments in the United States, as well as many other countries, continue to compete for government funding. Most benchmarks suggest that the specialty of anesthesiology in the United States fares poorly in National Institutes of Health funding when compared with other disciplines.37 As a result, anesthesia departments, particularly in the United States have had to identify other funding sources, including foundations, industry, and philanthropy, particularly for early-career investigators.38 For example the Foundation for Anesthesia Education and Research (FAER) has awarded more than $40 million in grants since 1986 and has demonstrated the leverage that these grants provide in achieving federal funding ($17 in funding for every $1 investment). Similar programs are funded by the International Anesthesia Research Society and by other anesthesiology organizations and foundations worldwide. At the same time, and in many respects related to the funding challenges and competing clinical needs, research support and peer-reviewed publications, which have increased in other countries, have not kept pace in the United States. As a result, an increasing number of publications in peer-reviewed journals are from authors outside the United States. Other factors have impact on what resources are available for research. The clinical demands put on the faculty in academic departments make it difficult for clinician scientists to pursue research activities. Associated with the increasing clinical volume, supervised residents cannot provide all of the clinical care without compromising their educational experiences and fulfilling duty hour and other requirements. As a result, the faculty members are delivering a larger percentage of care on their own. At the same time, the complexity of some of the basic and translational research requires significant dedicated time and skills that are difficult to maintain when the investigator is also encumbered with a high clinical demand. Historically, clinically generated income was used to support research in general and young investigators in particular. As labor and other costs increase (including those associated with quality of care initiatives, clinical and research compliance, and other activities), fewer funds are available to support research. As a result of the high cost of developing new drugs with insufficient incentives for the pharmaceutical industry to develop new anesthetic agents, there is a reduced pipeline of anesthesia drugs.39 Despite these challenges, basic science, as well as clinical and translational research, is being performed by anesthesiologists and advances in the specialty are taking place. New models for research have contributed to advances in

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SECTION I  •  Introduction

our understanding of basic concepts of anesthesia care as well as clinical advances. As is true for clinical care, collaboration has always been vital in biomedical research. In recent years anesthesiology research has increasingly been conducted by multiprofessional, multidisciplinary teams including biostatisticians, health informaticians, and health economists. Translation from discovery to practice has been facilitated by partnerships among basic scientists, clinical scientists, and implementation scientists.40 In addition to collaborations among colleagues within one institution, increasingly clinical trials are being conducted by large, multicenter networks because of the recognition that single-center studies take too long and cannot recruit enough patients to answer the really important questions in anesthesiology.41-44 Research based on electronic medical records and databases also requires collaboration between institutions, clinicians, and database experts (see later). One of the primary motivators to support the research agenda for anesthesiology is the need to define reliable and peer-reviewed data upon which to advance the specialty. Although the volume of anesthesiology information and its ease of access have increased exponentially in the last decade, particularly through social media, anesthesiologists are progressively challenged to find reliable information to guide their practice. In addition to the difficulty of assessing the quality of some of the information posted on various web sites, anesthesiology has also been plagued by high-profile cases of research misconduct, including fabrication, falsification, and misleading reporting of research findings.45 This has damaged the reputation of anesthesiology research and, as a result of unreliable data upon which to make clinical decisions, put patients at risk. Each anesthesiologist must be diligent in selecting a source of information that takes into consideration the standards of peer review of the material and the financial relationships between the authors and publishers.46 

INCREASING AVAILABILITY OF DATA One of the areas of opportunity with respect to better understanding our clinical practices and defining ways to improve care is the increasing amount of data that can inform us. The last decade has seen unprecedented growth in the volume and availability of healthcare data. Electronic health record (EHR) systems (see Chapter 4) facilitate complete data capture and integration from multiple sources, including surgical equipment, anesthesia delivery systems, and physiologic monitors. The EHR has greatly facilitated documentation of individual patient care and provided aggregate data for healthcare services and populations. Other sources of routinely-collected data include health service billing systems, government and insurance databases, disease registries, and public health reporting. In addition, data specifically collected for research and quality improvement is increasingly shared, including research databases and biobanks (including genetic databanks). Meta-data related to the use of electronic resources and social media is also available for interrogation. These data require new management and analysis techniques that are beyond the scope of the practicing anesthesiologist or researcher (see Chapter 4). Truly “big” data includes terabytes of information, is generated and analyzed at high speed, and includes data in a wide variety of formats and from a wide variety of sources.47

These large data sets are increasingly being used to answer important research questions, to develop evidencebased clinical guidelines, and to assess the safety and quality of anesthesia and perioperative care, within and across different clinical environments and regions. Although technologic resources are not replacing randomized clinical trials, the information gleaned from large databases can be used to address important questions about how to most effectively deliver cost-effective care. At the same time, it is important to acknowledge the limitations of large databases, which may have missing critical elements of care or outcomes, could misclassify data, or in some cases, lack verification.48 

Conclusions The scope of modern anesthetic practice is continually changing and expanding. The forces for change include changes in our patient population, locations of care, workforce, costs, quality and safety initiatives, research, and the availability of data. This chapter emphasizes the implications for these forces on the specialty as well as the influence they have on the delivery of health care in general. The changes occurring in health care in the 21st century obviously have implications for the role of anesthesiology in both the practice and delivery of medicine overall, and provide exciting opportunities for the next generation of practitioners and leaders in our specialty.

Acknowledgment The editors and publisher recognize the contributions of Ronald D. Miller, who was a contributing author to this topic in previous editions of this work. It has served as the foundation for the current chapter. Complete references available online at expertconsult.com.

References 1. Weiser TG, et al. Lancet. 2015;385(suppl 2):S11. 2. World Health Organisation. World report on ageing and health. Geneva. https://www.who.int/ageing/events/world-report-2015launch/en/. Accessed October 18 2018. 3. World Health Organisation. Fact sheet on overweight and obesity. http://www.who.int/en/news-room/fact-sheets/detail/obesity-andoverweight. Accessed October 18 2018. 4. Centers for Disease Control and Prevention. U.S. opioid prescribing rate maps. Atlanta. https://www.cdc.gov/drugoverdose/maps/rxr ate-maps.html. Accessed October 18 2018. 5.  World Health Organisation. Information sheet on opioid overdose. Geneva. http://www.who.int/substance_abuse/informationsheet/en/. Accessed October 18 2018. 6.  Department of Health and Human Services. Help, resources and information. National opioid crisis. Washington. https://www.hhs.gov/opioids/. Accessed October 18 2018. 7. American Society of Anesthesiologists. Guidelines for office-based anesthesia. Schaumberg. https://www.asahq.org/quality-andpractice-management/standards-guidelines-and-related-resourcessearch. Accessed October 18 2018. 8. Kehlet H. Br J Anaesth. 1997;78:606. 9. Fleisher LA, et al. Arch Surg. 2004;139:67. 10. American Society of Anesthesiologists. Statement on non-operating room anesthetizing locations. Schaumberg. https://www.asahq.org/ quality-and-practice-management/standards-guidelines-andrelated-resources-search. Accessed.

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1 • The Scope of Modern Anesthetic Practice 11. American Society of Anesthesiologists task force on moderate procedural sedation and analgesia. Anesthesiology. 2018;128:437. 12. National Cancer Institute. Colorectal cancer screening. Bethesda. http s://progressreport.cancer.gov/detection/colorectal_cancer. Accessed October 18 2018. 13.  Quality Management and Departmental Administration Committee. Advisory on granting privileges for deep sedation to non-anesthesiologist physicians (amended October 25, 2017). Schaumburg. http://www.asahq.org/quality-and-practice-management/standards-guidelines-and-related-resources. Accessed March 5 2018. 14. The Academy of Medical Royal Colleges. Safe sedation practice for healthcare procedures. London. https://www.rcoa.ac.uk/system/file s/PUB-SafeSedPrac2013.pdf. Accessed March 5 2018. 15. Hinkelbein J, et al. Eur J Anaesthesiol. 2017;35:6. 16. Organisation for Economic Co-operation and Development. Medical graduates. Paris. https://data.oecd.org/healthres/medicalgraduates.htm. Accessed October 18 2018. 17.  American Society of Anesthesiologists. Statement on the anesthesia care team. Schaumberg. http://www.asahq.org/qualityand-practice-management/standards-guidelines-and-relatedresources/statement-on-anesthesia-care-team. Accessed October 18 2018. 18. Leslie K, et al. Anesth Analg. 2017;124:1394. 19.  Equality Challenge Unit. Athena SWAN Charter. London. https://www.ecu.ac.uk/equality-charters/athena-swan/. Accessed October 18 2018. 20.  Organisation for Economic Co-operation and Development. Health spending. Paris. https://data.oecd.org/healthres/healthspending.htm. Accessed October 18 2018. 21. National Research Council and Institute of Medicine. U.S. Health in International Perspective: shorter Lives, Poorer Health. Washington: National Academies Press. 2013. 22. Bonfrer I, et al. BMJ. 2018;360:j5622. 23. European Observatory on Health Systems and Policies. Paying for performance in healthcare. Implications for health system performance and accountability. Maidenhead. http://www.euro.who.int/__data/ assets/pdf_file/0020/271073/Paying-for-Performance-in-Health-Ca re.pdf. Accessed October 18 2018.

9

24. Scott AV, et al. Anesthesiology. 2015;123:116. 25. Centers for Medicare & Medicaid Services. Bundled Payments for Care Improvement (BPCI) Initiative: General Information. Washington DC. https://innovation.cms.gov/initiatives/bundled-payments/. Accessed October 18 2018. 26. American Society of Anesthesiologists. Perioperative surgical home. Schaumberg. https://www.asahq.org/psh. Accessed October 18 2018. 27. Kohn L, Corrigan J, Donaldson M. To Err Is Human: Building a Safer Health System. Washington DC: National Academy Press; 1999. 28. Li G, et al. Anesthesiology. 2009;110:759. 29. Anesthesia Quality Institute. Anesthesia incident reporting system (AIRS). Schaumberg. https://qualityportal.aqihq.org/AIRSMain/AIR SSelectType/0. Accessed October 18 2018. 30. Society for Pediatric Anesthesia. Wake up safe. Richmond. http://ww w.wakeupsafe.org/. Accessed October 18 2018. 31. Webb LE, et al. Jt Comm J Qual Patient Saf. 2016;42:149. 32. Haynes A, et al. N Engl J Med. 2009;360:491. 33. de Jager E, et al. World J Surg. 2016;40:1842. 34. Liau A, et al. Anesth Analg. 2015;121:1604. 35. Peden CJ, et al. Br J Anaesth. 2017;119:i5. 36. Moses H 3rd, et al. JAMA. 2015;313:174. 37. Reves JG. Anesthesiology. 2007;106:826. 38. Speck RM, et al. Anesth Analg. 2018;126:2116. 39. Vlassakov KV, Kissin I. Trends Pharmacol Sci. 2016;37:344. 40. Kharasch ED. Anesthesiology. 2018;128:693. 41. Myles P, et al. BMJ Open. 2017;7:e015358. 42. Pearse RM, et al. JAMA. 2014;311:2181. 43. Wijeysundera DN, et al. Lancet. 2018;391:2631. 44. Devereaux P, et al. N Engl J Med. 2014;370:1494. 45. Moylan EC, Kowalczuk MK. BMJ Open. 2016;6:e012047. 46. Shen C, Bjork BC. BMC Med. 2015;13:230. 47. Levin MA, et al. Anesth Analg. 2015;121:1661. 48. Fleischut PM, et al. Br J Anaesth. 2013;111:532.

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References 1. Weiser TG, Haynes AB, Molina G, et al. Estimate of the global volume of surgery in 2012: an assessment supporting improved health outcomes. Lancet. 2015;385(suppl 2):S11. 2. World Health Organisation. World report on ageing and health. Geneva. https://www.who.int/ageing/events/world-report-2015-launch/en/. Accessed October 18 2018. 3. World Health Organisation. Fact sheet on overweight and obesity. http://www.who.int/en/news-room/fact-sheets/detail/obesity-andoverweight. Accessed October 18 2018. 4. Centers for Disease Control and Prevention. U.S. opioid prescribing rate maps. Atlanta. https://www.cdc.gov/drugoverdose/maps/rxratemaps.html. Accessed October 18 2018. 5.  World Health Organisation. Information sheet on opioid overdose. Geneva. http://www.who.int/substance_abuse/informationsheet/en/. Accessed October 18 2018. 6.  Department of Health and Human Services. Help, resources and information. National opioid crisis. Washington. https://www.hhs. gov/opioids/. Accessed October 18 2018. 7. American Society of Anesthesiologists. Guidelines for office-based anesthesia. Schaumberg. https://www.asahq.org/quality-and-practicemanagement/standards-guidelines-and-related-resources-search. Accessed October 18 2018. 8. Kehlet H. Multimodal approach to control postoperative pathophysiology and rehabilitation. Br J Anaesth. 1997;78:606–617. 9. Fleisher LA, Pasternak LR, Herbert R, Anderson GF. Inpatient hospital admission and death after outpatient surgery in elderly patients: importance of patient and system characteristics and location of care. Arch Surg. 2004;139:67–72. 10. American Society of Anesthesiologists. Statement on non-operating room anesthetizing locations. Schaumberg. https://www.asahq.org/ quality-and-practice-management/standards-guidelines-andrelated-resources-search. Accessed. 11. American Society of Anesthesiologists Task Force on Moderate Procedural Sedation and Analgesia, the American Association of Oral and Maxillofacial Surgeons, American College of Radiology, American Dental Association, American Society of Dentist Anesthesiologists, and Society of Interventional Radiology. Practice guidelines for moderate procedural sedation and analgesia 2018. Anesthesiology. 2018;128:437–479. 12. National Cancer Institute. Colorectal cancer screening. Bethesda. http s://progressreport.cancer.gov/detection/colorectal_cancer. Accessed October 18 2018. 13.  Quality Management and Departmental Administration Committee. Advisory on granting privileges for deep sedation to non-anesthesiologist physicians (amended October 25, 2017). Schaumburg. http://www.asahq.org/quality-and-practice-management/standards-guidelines-and-related-resources. Accessed March 5 2018. 14. The Academy of Medical Royal Colleges. Safe sedation practice for healthcare procedures. London. https://www.rcoa.ac.uk/system/file s/PUB-SafeSedPrac2013.pdf. Accessed March 5 2018. 15. Hinkelbein J, Lamperti M, Akeson J, et al. European Society of Anaesthesiology and European Board of Anaesthesiology guidelines for procedural sedation and analgesia in adults. Eur J Anaesthesiol. 2017;35:6–24. 16. Organisation for Economic Co-operation and Development. Medical graduates. Paris. https://data.oecd.org/healthres/medical-graduates. htm. Accessed October 18 2018. 17.  American Society of Anesthesiologists. Statement on the anesthesia care team. Schaumberg. http://www.asahq.org/qualityand-practice-management/standards-guidelines-and-relatedresources/statement-on-anesthesia-care-team. Accessed October 18 2018. 18. Leslie K, Hopf HW, Houston P, O’Sullivan E. Women, minorities, and leadership in anesthesiology: Take the pledge. Anesth Analg. 2017;124:1394–1396. 19.  Equality Challenge Unit. Athena SWAN Charter. London. https://www.ecu.ac.uk/equality-charters/athena-swan/. Accessed October 18 2018. 20.  Organisation for Economic Co-operation and Development. Health spending. Paris. https://data.oecd.org/healthres/healthspending.htm. Accessed October 18 2018.

21. National Research Council and Institute of Medicine. U.S. health in international perspective: shorter lives, poorer health. Washington: National Academies Press; 2013. 22. Bonfrer I, Figueroa JF, Zheng J, Orav EJ, Jha AK. Impact of financial incentives on early and late adopters among us hospitals: Observational study. BMJ. 2018;360:j5622. 23. European Observatory on Health Systems and Policies. Paying for performance in healthcare. Implications for health system performance and accountability. Maidenhead. http://www.euro.who.int/__data/ assets/pdf_file/0020/271073/Paying-for-Performance-in-Health-Ca re.pdf. Accessed October 18 2018. 24. Scott AV, Stonemetz JL, Wasey JO, et  al. compliance with surgical care improvement project for body temperature management (SCIP Inf-10) is associated with improved clinical outcomes. Anesthesiology. 2015;123:116–125. 25. Centers for Medicare & Medicaid Services. Bundled Payments for Care Improvement (BPCI) Initiative: General Information. Washington DC. https://innovation.cms.gov/initiatives/bundled-payments/. Accessed October 18 2018. 26. American Society of Anesthesiologists. Perioperative surgical home. Schaumberg. https://www.asahq.org/psh. Accessed October 18 2018. 27. Kohn L, Corrigan J, Donaldson M. To Err Is Human: Building a Safer Health System. Washington DC: National Academy Press; 1999. 28. Li G, Warner M, Lang BH, Huang L, Sun LS. Epidemiology of anesthesia-related mortality in the United States, 1999-2005. Anesthesiology. 2009;110:759–765. 29. Anesthesia Quality Institute. Anesthesia incident reporting system (AIRS). Schaumberg. https://qualityportal.aqihq.org/AIRSMain/AIR SSelectType/0. Accessed October 18 2018. 30. Society for Pediatric Anesthesia. Wake up safe. Richmond. http://ww w.wakeupsafe.org/. Accessed October 18 2018 31. Webb LE, Dmochowski RR, Moore IN, et al. Using coworker observations to promote accountability for disrespectful and unsafe behaviors by physicians and advanced practice professionals. Jt Comm J Qual Patient Saf. 2016;42:149–164. 32. Haynes A, Weiser T, Berry W, et  al. A surgical safety checklist to reduce morbidity and mortality in a global population. N Engl J Med. 2009;360:491–499. 33. de Jager E, McKenna C, Bartlett L, Gunnarsson R, Ho YH. Postoperative adverse events inconsistently improved by the World Health Organization Surgical Safety Checklist: a systematic literature review of 25 studies. World J Surg. 2016;40:1842–1858. 34. Liau A, Havidich JE, Onega T, Dutton RP. The National Anesthesia Clinical Outcomes Registry. Anesth Analg. 2015;121:1604–1610. 35. Peden CJ, Campbell M, Aggarwal G. Quality, safety, and outcomes in anaesthesia: what’s to be done? An international perspective. Br J Anaesth. 2017;119:i5–i14. 36. Moses H 3rd, Matheson DH, Cairns-Smith S, George BP, Palisch C, Dorsey ER. The anatomy of medical research: US and international comparisons. Jama. 2015;313:174–189. 37. Reves JG. We are what we make: transforming research in anesthesiology: the 45th Rovenstine Lecture. Anesthesiology. 2007;106:826– 835. 38. Speck RM, Ward DS, Fleisher LA. Academic anesthesiology career development: a mixed-methods evaluation of the role of Foundation for Anesthesiology Education and Research funding. Anesth Analg. 2018;126:2116–2122. 39. Vlassakov KV, Kissin I. Decline in the development of new anesthetics. Trends Pharmacol Sci. 2016;37:344–352. 40. Kharasch ED. The challenges of translation. Anesthesiology. 2018;128:693–696. 41. Myles P, Bellomo R, Corcoran T, et al. Restrictive versus liberal fluid therapy in major abdominal surgery (RELIEF): rationale and design for a multicentre randomised trial. BMJ Open. 2017;7:e015358. 42. Pearse RM, Harrison DA, MacDonald N, et al. Effect of a perioperative, cardiac output-guided hemodynamic therapy algorithm on outcomes following major gastrointestinal surgery: a randomized clinical trial and systematic review. JAMA. 2014;311:2181–2190. 43. Wijeysundera DN, Pearse RM, Shulman MA, et  al. Assessment of functional capacity before major non-cardiac surgery: an international, prospective cohort study. Lancet. 2018;391:2631–2640.

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9.e2

References

44. Devereaux P, Sessler D, Mrkobrada M, et al. Aspirin in patients having non-cardiac surgery. N Engl J Med. 2014;370:1494–1503. 45. Moylan EC, Kowalczuk MK. Why articles are retracted: a retrospective cross-sectional study of retraction notices at BioMed Central. BMJ Open. 2016;6:e012047.

46. Shen C, Bjork BC. Predatory’ open access: a longitudinal study of article volumes and market characteristics. BMC Med. 2015;13:230. 47. Levin MA, Wanderer JP, Ehrenfeld JM. Data, big data, and metadata in anesthesiology. Anesth Analg. 2015;121:1661–1667. 48. Fleischut PM, Mazumdar M, Memtsoudis SG. Perioperative database research: possibilities and pitfalls. Br J Anaesth. 2013;111:532–534.

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2

Anesthesia and Analgesia in the Global Context MICHAEL S. LIPNICK, RONALD D. MILLER, and ADRIAN W. GELB, EDITORS. SEE CHAPTER OUTLINE FOR CO-AUTHORS.

CHAPTER OUTLINE

KEY POINTS

Introduction Section 1: Anesthesia and “Global Health” Scope and Scale of the Global Anesthesia, Surgery, and Pain Crises Global Burden of Surgical Disease Global Burden of Pain Disparities in Access, Affordability, and Safety Global Anesthesia, Surgery, and Pain Crises: Origins and Areas for Intervention Misperceptions and Limited Data Advocacy and Policy Workforce Shortages and Strategies for Expansion Infrastructure Challenges Inequities in Analgesia Section 2: Evolution of Anesthesia Care Models and Challenges Around the World Africa Uganda (Mary T. Nabukenya and Sarah Hodges) South Africa (Hyla Kluyts) North America Canada (Tyler Law) Mexico (Gerardo Prieto) United States (Ronald D. Miller and Adrian W. Gelb)

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Europe Norway (Jannicke Mellin-Olsen) Romania (Daniela Filipescu) Asia and The Middle East India (Bala Krishnan Kanni) Lebanon and The Middle East (Patricia Yazbeck) Pakistan (Fauzia Khan) China (Yugaung Huang) Vietnam (Thi Thanh Nguyen and Thang Cong Quyet) South America Paraguay (Rodrigo Sosa Argana) Colombia (Pedro Ibarra) Oceania Australia and New Zealand (Rob McDougall) Fiji and Pacific Island Nations(Sereima Bale) Section 3: Essentials for Practice in Resource-Constrained Settings Clinical and Technical Skills Personnel Equipment Drugs Patients Global Health Competencies Conclusions

 ore than 5 of the world’s 7 billion people lack access to safe anesthesia and surgical services. M Surgical disease accounts for 30% of global disease burden, yet less than 1% of development assistance for health supports delivery of anesthesia and surgical care. Lack of access to safe, timely, and affordable anesthesia and surgery kills more than 4 times as many as acquired immunodeficiency syndrome (AIDS), tuberculosis (TB), and malaria combined. Lack of access to safe anesthesia and surgical services are among the most neglected crises in global health. Anesthesia-related mortality in some low-income countries (LICs) is reported in the 1:100s and is mostly avoidable. The burden of surgical disease is growing and disproportionately affects low- and middle-income countries. Pain is one of the top causes of morbidity worldwide, and inadequate access to analgesia is among the most inequitable global public health crises the world faces today. Five and a half billion people have limited or no access to narcotic medications for analgesia. Six high-income countries (HICs) account for 80% of the world’s opioid consumption. Key drug control policies, organizations, and politics continue to influence issues of access and abuse, with disproportionately negative impacts for underserved populations. Critical shortages and the inequitable distribution of anesthesia providers are significant barriers to increasing access to safe anesthesia and surgical care. The density of surgery, anesthesia, and obstetric providers is 0.7 per 100,000 population for LICs as compared with 57 per 100,000 population for HICs.

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2 • Anesthesia and Analgesia in the Global Context

KEY POINTS—cont’d

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11

 odern anesthesia workforce training and practice models vary widely from country to counM try. Innovative workforce solutions are needed to increase provider numbers while simultaneously ensuring quality and promoting access for underserved populations. Anesthesia, analgesia, and surgical services are feasible in resource-constrained settings and are as cost-effective as many other public health interventions (e.g., vaccinations). Issues of access, safety, and resource utilization are relevant to all anesthesia providers. Equipping anesthesia providers with knowledge and skills needed to address global challenges in anesthesia will become increasingly important in order to expand access to safe and affordable anesthesia care worldwide. Health care providers from multiple disciplines (nursing, surgery, obstetrics, anesthesia, and many more) are needed to effectively provide surgical and perioperative care. Anesthesiologists routinely work across the perioperative disciplines and can play a significant role to improve cohesive advocacy efforts and lead progress in global health equity for surgical disease and analgesia. The global anesthesia community is lagging behind other health disciplines in addressing global health challenges and must rapidly expand investment in initiatives to help characterize (research), address (implementation and policy), and support (financing) global anesthesia challenges. Developing infrastructure, expanding workforce, improving data to drive policy, providing financial risk protection mechanisms for surgical patients, improving referral and prehospital systems, and providing essential medicines are actions the global anesthesia community must prioritize. The need to act promptly is immense and must be balanced but not overshadowed by research agendas.

Introduction There have been considerable efforts in recent years to define a global “standard” or “optimal” practice of anesthesia.1-4 These debates, investigations, and innovations have most often been framed in the context of maximizing patient safety. More recently the focus of these efforts has expanded to also incorporate the important goals of maximizing not only safety, but also accessibility and affordability of anesthesia services.5 With scientific advancement and economic development, anesthesia—like much of medicine—has changed dramatically since the first public display of ether anesthesia in October of 1846. However, over the past 150-plus years, advances in anesthesia have been neither uniform nor universal, resulting in vastly heterogeneous anesthesia practice models and massive inequities in access to safe anesthesia care worldwide. The majority of the world’s population does not have access to safe, affordable surgical, anesthesia, or pain services, and relatively few resources are being invested by governments, donors, or the global anesthesia community to address this crisis. In this chapter we build off the work of Dr. Miller and colleagues’ to explore not only the evolution and diversity of anesthesia practice models from around the world, but also challenges facing the global anesthesia community. A better understanding of the evolution of modern anesthesia care models, as well as the challenges they face and have overcome, is a key step to improving access and patient safety worldwide. The first section of this chapter describes the scope and magnitude of the ongoing global surgical, anesthesia, and pain crises. This section also explores reasons why these crises have been relatively neglected by the global public health community, and reviews potential areas for intervention, advocacy, and change.

TABLE 2.1  World Bank Income Classifications by Gross National Income per Capita GNI per Capita (US $) Low income

12,235

GNI, Gross national income. Source: https://blogs.worldbank.org/opendata/new-country-classificationsincome-level-2017-2018.

The second section of this chapter presents examples of different anesthesia care models from around the world, including select historical milestones and snapshots of current challenges from regional and country-level perspectives. The final section of this chapter provides a primer on essential clinical and nonclinical knowledge relevant for anesthesia practice in resource-constrained settings. The chapter concludes by discussing the role of anesthesia providers beyond the confines of the operating room or hospital setting, who increasingly will be called upon for solutions that increase access to safe anesthesia, surgery, and analgesia in the global context. 

Section 1: Anesthesia and “Global Health” The terms anesthesia and global health, when used together, often invoke thoughts of providers from highincome countries (HICs) providing clinical care in low- and middle-income countries (LMICs) as part of humanitarian outreach or “mission trips” (Table 2.1). Although such initiatives comprise a substantial proportion of efforts that

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12

SECTION I  •  Introduction

TABLE 2.2  Definitions of Global Health and Global Surgery Global Health*

Global Surgery†

Approach

Field of study, research, practice and advocacy. Emphasizes global perspective and a scientific approach to health promotion and disease prevention, including broad determinants of health.

Area for study, research, practice, and advocacy that places priority on improving health outcomes and achieving health equity for all people worldwide who are affected by surgical conditions or have a need for surgical care.

Geography

Focuses on issues that directly or indirectly affect health but that can transcend national boundaries.

Global surgery emphasizes supraterritorial and transnational issues, determinants, and solutions.

Level of cooperation

Development and implementation of solutions often require global cooperation.

Recognizes that the determinants of inadequate or inequitable surgical care are often the result of common and interdependent global structures and processes, and require global cooperation for global solutions.

Individuals or populations

Embraces both prevention in populations and clinical care of individuals.

Encompasses surgical care for underserved populations in all countries with special emphasis on those affected by conflict, displacement, and disaster.

Access to health

Health equity among nations and for all people is a major objective.

Equitable access to safe and affordable anesthesia, analgesia, and surgical care is a major objective.

Range of disciplines

Highly interdisciplinary and multidisciplinary within and beyond health sciences.

Incorporates all surgical specialties including obstetric and gynecological surgery, anesthesia, perioperative care, aspects of emergency medicine, rehabilitation, and palliative care, and nursing and the allied health professions involved in the care of the surgical patient. Engages non-clinical stakeholders including health economists, governments, and policymakers.

*Modified from Koplan JP, Bond TC, Merson MH, et al. Towards a common definition of global health. Lancet. 2009;(9679);1993–1995; Fried LP, Bentley ME, Buekens P, et al. Global health is public health. Lancet. 2010;375(9714):535–537. †Modified from Dare AJ, Grimes CE, Gillies R, et al. Global surgery: defining an emerging global heath field. Lancet. 2014;384(9961):2245–2247.

aim to increase access to surgical and anesthesia services in resource-constrained settings, they represent only a fraction of the ever-expanding role of the anesthesia community in global health. In this chapter, the term “global health” refers to a multidisciplinary field of study, research, practice, and advocacy that develops and implements solutions to promote health equity. Global health transcends national boundaries, requires global cooperation, and utilizes both population-level (e.g., injury prevention) and individual-level (e.g., clinical care) strategies (Table 2.2). Although some debate exists over the optimal definition of global health and its distinction, or lack thereof, from public health, it is worth highlighting that global health is not synonymous with international aid (i.e., going abroad from one’s own country) or the transfer of technologies or interventions from HICs to LMICs.6,7 Global health encompasses much more, including local providers working in the local environment (whether that is a low-, middle-, or high-income setting), and increasing emphasis on health equity.8 Global health has received unprecedented levels of interest in recent decades, expanding from its infectious disease origins to now incorporate a wider range of diseases, including the social and environmental factors affecting health.9,10 Despite this expanded scope, surgery and anesthesia have remained relatively forgotten by the global health community. In June of 1980, then Director-General of the World Health Organization (WHO), Dr. Halfdan Mahler, gave a presentation to the International College of Surgeons in Mexico City entitled “Surgery and Health for All.” In this speech, Dr. Mahler stated that “Surgery clearly has an important role to play in primary health care and in the services supporting it. Yet, the vast majority of the world’s population has no access whatsoever

to skilled surgical care, and little is being done to find a solution. I beg of you to give serious consideration to this most serious manifestation of social inequity in health care.”11 Despite recognition of the global anesthesia and surgical crises several decades ago, it has been only recently that the global health community has begun to take notice and action.12–17 In 2004, the WHO created the Emergency and Essential Surgical Care Program (EESC) and in 2005, the WHO Global Initiative for Emergency and Essential Surgical Care (GIEESC) was formed to convene multidisciplinary stakeholders interested in surgical disease. In 2007, the Bellagio Essential Surgery Group and Burden of Surgical Disease Working Group (later renamed the Alliance for Surgery and Anesthesia Presence [ASAP]) formed as two of the earliest concerted efforts to raise international awareness for surgical disease by advocating for the integration of surgery into health systems and the promotion of research and collaboration across disciplines.18 These efforts followed in the wake of a seminal chapter on surgery in the Second Edition of the Disease Control Priorities in Developing Countries (DCP2) book in 2006.19 In 2008, the WHO launched the Safe Surgery Saves Lives initiative along with the WHO Safe Surgery Checklist.20,21 Also in 2008 multiple leaders in global health highlighted surgery as the “neglected stepchild” and as the “other neglected disease” in global health, drawing comparison with the then emerging term, “neglected tropical diseases.”22,23 Despite these pleas and consistent, albeit limited, data demonstrating the massive scale of the surgical disease crisis, it was not until 2014–15 that greater attention began to be realized. In 2014, the Amsterdam Declaration on Essential Surgical Care was created, and in 2015, the 68th World Health Assembly (WHA) unanimously passed resolution 68.15 (WHA68.15) to strengthen emergency and essential

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2 • Anesthesia and Analgesia in the Global Context

BOX 2.1  Key Messages From the Disease Control Priorities 3rd Edition □

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 rovision of essential surgical procedures would avert an P estimated 1.5 million deaths a year, or 6%-7% of all avertable deaths in low- and middle-income countries (LMICs). Essential surgical procedures rank among the most costeffective of all health interventions. The surgical platform of first-level hospitals delivers 28 of the 44 essential procedures, making investment in this platform also highly cost-effective. Measures to expand access to surgery, such as task-sharing, have been shown to be safe and effective while countries make long-term investments in building surgical and anesthesia workforces. Because emergency procedures constitute 23 of the 28 procedures provided at first-level hospitals, such facilities must be widely geographically available. Substantial disparities remain in the safety of surgical care, driven by high perioperative mortality rates and anesthesiarelated deaths in LMICs. Feasible measures, such as the World Health Organization’s (WHO’s) Surgical Safety Checklist,27a have led to improvements in safety and quality. The large burden of surgical conditions, the cost-effectiveness of essential surgery, and the strong public demand for surgical services suggest that universal coverage of essential surgery (UCES) should be financed early on the path to universal health coverage. We point to estimates that full coverage of the component of UCES applicable to first-level hospitals would require slightly more than $3 billion annually of additional spending and yield a benefit to cost ratio of better than 10:1. It would efficiently and equitably provide health benefits and financial protection, and it would contribute to stronger health systems.

From Jemison DT, Alwan A, Mock CN, et al: Universal health coverage and intersectoral action for health: key messages from Disease Control Priorities, 3rd edition. The Lancet 391, Issue 10125, 2018:1108–1120.

surgical and anesthesia care as a component of universal health coverage.24,25 Also in 2015, publication of DCP3 and the Lancet Commission on Global Surgery (LCOGS) “Global Surgery 2030” report significantly expanded the body of data characterizing the global surgical and anesthesia crises, and also outlined strategies for addressing some of these challenges (Boxes 2.1and 2.2).5,26 During the LCOGS development, Jim Kim, President of the World Bank, echoed the words of Dr. Mahler from 35 years earlier by stating, “…surgery is an indivisible, indispensable part of health care and of progress towards universal health coverage.”27 These events provided a much needed boost to efforts aimed at improving the accessibility, affordability, and safety of surgical, obstetric, and anesthesia care worldwide. They also helped provide a framework for including surgery and anesthesia as global health priorities by linking surgery and anesthesia care to universal health coverage. Surgery and anesthesia were not included in previous priority-setting efforts, in part, because it was not clear how to incorporate them. Limited data about the scale of the crises, as well as misperceptions around complexity and cost-effectiveness (as discussed in the next section) resulted in surgery and anesthesia care being peripheral to global health prioritysetting efforts like the Millennium Development Goals (MDGs). Although surgery and anesthesia are not explicitly a focus of more recent global health priority initiatives

13

BOX 2.2  Key Messages From The Lancet Commission on Global Surgery □

□

□

□

 billion people do not have access to safe, affordable surgical 5 and anesthesia care when needed. Access is worst in lowincome and lower-middle-income countries (LMICs), where 9 of 10 people cannot access basic surgical care. 143 Million additional surgical procedures are needed in LMICs each year to save lives and prevent disability. Of the 313 million procedures undertaken worldwide each year, only 6% occur in the poorest countries, where over a third of the world’s population lives. Low operative volumes are associated with high case-fatality rates from common, treatable surgical conditions. Unmet need is greatest in eastern, western, and central sub-Saharan Africa, and South Asia. 33 Million individuals face catastrophic health expenditure due to payment for surgery and anesthesia care each year. An additional 48 million cases of catastrophic expenditure are attributable to the nonmedical costs of accessing surgical care. A quarter of people who have a surgical procedure will incur financial catastrophe as a result of seeking care. The burden of catastrophic expenditure for surgery is highest in low-income and lower-middle-income countries and, within any country, lands most heavily on poor people. Investing in surgical services in LMICs is affordable, saves lives, and promotes economic growth. To meet present and projected population demands, urgent investment in human and physical resources for surgical and anesthesia care is needed. If LMICs were to scale-up surgical services at rates achieved by the present best-performing LMICs, two thirds of countries would be able to reach a minimum operative volume of 5000 surgical procedures per 100,000 population by 2030. Without urgent and accelerated investment in surgical scale-up, LMICs will continue to have losses in economic productivity, estimated cumulatively at US$12.3 trillion (2010 US$, purchasing power parity) between 2015 and 2030. Surgery is an “indivisible, indispensable part of health care.”1 Surgical and anesthesia care should be an integral component of a national health system in countries at all levels of development. Surgical services are a prerequisite for the full attainment of local and global health goals in areas as diverse as cancer, injury, cardiovascular disease, infection, and reproductive, maternal, neonatal, and child health. Universal health coverage and the health aspirations set out in the post-2015 Sustainable Development Goals will be impossible to achieve without ensuring that surgical and anesthesia care is available, accessible, safe, timely, and affordable.

Mock CN, Donkor P, Gawande A, et al: Essential surgery: key messages from Disease Control Priorities, 3rd edition. The Lancet 385, Issue 9983, 2015: 2209–2219.

like the Global Health 2035 report and the United Nations (UN) Sustainable Development Goals (SDGs), these reports emphasize noncommunicable diseases, injuries, healthcare workforce expansion, and universal health coverage, which incontrovertibly depend on surgery and anesthesia.28,29 Milestones like LCOGS, the WHA resolution 68.15, and the Lancet Commission on Palliative Care and Pain Relief have helped call attention to the global anesthesia, analgesia, and surgery crises at hand.30 Entities like the World Federation of Societies of Anaesthesiologists (WFSA), Association of Anesthetists of Great Britain and Ireland (AAGBI), Canadian Anesthesiologists’ Society International Education Foundation (CASIEF), and Lifebox are among the increasing

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SECTION I  •  Introduction

number of anesthesia organizations working on systemlevel changes, research, and large-scale education initiatives in LMICs. Many national anesthesia societies, such as the United Kingdom’s Royal College of Anaesthetists (RCoA), the Royal College of Anesthesiologists of Thailand, and the Chilean Society of Anesthesiologists are also actively engaged in such activities. The number of these global anesthesia efforts is unprecedented, but still nascent and evolving. If surgery is described as the neglected step-child of global health, then anesthesia is the forgotten relative. Despite significant interdependence, surgery, anesthesia, and obstetrics have yet to harmonize global health efforts and maximize impact. Global health efforts involving either surgery or anesthesia have become known collectively as “global surgery” (see Table 2.2). In 2014, “global surgery” was defined “…as an area for study, research, practice, and advocacy that places priority on improving health outcomes and achieving health equity for all people worldwide who are affected by surgical conditions or have a need for surgical care. Global surgery incorporates all surgical specialties, including obstetric and gynecologic surgery; anesthesia; perioperative care; aspects of emergency medicine; rehabilitation; palliative care; and nursing and the allied health professions involved in the care of the surgical patient. It encompasses surgical care for underserved populations in all countries and for populations affected by conflict, displacement, and disaster, and promotes access to safe, quality care. Global surgery emphasizes supraterritorial and transnational issues, determinants, and solutions, recognizing that the determinants of inadequate or inequitable surgical care are often the result of common and interdependent global structures and processes, even though they are predominantly experienced within individual countries and communities.31” This definition was abbreviated to state “global surgery is an area of study, research, practice, and advocacy that seeks to improve health outcomes and achieve health equity for all people who require surgical care, with a special emphasis on underserved populations and populations in crisis. It uses collaborative, cross-sectoral, and transnational approaches and is a synthesis of populationbased strategies with individual surgical care.” Although anesthesia is not directly mentioned in this definition, “global surgery” has become a rallying point for anesthesia global health efforts.

SCOPE AND SCALE OF THE GLOBAL ANESTHESIA, SURGERY, AND PAIN CRISES Global Burden of Surgical Disease Nearly 30% of global morbidity and mortality is surgically treatable, with tens of millions of lives lost each year due to surgical conditions.5 This burden of surgical disease predominantly affects LMICs and kills 4 times more people than human immunodeficiency virus (HIV), TB, and malaria combined (Fig. 2.1).32 In addition to negative impacts on health and well-being, there is also significant economic burden associated with surgical morbidity and mortality. By 2030, morbidity and mortality from surgical conditions could reduce annual gross domestic product (GDP) growth by an estimated 2% in LMICs. In the

past, similar calculations were used to successfully generate global investment in malaria, but had estimated much lower (1.3%) decreases in GDP due to malaria.33 Without significant and immediate intervention, surgical disease will produce economic productivity losses of more than US$12 trillion for LMICs between 2015 and 2030. While it is generally agreed that surgical conditions account for a large proportion of global morbidity and mortality, precise data to support this have been lacking. This challenge has been attributed in part to a lack of resources being invested in such research and also to several inherent difficulties in quantifying surgical diseases. The term “global burden of disease” (GBD) uses the disability-adjusted-life-year (DALY) as a unit to quantify premature death (years of life lost) and disability (years of life lived in a state of less than full health) (Fig. 2.2). The DALY was originally developed for the seminal GBD 1990 Study to quantify the burden of different diseases around the world and has since become commonly used in public health and health economics.34,35 Because the DALY is routinely used to inform resource allocation, it has been utilized to describe surgical and pain disease burdens as well. The global health community has moved away from using terms such as third world, developed, or developing when describing countries’ level of economic development. Leading causes of DALYs are often reported geographically by World Bank income level (see Table 2.1) or more recently by socio-demographic index (SDI) (Figs. 2.3 and 2.4). The SDI is a composite average of three indicators predictive of health outcomes: income per capita, average educational attainment (for population >15 years old), and total fertility rate. The 2006 DCP2 publication was one of the first attempts to quantify surgical disease burden and did so by asking 18 surgeons for an educated guess, using convenience sampling and an online survey. Although the reported number

20 18 Deaths per year (millions)

14

16 14 12 10 8 6 4 2 Surgical conditions

HIV/AIDS, TB, and malaria

Fig. 2.1  Surgical conditions account for more annual deaths (16.9 million) than HIV/AIDS (1.03 million), TB (1.21 million), and malaria (0.72 million) combined.  AIDS, Acquired immunodeficiency syndrome; HIV, human immune virus, TB, tuberculosis. (Data from Shrime MG, Bickler WS, Alkire BC, et al. Global burden of surgical disease: an estimation from the provider perspective. Lancet Glob Health. 2015;3:S8–S9; and GBD collaborators 2016. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390[10100]:1151–1210.)

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2 • Anesthesia and Analgesia in the Global Context

DALY Disability Adjusted Life Year is a measure of overall disease burden, expressed as the cumulative number of years lost due to ill-health, disability, or early death

Healthy life

=

YLD Years Lived With Disability

Disease or disability

+

15

YLL Years of Life Lost

Early death

Expected Life years

Fig. 2.2  The disability-adjusted life year (DALY). (From Wikipedia. https://en.wikipedia.org/wiki/Disabilityadjusted_life_year#/media/File:DALY_disability _affected_life_year_infographic.svg. Creative commons license: CC BY-SA 3.0.)

(11%) was eye-opening and widely quoted, it was likely a significant underestimation. In 2015, the DCP3 provided another attempt to assess the public health impact of surgical care by estimating morbidity and mortality averted by scaling up basic surgical and anesthesia services in LMICs (i.e., surgical care for appendicitis, paralytic ileus, intestinal obstruction, hernias, gallbladder and bile duct disease, maternal hemorrhage, obstructed labor, abortion and neonatal encephalopathy, trauma resuscitation, surgical airway, peripheral venous access, suturing, laceration and wound management, chest tube or needle decompression, fracture reduction, escharotomy, fasciotomy, skin grafting, and trauma-related laparotomy and amputation). They concluded that an estimated 1.4 million deaths and 77.2 million DALYs could be prevented each year by scaling up basic surgical and anesthesia services in LMICs.26

The LCOGS produced another attempt to estimate global morbidity and mortality from surgical disease by asking 173 surgeons, anesthesiologists, internists, nurses, and public health practitioners from around the world, “What proportion of patients with the following conditions would, in an ideal world, require a surgeon for management?” The result of this survey was 28% to 32% of overall GBD requires a surgeon for management. Based on these results, LCOGS estimated that 30% of GBD is surgically treatable with an estimated 17 million lives lost per year due to surgical conditions.5 These reports are consistent with the 1990 GBD Study data, which demonstrate that the morbidity and mortality associated with surgical diseases is significantly larger than that of HIV, TB, and malaria combined.32 Unintentional injuries are the single largest contributor of DALYs worldwide. The majority of deaths that can be prevented with surgical care are due to injuries (77%), maternal-neonatal

Low SDI Low–Middle SDI Middle SDI High–Middle SDI High SDI

Fig. 2.3  Socio-demographic Index (SDI) is calculated for each geography as a function of lag-dependent income per capita, average educational attainment in the population older than age 15 years, and the total fertility rate. SDI units are interpretable; a zero represents the lowest level of income per capita and educational attainment and highest total fertility rate observed during 1980–2015, whereas a one represents the highest income per capita and educational attainment and lowest total fertility rate observed in the same period. Cutoffs on the SDI scale for the quintiles have been selected on the basis of examination of the entire distribution of geographies 1980–2015. GBD, Global Burden of Disease. (From GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388[10053]:1459–1544. Copyright © 2017 The Author[s]. Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

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SECTION I  •  Introduction

1990 rank

Global Both sexes, all ages, DALYs Per 100,000

2016 rank Communicable, maternal, neonatal, and nutritional diseases

1 Diarrhea/LRI/other

1 Cardiovascular diseases

2 Cardiovascular diseases

2 Diarrhea/LRI/other

3 Neonatal disorders

3 Neoplasms

Noncommunicable diseases

4 Other noncommunicable

4 Other noncommunicable

Injuries

5 Neoplasms

5 Neonatal disorders

6 Unintentional Inj

6 Mental disorders

7 Mental disorders

7 Musculoskeletal disorders

8 NTDs and malaria

8 Diabetes/urog/blood/endo

10 Musculoskeletal disorders

9 Unintentional inj

12 Diabetes/urog/blood/endo

14 NTDs and malaria

1990 rank

Low SDI Both sexes, all ages, DALYs Per 100,000

2016 rank

1 Diarrhea/LRI/other

1 Diarrhea/LRI/other

2 Neonatal disorders

2 Neonatal disorders

3 NTDs and malaria

3 NTDs and malaria

Communicable, maternal, neonatal, and nutritional diseases Noncommunicable diseases

4 Nutritional deficiencies

4 HIV/AIDS & tuberculosis

Injuries

5 HJV/AlDS & tuberculosis

5 Cardiovascular diseases

6 Other noncommunicable

6 Other noncommunicable

7 Cardiovascular diseases

7 Nutritional defldencles

8 Unintentional Inj

8 Unintentional Inj

9 Other group I

9 Mental disorders

12 Mental disorders

12 Other group I

Fig. 2.4  Leading causes of death and disability-adjusted-life-years (DALYs), 1990–2016, global versus low Socio-Demographic Index (SDI). AIDS, Acquired immunodeficiency syndrome; HIV, human immune virus. (From https://vizhub.healthdata.org/gbd-compare/. Reproduced under Creative Commons NonCommercial-No Derivatives 4.0 International License.)

conditions (14%), and digestive diseases (9%).26 Global industrialization and an “epidemiological transition” (i.e., people living longer) in many LMICs have resulted in rising noncommunicable disease and injury burdens (most notably from road traffic crashes) that will likely contribute to increased global surgical disease burden in the coming years. Each of the methods previously described to estimate surgical disease burden is imperfect. Challenges and limitations include complex methodologies (e.g., Institute for Health Metrics and Evaluation [IHME], GBD Studies), difficulty with measuring and defining surgical diseases (e.g., the same neoplasm in one person may be treated with surgery but in another person may be treated with chemotherapy), and challenges in assigning DALYs to diseases (i.e., disability weighting) and assigning DALYs averted to surgical procedures.26 To overcome these shortcomings, additional metrics for global surgery and anesthesia have been proposed and include measuring disease prevalence, treatment backlogs for non fatal conditions, morbidity and mortality as a result of delays in care, social benefit, economic benefit, and value of a statistical life (rather than costs per DALY averted).36 One significant role for the academic anesthesia community in the global context is working to increase efforts that

better quantify the growing surgical disease and pain burdens in order to facilitate appropriate resource allocation and subsequent evaluation of interventions. 

Global Burden of Pain As with surgical disease burden, there is general consensus on the staggering prevalence and incidence of pain worldwide though there are relatively limited data and significant challenges to quantifying pain burden in the global context. Pain is one of the most common reasons for seeking medical attention, is among the top five causes of DALYs worldwide, and directly accounts for four (low back pain, neck pain, musculoskeletal pain, migraine) of the top 10 causes of years lived with disability (YLDs).32,37 These statistics do not even account for pain secondary to oncology, injury, or postoperative etiologies, which likely increase these numbers substantially. It is estimated that 10% to 25% of the world’s population suffer from recurring and chronic pain, with increasing numbers caused by intentional physical harm such as war, violence, and torture.38 Uncontrolled pain has many potential negative impacts on health, wellbeing, and economic productivity, including increased risk of myocardial infarction and chronic pain. The 2017 Lancet Commission on Palliative Care and Pain Relief defined serious health-related suffering (SHS)

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2 • Anesthesia and Analgesia in the Global Context

as suffering associated with illness or injury that compromises physical, social, or emotional functioning, and cannot be relieved without medical intervention.30 Approximately half of all deaths worldwide involve SHS and more than 80% of people who die with SHS are from LMICs. It is estimated that 2.5 million children die with SHS each year. Ninety-eight percent of these children live in LMICs, and more than 90% of these deaths are avoidable. Among the top 10 conditions associated with SHS are HIV, malignancy, and injury. Though not as obvious as injury or cancer, HIV/AIDS is a major source of pain and analgesia need.39 Pain related to HIV is not routinely managed by anesthesiologists when compared to other more common pain etiologies, however, the relevance of HIV as a rallying point to advocate for greater access to analgesics in LMICs is discussed further in this chapter. In many countries, conditions such as diabetes, sickle cell, and leprosy are also responsible for significant pain burdens. With increasing longevity and industrialization, the disease burden for malignancy and injury are expected to increase significantly in LMICs. As providers with often the most experience administering analgesics, anesthesia providers play an expanded and critical role in pain management, especially in resource-constrained settings. 

Disparities in Access, Affordability, and Safety The exact level of disease burden attributable to surgical disease or pain is a focus of ongoing debate and research, yet it is generally accepted that the surgical, anesthesia, and pain crises are massive, largely avoidable, and disproportionately affect LMICs. Of the roughly 300,000 maternal deaths worldwide, 99% occur in low-resource settings (66% in subSaharan Africa) and the majority are preventable with relatively basic surgical, anesthesia, and perioperative care.40 Approximately 70% of global cancer deaths occur in LMICs, with the majority requiring surgical, anesthesia, or analgesia services.41 Scaling access to basic surgical and anesthesia services in LMICs could avert 77 million DALYs and 1.5 million deaths per year.26 Injury represents the majority (77%) of this avoidable morbidity and mortality, followed by maternal and neonatal conditions (14%). Approximately 90% of deaths and DALYs that are lost due to road traffic accidents occur in LMICs. Based solely on the inequitable distribution of operating theatres, more than two billion people have no access to surgical services.42 When also accounting for timeliness, facility capacity, safety, and affordability, nearly 5 billion people—the majority of the world’s population—lack access to surgical and anesthesia care. The Global Initiative for Children’s Surgery (GICS) estimates that 1.7 billion children lack access to surgical care.42a It is estimated that approximately 143 million additional surgeries are required each year.5 Of the 234 million major surgical procedures performed annually, only 3% to 6% of them are estimated to occur in LIMCs.5,43 Disparities in access disproportionally affect lower-income areas like sub-Saharan Africa or South Asia, where more than 95% of the population do not have access to surgical and anesthesia care. In some higher-income areas like North America and Europe, access varies considerably, but generally more than 95% of the population has access (Fig. 2.5).44 Even in HIC like

17

the United States, access to anesthesia, surgical, and analgesia care can be limited for rural and underserved populations.45,46 It is estimated that universal access to “essential” surgical procedures (which include treatments for injury, obstetric complications, abdominal emergencies, cataracts, and congenital anomalies) would prevent approximately 1.5 million deaths per year or 6% to 7% of all preventable deaths in LMICs.26 Inadequate access to analgesia is among the most neglected and inequitable global public health challenges. The global burden of pain disproportionately affects the world’s poor due to the high-burden conditions associated with pain (e.g., HIV, malignancy, and injury) in LMICs, and the general lack of access to analgesics. Although pain is the most common reason for seeking medical attention, and analgesia is considered a basic human right, gaps in access to analgesia are significant and among the most striking global health disparities worldwide.47–49 Injury and malignancy, two conditions with significant analgesia needs, represent a significant proportion of surgical disease burden in LMICs, yet the vast majority of LMIC populations have limited or nonexistent access to opiate analgesia. Six HICs account for 80% of the world’s opiate consumption, and countries that contain 17% of the world’s population (Canada, United States, Western Europe, Australia, and New Zealand) are responsible for 92% of the world’s opiate consumption (Figs. 2.6 and 2.7).30,50-52 Pain and palliative care remain relatively neglected by the global health community and disproportionately affect vulnerable populations in LMICs.30,53 In recent decades, access to opiates has improved in some LMICs, but not all (e.g., consumption in Africa and South Asia has declined).52 Inequitable access to analgesia is not unique to LMICs and has been repeatedly described in many HICs, including the United States.54-56 Reasons for the inequitable distribution of analgesia are discussed further in the next section of this chapter. For the proportion of the world’s population that has access to surgical and anesthesia care, they must confront significant disparities in safety. In the last half-century perioperative patient safety has improved by more than 10-fold, though the majority of the gains have been seen in HICs.57 In the United States during the 21st century, anesthesia-related mortality decreased from 1:1560 around 1950 to less than 1:13,000, and is significantly better than this in healthy patients.58,59 Worldwide, approximately 32 million people per year receive anesthesia without adequate monitoring, and more than 77,000 operating rooms (19%) worldwide lack pulse oximetry. In some regions, more than 70% of operating rooms lack pulse oximetry.42 Data on surgical outcomes in LMICs remain limited but have expanded significantly in the early part of the 21st century. Reports of perioperative mortality rates (POMRs) from low-income countries (LICs) have varied widely in both methodology and results, ranging from 0.2% to 6% overall, with significantly higher mortality for emergent procedures (10% overall, 20% for typhoid intestinal perforations).60–64 One international, prospective, observational cohort study of adults undergoing inpatient surgery in 247 hospitals from 25 African countries reported a 30-day in-hospital mortality rate (2.1%) that was twice the reported global average, despite a significantly younger and lower American Society of Anesthesiologists (ASA) physical classification patient population.65

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SECTION I  •  Introduction

Proportion of population without access to surgery 0% 100%

Fig. 2.5  The proportion of population without access to surgery. (From Alkire BC, Raykar NP, Shrime MG, et al. Global access to surgical care: a modelling study. Lancet Glob Health. 2015;3:e316–e323. doi: 10.1016/S2214-109X(15)70115-4. Epub 2015 Apr 27. Copyright © 2015 Alkire et al. Open Access article distributed under the terms of CC.)

Consumption in S-DDD per million inhabitants per day 10000

Fig. 2.6  Mean availability of opioids for pain management in 2011–2013.  S-DDD, Defined daily doses for statistical purposes. (From Berterame S, Erthal J, Thomas J, et al. Use of and barriers to access to opioid analgesics: a worldwide, regional, and national study. Lancet. 2016;387:1644–1656. https://doi.o rg/10.1016/S0140-6736[16]00161-6. Copyright © 2015 Berterame et al. Open Access article distributed under the terms of CC.) Downloaded for alex arman davidson ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on October 21, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.

2 • Anesthesia and Analgesia in the Global Context

19

Western Europe 18316 mg (870%) Afghanistan Russia 2·4 mg (0·2%) 124mg(8%) Canada 68194 mg (3090%)

China 314mg(16%) Vietnam 125 mg (9%)

USA 55704 mg (3150%)

India 43 mg Uganda (4%) 53 mg (11%) Haiti 5.3mg(0.8%)

Mexico 562mg(36%) Bolivia 74mg(6%)

Nigeria 0.8 mg (0.2%)

Australia 40636 mg (1890%)

Fig. 2.7  Distributed opioid morphine-equivalent (morphine in mg/patient in need of palliative care, average 2010–2013), and estimated percentage of need that is met for the health conditions most associated with serious health-related suffering. (From Knaul FM, Bhadelia A, Rodriguez NM, et al. The Lancet Commission on Palliative Care and Pain Relief—findings, recommendations, and future directions. Lancet Glob Health. 2018;6:S5–S6. Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY 4.0 license.)

In several African countries, anesthesia-related mortality has been reported to be in the 1:100s (Malawi 1:504; Zimbabwe 1:482; Nigeria 1:387 for C-sections; Togo 1:133 to 1:250).66–69 In one report of 24-hour surgical outcomes in Togo, 30 deaths occurred (total cases 1464), 22 were deemed avoidable, and 11 were due to avoidable anesthesia complications.15 Another report from Togo reported a mortality rate of 1:250 and found less than half of the 26 facilities surveyed had pulse oximetry, and none had capnography.70 In a national report on maternal mortality in South Africa, nearly 2.35% of recorded maternal mortalities were anesthesia related, and the majority (93%) were deemed avoidable. One of the most common causes of anesthesia death in this report was the provision of spinal anesthesia without skills necessary to manage an airway or convert to general anesthesia.71 Other commonly cited causes of avoidable anesthesia mortality in resourceconstrained settings include inadequate staffing, monitoring, and drug overdose. A recent meta-analysis of anesthesiarelated maternal mortality in LMICs found the risk of death from anesthesia for women undergoing obstetric procedures to be 1.2 per 1000 (vs. 3.8 per million in the United States), with higher risk reported if general anesthesia was used or if anesthesia was provided by a nonphysician72. In this analysis, anesthesia was the cause in 2.8% of maternal deaths in LMICs and 13.8% of all deaths during or after C-section in LMICs. To

state this differently, anesthesia-related maternal mortality is 300-fold higher for neuraxial and 900-fold higher for general anesthesia than is reported in the United States. It is important to note that the relationship between hospital-based perioperative morbidity and mortality and surgical disease morbidity and mortality must be interpreted with caution in settings where patients lack access to hospitals. In other words, in an HIC a patient’s chances of dying from a ruptured viscous are roughly the same as the chances of dying from surgery for a ruptured viscous because more than 95% of the population has access to care. However, in an LIC, while the perioperative mortality for a ruptured viscous may be 10%, the majority of patients with this condition never make it to surgery and have mortality rates that are dramatically higher. Affordability is another significant barrier to accessing surgical and anesthesia services. Each year, approximately 33 million people face catastrophic out-of-pocket expenditure due to payment for surgery and anesthesia (Fig. 2.8) with an additional 48 million people facing catastrophic expenditure related to non medical costs of accessing surgical care (e.g., transportation, lodging, and food).5,73 Nearly half (3.7 billion) of the world’s population is at risk of catastrophic expenditure if they were to have surgical and anesthesia care. The majority of those at risk live in

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SECTION I  •  Introduction

20% 40% 60% 80% Fig. 2.8  Risk of catastrophic expenditure for surgical care in 2014 (% of people at risk). (Data from http://databank.worldbank.org/data/home.aspx. Originally printed: http://blogs.worldbank.org/opendata/africacan/pt/comment/reply/2341. Copyright © 2018 The World Bank. Reproduced under CC BY 4.0 license.)

sub-Saharan Africa, and South and Southeast Asia. The issue of affordability applies not only to surgery itself but also to components of perioperative care including analgesia and transfusions.74 For example, in South America, a monthly prescription of opiate for chronic pain may cost 200% of annual income.57 In India (where nominal gross national income per capita is $1670), a unit of blood often costs up to $247 despite a legal limit of $25.75,76 Global health and development leaders including the WHO and World Bank prioritize financial risk protection as a key component of achieving universal health coverage goals for all countries. Despite relatively high out-of-pocket costs at the individual level for some procedures, surgery is a highly cost-effective public health intervention as discussed further in the following sections. 

GLOBAL ANESTHESIA, SURGERY, AND PAIN CRISES: ORIGINS AND AREAS FOR INTERVENTION Workforce shortages, inadequate infrastructure, lack of policy and prioritization, and increasing burden of surgical disease are among many factors contributing to current limitations in access, affordability, and safety of anesthesia and surgical services worldwide.77 As previously discussed, global industrialization and an “epidemiological transition” in many LMICs have resulted in rising noncommunicable disease and injury burdens with lagging investment to address these issues. While these fundamental imbalances between healthcare needs and healthcare resources underlie much of the current global surgery, anesthesia, and pain crises, several additional factors have also contributed.

Misperceptions and Limited Data Two common misperceptions about surgery and anesthesia have contributed to the delayed recognition of these fields as global public health priorities: (1) the scope and

scale of surgical disease and pain burdens were vastly underestimated; and (2) surgical and anesthesia care were erroneously assumed to be too expensive and technology dependent to be done safely or cost-effectively in resource-constrained environments. In this section we discuss reasons why the surgical disease and pain burdens are historically poorly characterized. Misperceptions about cost-effectiveness and feasibility of safe surgery and anesthesia care also have roots in a historical data void, especially from LMICs. Several innovative service delivery models in the public and private sectors of LMICs (e.g., Indus hospital, Aravind Eye Hospitals, and Narayana Hrudayalaya Heart Hospital) have demonstrated that it is feasible to provide cost-effective, safe, and affordable surgical and anesthesia care in resource-constrained countries.78–81 Recent data have consistently demonstrated that surgical services are among the most cost-effective public health interventions (Fig. 2.9). There are several methods to define costeffectiveness thresholds, each with pros and cons.82 One of the most commonly cited methods uses GDP-based thresholds. This approach was suggested by the WHO Commission on Macroeconomics and Health and has been defined by authors from the WHO’s Choosing Interventions that are Cost–Effective project (WHO-CHOICE) as, “interventions that avert one DALY for less than average per capita income for a given country or region are considered very cost–effective; interventions that cost less than three times average per capita income per DALY averted are still considered cost–effective; and those that exceed this level are considered not cost–effective.”83 In 2003 in Bangladesh, one of the earliest cost-effectiveness studies on surgical care reported the cost of emergency obstetric care at less than $11 per DALY averted.16 This was 3 times more cost-effective than the measles vaccine (in 2003 dollars). The DCP2 and DCP3 demonstrated costeffectiveness of the first-level surgical hospital, with essential surgical services all being highly cost effective and many

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2 • Anesthesia and Analgesia in the Global Context

21

381.15

Orthopedic surgery 315.12

Cesarean deliveries

136

Ophthalmic surgery 108.74

Hydrocephalus repair

82.32 General surgery 47.74

Cleft lip or palate repair Adult male circumcision

13.78

500.41

706.54

Aspirin and ß-blocker for ischaemic heart disease 453.74

Antiretroviral therapy for HIV

51.86

648.20

220.39

BCG vaccine for tuberculosis prevention Vaccines for tuberculosis, diptheria, pertussis, tetanus, polio, and measles

12.96 25.93 6.48 22.04

Bednets for malaria prevention

0

100

200

300

400

500

600

700

800

$ per DALY averted (2012 US$)

Fig. 2.9  Cost-effectiveness of surgery in low-income and middle-income countries compared with other public health interventions. Data points are medians, error bars show range. Surgical interventions are denoted by the diamonds and solid lines, public health interventions by the circles and dashed lines. BCG, Bacillus Calmette–Guérin; DALY, disability-adjusted life-year; HIV, human immune virus. (Source: Chao TE, Sharma K, Mandigo M, et al. Cost-effectiveness of surgery and its policy implications for global health: a systematic review and analysis. Lancet Glob Health. 2014;2:e334–e345. Copyright © 2015 Elsevier Ltd. Creative Commons Attribution License [CC BY].)

costing $10 to $100 per DALY averted. This is comparable to the cost-effectiveness of other public health interventions such as immunizations ($13-$26 per DALY) or bed nets for malaria prevention ($6-$22 per DALY), and much more cost-effective than other high-priority public health interventions such as HIV treatment ($500 per DALY).84 A recent analysis of the cost-effectiveness of a pediatric operating room in Uganda found a cost of $6.39 per DALY averted and $397.95 per life saved, with a net economic benefit of over US$5 million per year (cost of $41,000 per year).85 In a 2012 forum hosted by the Copenhagen Consensus, five leading health economists, including four Nobel laureates, were asked how best to spend US$75 billion over 4 years to “advance global welfare,” especially in LMICs. The leading priority identified by the group was the expansion of surgical care capacity (US$3 billion per year).86 In the past 5 years the global surgery and anesthesia communities have expanded the volume of data that dispel prior misconceptions and support prioritization of surgical and anesthesia care in the global health agenda. During this timeframe, there has also been an explosion of articles that expand available data on a wide range of global anesthesia and surgical topics. The majority of these articles have been published in the surgical journals though recently anesthesia publications have begun to actively support global anesthesia research. The global anesthesia community must increase research productivity in global health and also invest in advocacy, policy, and implementation sciences in order to ensure impact. 

Advocacy and Policy There are many reasons why surgery, anesthesia, and pain have historically not been prioritized by national health systems, donors, or the broader global health community. Although surgical disease accounts for 30% of global disease burden, less than 1% of development assistance for health supports delivery of anesthesia and surgical care.87 Imbalance between resource allocation and disease burden is found in many health conditions, though the degree of this disparity for surgical disease and pain is particularly striking.

As discussed previously, lack of disease burden data and misperceptions about safety and cost-effectiveness have significantly hindered advocacy efforts for global anesthesia and surgery. In a qualitative analysis of factors that have hindered political prioritization for global surgery, several additional factors were identified including: fragmentation of the global surgery community, lack of leadership and consensus, and inadequate political strategy (e.g., not capitalizing on opportunities such as the MDGs).88 In another analysis to determine why certain disease-specific global health networks are relatively more or less effective than others, four common challenges were highlighted, each with relevance to global anesthesia and surgery: (1) defining the problem and how it should be addressed; (2) positioning the issue in a way to inspire action by external audiences; (3) building coalitions that include stakeholders outside the healthcare sector (coalitions are too often dominated by HIC providers); and (4) creating governance institutions that facilitate collective action (Fig. 2.10).89 Another study that examined factors influencing prioritization of surgery in national health systems concluded that sustained advocacy, effective framing of problems and solutions, robust country-level data, and support from regional and international partners were critical for success but often lacking.90 Advocacy efforts for surgery, anesthesia, and pain face a few additional and relatively unique challenges. Unlike infectious diseases such as HIV or Ebola, surgical disease and pain are not pandemic and do not incite similar action by the HIC donor community. Furthermore, most surgical conditions and pain are difficult to advertise and are not disease specific. While select pediatric conditions (e.g., cleft lips) are easily marketable, other conditions like trauma, hernias, and cesarean section are more difficult to compassionately portray in media in attempts to improve public awareness. The WHA resolution 68.15 emphasized advocacy and resource development in five key focus areas for global surgery (workforce, essential medicines, information management,

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22

SECTION I  •  Introduction

Problem definition

Positioning

Generating internal consensus on the nature of the problem and solutions

Portraying the issue in ways that inspire external audiences to act

Governance Establishing institutions to facilitate collective action

Coalition-building Forging alliances with external actors, particularly ones outside the health sector Fig. 2.10  Four challenges that global health networks face. (From Shiffman J. Four challenges that global health networks face. Int J Health Policy Manag. 2017;6[4]:183–189. Copyright © 2018 The Author[s]. Published by Kerman University of Medical Sciences. This is an open access article under the CC BY 4.0 license.)

service delivery, and advocacy). The LCOGS provided clear framing of problems (see Box 2.2), outlined priorities for country-level data collection, and helped to provide frameworks for national surgical, obstetric, and anesthesia plans (NSOAPs) in LMICs. As more NSOAPs are produced, they have the potential to serve as key rallying points for national advocacy efforts. Anesthesia, surgery, and pain need global champions. Only recently has advocacy by leading global organization (e.g., the World Bank, WHO) and select local governments in LMICs focused attention on anesthesia and surgery in the global context. This is in part due to advocacy efforts by several relatively recent initiatives (e.g., LCOGS, The Global Alliance for Surgical, Obstetric, Trauma, and Anaesthesia Care [G4 Alliance], WFSA, GICS, and several more). These multidisciplinary efforts must be expanded and sustained in order to reach the critical mass needed to overcome prior misperceptions and affect change. It is essential that advocacy efforts for surgery, anesthesia, and pain be consistent with the key messages of LCOGS, the Global Health 2035 Report, WHA resolution 68.15, and the SDGs, and emphasize that anesthesia, surgery, and analgesia are indispensable components of “universal health coverage.” No longer can surgery be seen as a vertical (i.e., disease-specific) program. One key objective for advocacy efforts will be to identify new streams of funding from global donors, national budgets, private sectors, and innovative models. Similar to the large-scale funding initiatives to combat HIV/AIDS and other infectious diseases (e.g., the U.S. President’s Emergency Plan for AIDS relief, Gavi Vaccine Alliance, The Global Fund), surgery and pain require comparable attention and support. In addition to domestic and international financing mechanisms to support health system scale-up, public-private partnerships and innovative patient-level financial risk protection strategies must be integral components to advocacy efforts.5 As leaders in safety, pain, perioperative care, and more, the global anesthesia community must actively engage in policy, research, and innovative global initiatives to expand access to quality care. Academic institutions from all countries can play a significant role in supporting a coordinated research agenda, creating a global voice for advocacy,

sharing information, and harmonizing educational standards and opportunities. Anesthesia must follow the lead of other medical disciplines to not only cultivate but also support faculty and trainees with interests in global public health careers. Such advocacy will likely require coordination and partnership with multiple disciplines, including nonphysician provider cadres who perform a significant proportion of anesthesia services, especially in LICs.91 

Workforce Shortages and Strategies for Expansion The critical shortage of trained anesthesia providers in resource-constrained settings is one of the most significant barriers to expanding access to safe surgical, anesthesia, and pain services for billions of people worldwide. Although shortages of many key members of the surgical workforce exist (including surgeons, obstetricians, pathologists, radiologists, laboratory technicians, nurses, biomedical engineers, and more), anesthesia provider shortages in LMICs are particularly striking and relatively neglected. Countries like the Central African Republic have no physician anesthesiologists and only 24 nonphysician anesthesia providers (NPAPs) for a population of nearly 5 million. Ethiopia, with a population of over 100 million people, has only 35 physician specialist anesthesiologists. A survey of emergency obstetric care capacity at facilities in Uganda found that lack of staff had the greatest correlation with observed mortality rates.92 In a survey of 64 public and private hospitals in Uganda, 84% did not have a physician specialist anesthesiologist, and 8% had no trained anesthesia providers at all.93 In another survey of anesthesia providers from five main referral hospitals in East Africa (Uganda, Kenya, Tanzania, Rwanda, and Burundi), only 7% reported adequate anesthesia staffing.94 In settings where providers exist but in small numbers, the workforce shortage is compounded by heavy administrative burdens and non-clinical duties. While the anesthesia workforce shortage is most severe in LICs and particularly pronounced in sub-Saharan Africa, regional workforce shortages also exist in HICs and can significantly limit access to care for rural populations.95,96 In one survey of rural hospitals in the United States, 36% reported delay or cancellation of surgery due to a lack of anesthesia providers.97 Data from HICs demonstrate differences in trauma

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2 • Anesthesia and Analgesia in the Global Context

High income

90

Lower middle income

Upper middle income

23

Low income

Life expectancy at birth

85 80 75 70 65 60 55

Benchmark: 20 workers per 100,000 people

50

Specialist surgical workforce (per 100,000 population)

45 40 0

20

40

60

80

100

120

140

160

180

Fig. 2.11  Life expectancy tends to be higher in countries with a surgical workforce larger than 20 workers per 100,000 people. (Data source: http://da tabank.worldbank.org/data/home.aspx. Originally printed: http://blogs.worldbank.org/opendata/africacan/pt/comment/reply/2341. Copyright © 2018 The World Bank. Reproduced under CC BY 4.0 license.)

mortality are significantly worse starting at five miles from a trauma center in a major urban city.98 One can only imagine outcome differences in settings where there may be no surgical or anesthesia provider for tens or even hundreds of miles. The optimal number of specialist surgical, anesthetic, and obstetric workforce (SAO) providers needed to give access to safe surgery is unknown and likely to vary significantly based on local resources and needs. The SAO density correlates with life-expectancy and in one study, as SAO providers increased from 0 to 20 per 100,000 population, maternal mortality decreased by 13.1% for each 10 unit increase in provider density (Fig. 2.11). These benefits were also observed with workforce expansion beyond 20, though with less magnitude beyond 30 and 40 providers per 100,000 (Fig. 2.12).99 Based on these findings, the LCOGS recommended prioritizing expansion of the SAO workforce to 20 per 100,000 population by 2030, with anesthesia-specific targets of 5 to 10 anesthesia providers per 100,000.100 The density of SAO providers has been estimated at 0.7 per 100,000 population for LICs as compared with 56.9 per 100,000 population for HICs.101 Worldwide, 77 countries report an anesthesia provider density less than 5 per 100,000, with a 90-fold difference between the average physician workforce density in HICs as compared to LICs. The anesthesia workforce crisis is most severe in sub-Saharan Africa, where most countries have approximately 1.0 physician anesthesiologist per 100,000 population as compared to approximately 19 in Europe or 21 per 100,000 in the United States (Fig. 2.13).100 Twenty-six countries in sub-Saharan Africa reported less than 0.5 physician anesthesia providers (PAPs) per 100,000. In many LICs, NPAPs provide the majority of anesthesia care. When NPAPs are included in calculations of total anesthesia provider density, 16 countries in sub-Saharan Africa still report less than 1 anesthesia provider per 100,000, and worldwide 70 countries still report less than 5 anesthesia providers per 100,000 population. Estimates from the WHO Global

Surgical Workforce database demonstrate that 12% of the SAO workforce provides care for approximately a third of the world’s population.101 Worldwide, LICs and LMICs have 48% of the world’s population but only 20% of the SAO workforce. Multiple factors have contributed to the ongoing surgical and anesthesia workforce crises in LMICs, including limited training infrastructure, relatively low professional status, lack of career advancement (especially for NPAPs), perceived limited job opportunities relative to other professions (e.g., infectious disease in LMICs), cost of training, inefficient hiring mechanisms, provider burnout, as well as internal (e.g., private practice in urban settings) and external brain drain (e.g., leaving the country).102,103 Lack of consensus on anesthesia practice models and polarized views on who should provide anesthesia care (i.e., physician versus nonphysician, supervised versus independent) are additional factors limiting a clear path for rapidly scaling the global anesthesia workforce (Table 2.3).91 Task-sharing is a prominent and controversial component of many surgical workforce expansion efforts. Each of the aforementioned challenges must be addressed as part of any national or international effort to expand the anesthesia workforce. The long-term goal of building robust training infrastructures in low-resource settings requires locally led plans for national advocacy, implementation, and evaluation. Such efforts can benefit from international investment and collaboration.104-108 Significant heterogeneity in anesthesia care models exists worldwide. Although the varied anesthesia practice and training models have evolved to address different local needs and challenges, excess heterogeneity and lack of consensus on anesthesia workforce strategy may provide an additional challenge to global workforce expansion. For example, within sub-Saharan Africa, formal nonphysician training programs range from 3 to 72 months in duration with widely different entry requirements, no standardized curricula or assessment tools, and different scopes of practice. For countries seeking

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24

SECTION I  •  Introduction

100,200

Maternal survival (per 100,000 livebirths)

100,000

99,800

99,600

99,400

99,200

99,000

98,800 0 0

20

40

60

80

100

120

140

160

Workforce density (number of surgeons, anesthesiologists, and obstetricians per 100,000 population)

Fig. 2.12  Specialist surgical workforce density and maternal survival.  A surgical workforce density of less than 20 per 100,000 specialist surgeons, anesthesiologists, and obstetricians correlates with lower rates of maternal survival. Maternal survival per 100,000 livebirths = 98,292 × ln (workforce density) + 99,579. (From Meara JG, Leather AJ, Hagander L, et al. Global Surgery 2030: evidence and solutions for achieving health, welfare, and economic development. Lancet. 2015;386:569–624. Data from Holmer H, Shrime MG, Riesel JN, et al. Towards closing the gap of the global surgeon, anaesthesiologist and obstetrician workforce: thresholds and projections towards 2030. Lancet. 2015;385(suppl 2):S40. Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY 4.0 license.)

0– 45 yr). This relationship between CC and FRC explains decreasing oxygenation with age.

the PAW, the airway—if collapsible—will tend to close, and this usually commences at the bases because the basal PPL is greatest (see Fig. 13.7). Three applications of this important principle are of key relevance to anesthesia. First, airway closure depends on age: in youth, the closure does not occur until expiration is at or near RV, whereas with older age, it occurs earlier in expiration (i.e., at higher lung volumes). This occurs because PPL is on average more “positive” (i.e., atmospheric, equal to PAW) as age increases. Closing can occur at or above FRC in individuals aged 65 to 70 years,50 such that dependent regions will undergo closure during normal expiration. This may be the major reason why oxygenation decreases with age. Second, in the supine position, FRC is less than when upright, but CC is unchanged; therefore, exhalation of a usual VT (from FRC) encroaches on CC in a supine 45-year-old, and closure may be continuous in a supine 70-year-old (Fig. 13.9). Finally, COPD increases the lung volume at which closure occurs, possibly exacerbated by airway edema and increased bronchial tone.49 

DIFFUSION OF GAS Gas moves in the large and medium-sized airways by bulk flow (i.e., convection), meaning that the gas molecules travel together at a given mean velocity according to a driving pressure gradient. Flow is through multiple generations of bronchi, and the net resistance falls with each division. After the 14th generation, airways merge with alveoli and participate in gas exchange (respiratory bronchioles). The cross-sectional area expands massively (trachea, 2.5 cm2; 23rd generation bronchi, 0.8 m2; alveolar surface, 140 m2),51 resulting in a sharp drop in overall resistance. Because the number of gas molecules is constant, the velocity falls rapidly, which by the time the gas enters the alveoli is miniscule (0.001 mm/s); it is zero when it reaches the alveolar membrane. The velocity of the gas entering the alveolus is slower than the diffusion rates of O2 and CO2; therefore, diffusion—not convection—is necessary for transport in the distal airways and alveoli. Indeed,

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363

13 • Respiratory Physiology and Pathophysiology

CO2 is detectable at the mouth after just seconds of breathholding, because of rapid diffusion and because of cardiac oscillations (i.e., mixing). Gas mixing is complete in the alveoli of a normal lung during normal breathing. However, if the alveolus expands (e.g., emphysema), the diffusion distance may be too great to allow complete mixing, potentially leaving a layer of CO2rich gas lining the alveolar membrane and a core of O2-rich gas in the alveolus. This represents a “micro” version of inhomogeneous distribution of ventilation.52 

Perfusion The pulmonary circulation differs from the systemic circulation: it operates at a five to tenfold lower pressure, and the vessels are shorter and wider. There are two important consequences of the particularly low vascular resistance. First, the downstream blood flow in the pulmonary capillaries is pulsatile, in contrast to the more constant systemic capillary flow.53 Second, the capillary and alveolar walls are protected from exposure to high hydrostatic pressures; therefore, they can be sufficiently thin to optimize diffusion (i.e., exchange) of gas but not permit leakage of plasma or blood into the airspace. Whereas an abrupt increase in the pulmonary arterial (or venous) pressure can cause breaks in the capillaries,54 slower increases (i.e., months to years) stimulate vascular remodeling.55 This remodeling might protect against pulmonary edema56 (and possibly against lung injury57), but diffusion will be impaired.

DISTRIBUTION OF LUNG BLOOD FLOW Pulmonary blood flow depends on driving pressure and vascular resistance; these factors (and flow) are not homogenous throughout the lung. The traditional thinking about lung perfusion emphasized the importance of gravity;58 however, factors other than gravity are also important. 

DISTRIBUTION OF BLOOD FLOW IN THE LUNG: THE EFFECT OF GRAVITY Blood has weight and therefore blood pressure is affected by gravity. The height (base to apex) of an adult lung is approximately 25 cm; therefore, when a person is standing, the hydrostatic pressure at the base is 25 cm H2O (i.e., approximately 18 mm Hg) higher than at the apex. The mean pulmonary arterial pressure is approximately 12 mm Hg at the level of the heart, and the pulmonary artery pressure at the lung apex can therefore approach zero. Thus less blood flow will occur at the apex (versus the base), and in the setting of positive pressure ventilation, the apical alveoli can compress the surrounding capillaries and prevent any local blood flow. Based on such gravitational distribution of pulmonary artery pressure, as well as the effect of alveolar expansion, West and colleagues59 divided the lung into zones I to III (Fig. 13.10). This system is based on the principle that perfusion to an alveolus depends on the pressures in the pulmonary artery (PPA), pulmonary vein (PPV), and alveolus (PALV). In the apex (zone I), the key issue is that pulmonary arterial pressure is less than alveolar pressure; therefore,

Pulmonary vascular resistance (PVR) =

PPA - PLA •

QT (true only if lung is in zone III)

PALV  PPA  PPV

I

PPA  PALV  PPV

II

PPA  PPV  PALV

III

IV

PPA  PPV  PALV

Fig. 13.10  Vertical distribution of lung blood flow. The so-called zones I, II, III, and IV are indicated. In zone I there is no perfusion, only ventilation. In zone II, pulmonary artery pressure exceeds alveolar pressure which in turn exceeds venous pressure; the driving pressure is PPA−Palv. In zone III, arterial and venous pressures both exceed alveolar pressure, and here the driving pressure is PPA−PPV. In the lung base, blood flow is decreased possibly because of increased interstitial pressure that compresses extra alveolar vessels. PALV, intraalveolar pressure; PPV, pulmonary vein pressure; PPA, pulmonary artery pressure; QT, cardiac output.

no perfusion occurs. Zone I conditions can exist during mechanical ventilation and be exacerbated by low PPA. Whenever zone I conditions exist, the nonperfused alveoli constitute additional dead space (VD). Below the apex in zone II, PPV is less than alveolar pressure, and the veins are collapsed except during flow, as in a “vascular waterfall.” Although PALV is always greater than PPV, perfusion occurs when PPA exceeds PALV (i.e., intermittently, during systole). Below this zone is zone III, in which there are two important differences: PPA and PPV both always exceed PALV. As a result, there is perfusion throughout systole and diastole (and inspiration and expiration). Gravity results in equal increases in both PPA and PPV toward the lung base; therefore, gravity cannot affect flow throughout zone III by increasing the PPA to PPV pressure gradient alone. Nonetheless, it is possible that the greater weight of the blood nearer the base results in vessel dilatation, thereby lowering vascular resistance and increasing flow.58 It was subsequently recognized that there is also a decrease in perfusion in the lung base, or zone IV, that is thought to occur because of the effects of gravity compressing the lung at the bases—and the blood vessels therein—and thereby increasing vascular resistance.60 Finally, additional evidence for the effect of gravity comes from volunteer experiments in which gravity was increased or abolished by altering the flight pattern of a jet aircraft.61 In these experiments, zero gravity decreased cardiac oscillations of O2 and CO2 during a breath-hold, indicating development of more homogeneous perfusion. In contrast, more recent experiments of exhaled gas analysis (on the Mir space station) reported that the heterogeneity of lung perfusion was reduced, but not eliminated, in the presence of

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SECTION II  •  Anesthetic Physiology

Supine Prone

Relative flow per iso-gravitational plane

2.0

A

Supine Prone

2.0 Relative flow per iso-gravitational plane

364

1.6 1.2 0.8 0.4 6 cm

0.0 Dorsal

Ventral

B

1.6 1.2 0.8 0.4 0.0 Dorsal

Ventral

Fig. 13.11  Distribution of blood flow (ventral, dorsal) in supine versus prone position. The distributions from ventral to dorsal are similar, irrespective of position, suggesting that the anatomic features (and not simply gravity) determine the distribution of flow. The magnitude of the variability in either the prone (or in the supine) position (i.e., nongravitational inhomogeneity) is far greater than the differences in distribution between the prone and the supine positions (i.e., gravitational inhomogeneity). (From Glenny RW, Lamm WJ, Albert RK, Robertson HT. Gravity is a minor determinant of pulmonary blood flow distribution. J Appl Physiol. 1991;71:620–629.)

microgravity, indicating that gravity contributes to the heterogeneity of blood flow distribution but does not explain it entirely.62 While the precise role of gravity is disputed, it is likely to play a smaller role when supine versus when upright. 

DISTRIBUTION OF BLOOD FLOW IN THE LUNG: INFLUENCE OF FACTORS NOT RELATED TO GRAVITY Key experiments have reconsidered the effects of gravity. Blood flow measured in the same gravitational plane was less per unit of lung tissue at the apex than at the base.63 In addition, microsphere assessment demonstrated significant variability within iso-gravitational planes, and lung height appeared to account for less than 10% of the distribution of flow in either the prone or supine positions.64 In addition, inhomogeneity in the horizontal planes can exceed that in the vertical direction (Fig. 13.11).65 Other studies have reported a preponderance of perfusion to the central lung (versus peripheral) tissue,66 which can be reversed by the application of positive end-expiratory pressure (PEEP).67 Although greater length of radial blood vessels was considered to explain this central-peripheral difference, others have suggested that it is not significant.64 Finally, differences have been reported among lung regions in local vascular resistance.68 Fractal distribution of blood flow may be more important than the influence of gravity.69 A fractal pattern of perfusion means that in any given region, there will be “spatial correlation” (similarity) of the blood flow between neighboring regions. Although the methods to study lung perfusion are complex—and there is a spectrum of opinion70—the aggregate data suggest that factors other than gravity contribute to the heterogeneity of the distribution of perfusion. 

HYPOXIC PULMONARY VASOCONSTRICTION HPV is a compensatory mechanism that diverts blood flow away from hypoxic lung regions toward better oxygenated regions.71 The major stimulus for HPV is low alveolar

oxygen tension (PAO2), whether caused by hypoventilation or by breathing gas with a low PO2, and is more potent when affecting a smaller lung region. The stimulus of hypoxic mixed venous blood is weaker.72,73 Whereas in humans older volatile anesthetics were thought to inhibit HPV more than intravenously based anesthesia, modern volatile anesthetics, including sevoflurane74 and desflurane,75 have little effect. During intravenously based anesthesia, exposure of one lung to an FiO2 of 1.0 and the contralateral lung to a hypoxic gas mixture (FiO2, 0.12 to 0.05) reduced perfusion to the hypoxic lung to 30% of the cardiac output.76 Pulmonary hypertension, because of vascular remodeling owing to ongoing HPV, can develop in humans at high altitude77 or in the presence of chronic hypoxemic lung disease. 

Clinical Assessment of Lung Function SPIROMETRY—TOTAL LUNG CAPACITY AND SUBDIVISIONS The gas volume in the lung after a maximum inspiration is called the total lung capacity (TLC; usually 6 to 8 L). TLC can be increased in COPD either by overexpansion of alveoli or by destruction of the alveolar wall, resulting in loss of elastic tissue, as in emphysema (see Fig. 13.4).78 In extreme cases, TLC can be increased to 10 to 12 L. In restrictive lung disease, TLC is reduced, reflecting the degree of fibrosis, and can be as low as 3 to 4 L (see Fig. 13.4).78 Following maximum expiratory effort, some air is left in the lung and constitutes the RV (approximately 2 L). However, usually no region develops collapse because distal airways (0.4 but 100

3.0

Atracurium

16

40

2.5

Cisatracurium

>50

>50

None

d-Tubocurarine

0.6

2.0

0.6

STEROIDAL COMPOUNDS Vecuronium

20

>250

None

Rocuronium

3.0-5.0

>10

None

Pancuronium

3.0

>250

None

*In cats. human subjects. Definition: number of multiples of the dose causing on average 95% suppression of neuromuscular response (ED95) for neuromuscular blockade required to produce the autonomic side effect (ED50).

†In

bond to presumably inactive hydrolysis products (see Fig. 27.7).11,170 CW 1759-50 is degraded nonenzymatically by endogenous l-cysteine at physiological pH and temperature, which accounts for its ultrashort duration of action. In summary, the only short-acting nondepolarizing NMBD, mivacurium, is cleared rapidly and almost exclusively by metabolism by butyrylcholinesterase, thus resulting in much greater plasma clearance than that of any other nondepolarizing NMBD.9 NMBDs of intermediate duration, such as vecuronium, rocuronium, atracurium, and cisatracurium, have clearance rates in the range of 3 to 6 mL/kg/min because of multiple pathways of degradation, metabolism, and/or elimination. Atracurium is cleared two to three times more rapidly than the long-acting drugs.171-174 Similar clearance values have been obtained for rocuronium175-179 and cisatracurium.168,169,180 The long-acting NMBDs undergo minimal or no metabolism, and they are eliminated largely unchanged, mostly by renal excretion. Hepatic pathways are less important in their metabolism. 

ADVERSE EFFECTS OF NEUROMUSCULAR BLOCKING DRUGS NMBDs seem to play a prominent role in the incidence of adverse reactions that occur during anesthesia. The Committee on Safety of Medicines in the United Kingdom reported that 10.8% (218 of 2014) of adverse drug reactions and 7.3% of deaths (21 of 286) were attributable to the NMBDs.181

Autonomic Effects While NMBDs have little penetration through the bloodbrain barrier, they may interact with nicotinic and muscarinic cholinergic receptors within the peripheral nervous system, in particular the sympathetic and parasympathetic nervous systems and at the nicotinic receptors of the neuromuscular junction. Dose-response ratios comparing the neuromuscular blocking potencies of these drugs (the ED95) with their potencies in blocking vagal (parasympathetic) or sympathetic

ganglionic transmission (the ED50) can be constructed (Table 27.9). These ratios are termed the autonomic margin of safety of the relaxant in question. The higher the dose ratio, the lower is the likelihood of, or the greater the safety ratio for, the occurrence of the particular autonomic effect. The side effect is considered absent (none) in clinical practice if the safety ratio is greater than 5; it is weak or slight if the safety ratio is 3 or 4, moderate if 2 or 3, and strong or prominent if the ratio is 1 or less. These autonomic responses are not reduced by slower injection of the muscle relaxant. They are dose related and additive over time if divided doses are given. If identical to the original dose, subsequent doses will produce a similar response (i.e., no tachyphylaxis will occur). This is not the case, however, when the side effect of histamine release is in question. Cardiovascular responses secondary to histamine release are decreased by slowing the injection rate, and the response undergoes rapid tachyphylaxis. The autonomic effects of NMBDs are summarized in Table 27.10. Histamine Release. Quaternary ammonium compounds (e.g., NMBDs) are generally weaker histamine-releasing substances than are tertiary amines such as morphine. Nevertheless, when large doses of certain NMBDs are administered rapidly, erythema of the face, neck, and upper torso may develop, as well as a brief decrease in arterial pressure and a slight to moderate increase in heart rate. Bronchospasm in this setting is very rare. The clinical effects of histamine are seen when plasma concentrations increase 200% to 300% of baseline values, and these effects involve chemical displacement of the contents of mast cell granules containing histamine, prostaglandin, and possibly other vasoactive substances.182 The serosal mast cell, located in the skin and connective tissue and near blood vessels and nerves, is principally involved in the degranulation process.182 The side effect of histamine release is most often noted following administration of the benzylisoquinolinium class of muscle relaxants, although it has also been noted in steroidal relaxants of low potency. The effect is usually of short duration (1-5 minutes), is dose related, and is

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27 • Pharmacology of Neuromuscular Blocking Drugs

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TABLE 27.10  Clinical Autonomic Effects of Neuromuscular Blocking Drugs Autonomic Ganglia

Cardiac Muscarinic Receptors

Histamine Release

Stimulates

Stimulates

Slight

BENZYLISOQUINOLINIUM COMPOUNDS Mivacurium None

None

Slight

Atracurium

None

None

Slight

Cisatracurium

None

None

None

d-Tubocurarine

Blocks

None

Moderate

STEROIDAL COMPOUNDS Vecuronium

None

None

None

Rocuronium

None

Blocks weakly

None

Pancuronium

None

Blocks moderately

None

Drug Type DEPOLARIZING SUBSTANCE Succinylcholine

clinically insignificant in healthy patients. The hypotensive cardiovascular response to 0.6 mg/kg of dTc in humans is prevented both by antihistamines and by nonsteroidal antiinflammatory drugs (e.g., aspirin).183 The final step in dTcinduced hypotension is modulated by prostaglandins that are vasodilators.183 This side effect can be reduced considerably by using a slower injection rate that results in lower peak plasma concentrations of dTc. It is also prevented by prophylaxis with combinations of histamine1 and histamine2 blockers.184 If a minor degree of histamine release such as described earlier occurs after an initial dose of an NMBD, subsequent doses will generally cause no response at all, as long as they are no larger than the original dose. This is clinical evidence of tachyphylaxis, an important characteristic of histamine release. A much more significant degree of histamine release occurs during anaphylactoid or anaphylactic reactions, but these are very rare.  Clinical Cardiovascular Manifestations of Autonomic Mechanisms Hypotension.  The hypotension seen with the use of atracurium and mivacurium results from histamine release, whereas dTc causes hypotension by histamine release and ganglionic blockade.185,186 The effects of dTc occur closer to the dose required to achieve neuromuscular blockade.113 The safety margin for histamine release is approximately three times greater for atracurium and mivacurium than it is for dTc.182,183,186 Rapid administration of atracurium in doses greater than 0.4 mg/kg and of mivacurium in doses greater than 0.15 mg/kg has been associated with transient hypotension secondary to histamine release (Fig. 27.13).  Tachycardia.  Pancuronium causes a moderate increase in heart rate and, to a lesser extent, in cardiac output, with little or no change in systemic vascular resistance.187 Pancuronium-induced tachycardia has been attributed to the following: (1) vagolytic action,187 probably from inhibition of M2 receptors; and (2) sympathetic stimulation that involves both direct (blockade of neuronal uptake of norepinephrine) and indirect (release of norepinephrine from adrenergic nerve endings) mechanisms.188 In humans a decrease in plasma norepinephrine

levels was surprisingly found after administration of either pancuronium or atropine.189 The investigators postulated that the increase in heart rate or rate-pressure product occurs because pancuronium (or atropine) acts through baroreceptors to reduce sympathetic outflow.189 More specifically, the vagolytic effect of pancuronium increases heart rate and hence blood pressure and cardiac output, in turn influencing the baroreceptors to decrease sympathetic tone. Support for this concept is provided by the finding that prior administration of atropine attenuates or eliminates the cardiovascular effects of pancuronium.187 However, a positive chronotropic effect that places emphasis on the vagolytic mechanism has not been found in humans.190 The tachycardia seen with benzylisoquinolinium compounds is the result of histamine release.  Dysrhythmias.  Succinylcholine and dTc actually reduce the incidence of epinephrine-induced dysrhythmias.191 Possibly because of enhanced atrioventricular conduction,192 the incidence of dysrhythmias caused by pancuronium appears to increase during halothane anesthesia.187 There are reports of rapid tachycardia (>150 beats/min) that progressed to atrioventricular dissociation in two patients anesthetized with halothane who also received pancuronium.193 The only other factor common to those two patients was that both were taking tricyclic antidepressant drugs.  Bradycardia.  Several case reports described the occurrence of severe bradycardia and even asystole after vecuronium or atracurium administration.194,195 All these cases were also associated with opioid coadministration. Subsequent studies indicated that administration of vecuronium or atracurium alone does not cause bradycardia.196 When combined with other drugs that do cause bradycardia (e.g., fentanyl), however, the nonvagolytic relaxants such as vecuronium, cisatracurium, and atracurium allow this mechanism to occur unopposed. Thus the moderate vagolytic effect of pancuronium is often used to counteract opioid-induced bradycardia.  Respiratory Effects. The muscarinic cholinergic system plays an important role in regulating airway function. Five muscarinic receptors have been cloned,197 three of which (M1 to M3) exist in the airways.198 M1 receptors are under

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816

SECTION II  •  Anesthetic Physiology

Parasympathetic

120 Heart rate 100

* Control (%)

80

*

Preganglionic

*

*

*

Mean arterial pressure

* *

Postganglionic

*

60

ACh

+

40 20

Twitch

*

M3

SE P  .05

+

Negative feedback M2

0 0.07 0.10 0.15 0.25 0.20 0.03 0.05 Dose of mivacurium (mg/kg)

A

0.30

Bronchoconstriction

Fig. 27.14  The muscarinic (M3) receptors are located postsynaptically on airway smooth muscle. Acetylcholine (ACh) stimulates M3 receptors to cause contraction. M2 muscarinic receptors are located presynaptically at the postganglionic parasympathetic nerve endings, and they function in a negative-feedback mechanism to limit the release of ACh.

120 Mean arterial pressure 100 Heart rate Control (%)

80

30 s bolus

30 s bolus

60 40 20

Twitch SE

0

B

0.20 0.07 0.10 0.15 0.25 0.03 0.05 Dose of mivacurium (mg/kg)

0.30

Fig. 27.13 Dose response to mivacurium in patients under nitrous oxide–oxygen-opioid anesthesia. Maximum changes at each dose are shown; n = 9 subjects per group. (A) With fast injection, a 15% to 20% decrease in arterial pressure occurred at 2.5 to 3 times the ED95 (0.20-0.25 mg/kg). (B) The changes were less than 10% when slower injection (30 seconds) was done. (From Savarese JJ, Ali HH, Basta SJ, et al. The cardiovascular effects of mivacurium chloride [BW B1090U] in patients receiving nitrous oxide–opiate-barbiturate anesthesia. Anesthesiology. 1989;70:386–394.)

sympathetic control, and they mediate bronchodilation.199 M2 receptors are located presynaptically (Fig. 27.14), at the postganglionic parasympathetic nerve endings, and they function in a negative-feedback mechanism to limit the release of acetylcholine. The M3 receptors, which are located postsynaptically (see Fig. 27.14), mediate contraction of the airway smooth muscles (i.e., bronchoconstriction).199 Nondepolarizing NMBDs have different antagonistic activities at both M2 and M3 receptors.200 For example, blockade of M3 receptors on airway smooth muscle inhibits vagally induced bronchoconstriction (i.e., causes bronchodilation), whereas blockade of M2 receptors results in increased release of acetylcholine that acts on M3 receptors, thus causing bronchoconstriction. The affinity of the compound rapacuronium to block M2 receptors is 15 times higher than its affinity to block M3 receptors.200 This explains the high incidence (>9%) of severe bronchospasm201-203 reported with this drug that

resulted in its withdrawal from the market. In laboratory animals (guinea pig), CW 1759-50 is reported to have five times greater safety at both M2 and M3 receptors than rapacuronium.11b The administration of benzylisoquinolinium NMBDs (with the exception of cisatracurium) is associated with histamine release, which may result in increased airway resistance and bronchospasm in patients with hyperactive airway disease.  Allergic Reactions. The frequency of life-threatening anaphylactic (immune-mediated) or anaphylactoid reactions occurring during anesthesia has been estimated at 1 in 10,000 to 20,000 anesthetic procedures, whereas it is estimated at 1 in 6500 administrations of NMBDs in some countries.204,205 In France, the most common causes of anaphylaxis in patients who experienced allergic reactions were reported to be NMBDs (60.6%), antibiotics (18.2%), dyes (5.4%), and latex (5.2%).206,206a Patients were sensitized to 2 or more NMBDS in approximately 50% of the cases and no cross-sensitivity could be predicted without skin testing. Anaphylactic reactions are mediated through immune responses involving immunoglobulin E (IgE) antibodies fixed to mast cells. Anaphylactoid reactions are not immune mediated and represent exaggerated pharmacologic responses in very rare and very sensitive individuals. However, anaphylaxis to nondepolarizing NMBDs is not uncommon in patients without any previous exposure to any nondepolarizing NMBDs. Cross-reactivity occurs between NMBDs and food, cosmetics, disinfectants, and industrial materials.207 Sensitization to nondepolarizing NMBDs may also be related to pholcodine, a cough-relieving medicine. Cross-reactivity is seen in 70% of patients with a history of anaphylaxis to an NMBD.206 Six years after the withdrawal of pholcodine from the Norwegian market, the prevalence of IgE sensitization to NMBDs (succinylcholine) decreased significantly.207a Steroidal compounds (e.g., rocuronium, vecuronium, or pancuronium) result in no significant histamine release.186 For example, four times the ED95 of rocuronium (1.2 mg/

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27 • Pharmacology of Neuromuscular Blocking Drugs

kg) causes no significant histamine release.208 Nevertheless, rocuronium and succinylcholine are reportedly associated with a 43.1% and 22.6% incidence, respectively, of anaphylaxis in France.206 Rose and Fisher classified rocuronium and atracurium as having intermediate levels of risk for causing allergic reactions.209 These investigators also noted that the increased number of reports of anaphylaxis with rocuronium is in line with the market share of that drug’s usage. Watkins stated, “The much higher incidence of rocuronium reactions reported in France is currently inexplicable and is likely to remain so if investigators continue to seek a purely antibody-mediated response as an explanation of all anaphylactoid reaction presentations.”210 All nondepolarizing NMBDs may elicit anaphylaxis. More recent publications have highlighted the need for standardization of diagnostic procedures of anaphylactic reactions. Biochemical tests should be performed rapidly after occurrence of an anaphylactic reaction. An early increase in plasma histamine is observed 60 to 90 minutes after anaphylactic reactions. Serum tryptase concentration typically reaches a peak between 15 and 120 minutes, depending on the severity of the reaction, and is much more specific than histamine as a marker of anaphylactic reaction. It is highly suggestive of mast cell activation. Skin testing remains the gold standard for detection of the culprit agent.77a For many years, dilution thresholds have been debated. For instance, Laxenaire used a 1:10 dilution of rocuronium for interdermal skin testing,212 whereas Rose and Fisher used a 1:1000 dilution.209 Levy and associates showed that rocuronium in a 1:10 dilution can produce false-positive results in intradermal testing and suggested that rocuronium be diluted at least 100-fold to prevent such results.213 The authors also reported that high concentrations (≥10–4 M) of both rocuronium and cisatracurium were capable of producing a wheal-and-flare response to intradermal testing, which was associated with mild to moderate mast cell degranulation in the cisatracurium group only.213 However, in contrast to control patients, skin tests with nondepolarizing NMBDs that were performed in patients who had an anaphylactic reaction were considered reliable. In the case of suspected anaphylactic reaction to any NMBD, it is mandatory to complete investigation for cross-reactivity with other commercially available NMBDs to identify safe alternative regimens. All NMBDs can cause noncompetitive inhibition of histamine-N-methyltransferase, but the concentrations required for that inhibition greatly exceed those that would be used clinically, except in the case of vecuronium, with which the effect becomes manifest at 0.1 to 0.2 mg/ kg.214 This finding could explain the occurrence of occasional severe bronchospasm in patients after receiving vecuronium.215 For goals of treatment of anaphylactic reactions, see Chapters 5 and 6. 

DRUG INTERACTIONS AND OTHER FACTORS AFFECTING RESPONSE TO NEUROMUSCULAR BLOCKERS A drug-drug interaction is an in  vivo phenomenon that occurs when the administration of one drug alters the effects or kinetics of another drug. In  vitro physical or chemical incompatibilities are not considered drug interactions.216

817

Many drugs interact with NMBDs or their antagonists, or both, and it is beyond the scope of this chapter to review them all.216,217 Some of the more important drug interactions with NMBDs and their antagonists are discussed in the following sections.

Interactions Among Nondepolarizing Neuromuscular Blocking Drugs Mixtures of two nondepolarizing NMBDs are considered to be either additive or synergistic. Antagonistic interactions have not been reported in this class of drugs. Additive interactions have been demonstrated after administration of chemically related drugs, such as atracurium and mivacurium,218 or after coadministration of various pairs of steroidal NMBDs.98 Conversely, combinations of structurally dissimilar (e.g., a steroidal with a benzylisoquinolinium) NMBDs, such as the combinations of pancuronium and dTc,219 pancuronium and metocurine,219 rocuronium and mivacurium,142 or rocuronium and cisatracurium,109 produce a synergistic response. An additional advantage (rapid onset and short duration) is noted for mivacuriumrocuronium combinations.142 Although the precise mechanisms underlying a synergistic interaction are not known, hypotheses that have been put forward include the existence of multiple binding sites at the neuromuscular junction (presynaptic and postsynaptic receptors)220 and the nonequivalence of binding affinities of the two α subunits (αH and αL). Further, inhibition of butyrylcholinesterase by pancuronium results in decreased plasma clearance of mivacurium and marked potentiation of the neuromuscular blockade.221 The pharmacodynamic response to the use of two different nondepolarizing NMBDs during the course of anesthesia depends not only on the specific drugs used but also on the sequence of their administration.222,223 Approximately three half-lives are required for a clinical changeover (so that 95% of the first drug has been cleared) and for the duration of the blockade to begin to take on the characteristics of the second drug. After the administration of pancuronium, recovery from the first two maintenance doses of vecuronium is reportedly prolonged, although this effect becomes negligible by the third dose.222 Similarly, Naguib and colleagues noted that the mean duration of the first maintenance dose of mivacurium to 10% recovery of the first twitch was significantly longer after atracurium (25 minutes) than after mivacurium (14.2 minutes).218 However, the duration of the second maintenance dose of mivacurium after atracurium (18.3 minutes) was similar to that of mivacurium after mivacurium (14.6 minutes). The apparent prolongation of action of the first maintenance dose of mivacurium administered after atracurium,218 and of those reported with vecuronium after pancuronium,222,223 is not related to synergism. Combinations of atracurium and mivacurium218 and of vecuronium and pancuronium98 are simply additive. However, this prolongation in the duration of action could be attributed to the relative concentrations of these drugs at the receptor site. Because most receptors remain occupied by the drug administered initially, the clinical profile depends on the kinetics or dynamics (or both) of the drug administered first, rather than on those of the second (maintenance)

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818

First twitch depression (% control)

SECTION II  •  Anesthetic Physiology

Desflurane Sevoflurane Isoflurance TIVA

99 95 80 50 20 0.1

0.2 Rocuronium (mg/kg)

0.3

Fig. 27.15  Cumulative dose-response curves for rocuronium-induced neuromuscular blockade during 1.5 minimum alveolar concentration anesthesia with desflurane, sevoflurane, isoflurane, and total intravenous anesthesia (TIVA). (From Wulf H, Ledowski T, Linstedt U, et al. Neuromuscular blocking effects of rocuronium during desflurane, isoflurane, and sevoflurane anaesthesia. Can J Anaesth. 1998;45:526–532, with permission from the Canadian Journal of Anaesthesia.)

drug. However, with further incremental doses of the second drug, a progressively larger proportion of the receptors is occupied by that second drug, and its clinical profile becomes evident. 

Interactions Between Succinylcholine and Nondepolarizing Neuromuscular Blocking Drugs The interaction between succinylcholine and nondepolarizing NMBDs depends on the order of administration and the doses used.81,224,225 Small doses of different nondepolarizing NMBDs administered before succinylcholine to prevent fasciculations have an antagonistic effect on the development of subsequent depolarizing block produced by succinylcholine.27,81 Therefore it is recommended that the dose of succinylcholine be increased after the administration of a defasciculating dose of a nondepolarizing NMBD.27 Studies of the effects of administering succinylcholine before nondepolarizing NMBDs have produced conflicting results. Several investigators reported potentiation of the effects of pancuronium,224 vecuronium, and atracurium225 by prior administration of succinylcholine. In contrast, other investigators found no significant influence of succinylcholine on subsequent administration of pancuronium, rocuronium, or mivacurium.81,226,227  Interactions With Inhaled Anesthetics Deep anesthesia induced with potent volatile anesthetics (in the absence of neuromuscular blockade) may cause a slight reduction of neuromuscular transmission, as measured by depression of sensitive indicators of clinical neuromuscular function, such as tetanus and TOF ratio.228 Inhaled anesthetics also enhance the neuromuscular blocking effects of nondepolarizing NMBDs. Inhaled anesthetics decrease the required dose of NMBDs, and prolong both the duration of action of the NMBD and recovery from neuromuscular block,229 depending on the duration of anesthesia,228,230,231 the specific inhaled anesthetic,232 and the concentration (dose) given.233 The rank order of potentiation is desflurane > sevoflurane > isoflurane > halothane > nitrous oxide/barbiturate/opioid or propofol anesthesia (Fig. 27.15).234-236

The greater clinical muscle-relaxing effect produced by less potent anesthetics is mainly caused by their larger aqueous concentrations.237 Desflurane and sevoflurane have low blood-gas and tissue-gas solubility, so equilibrium between the end-tidal concentration and the neuromuscular junction is reached more rapidly with these anesthetics than with older inhaled anesthetics. The interaction between volatile anesthetics and NMBDs is one of pharmacodynamics, not pharmacokinetics.238 The proposed mechanisms behind this interaction include (1) a central effect on α motoneurons and interneuronal synapses,239 (2) inhibition of postsynaptic nAChR,240 and (3) augmentation of the antagonist’s affinity at the receptor site.237 

Interactions With Antibiotics Most antibiotics can cause neuromuscular blockade in the absence of NMBDs. The aminoglycoside antibiotics, the polymyxins, and lincomycin and clindamycin primarily inhibit the prejunctional release of acetylcholine and also depress postjunctional nAChR sensitivity to acetylcholine.241 The tetracyclines, in contrast, exhibit postjunctional activity only. When combined with NMBDs, the aforementioned antibiotics can potentiate neuromuscular blockade.242 The cephalosporins and penicillins have not been reported to potentiate neuromuscular blockade. Because antagonism of neuromuscular blockade with neostigmine has been reported to be more difficult after the administration of aminoglycosides,243 ventilation should be controlled until the neuromuscular blockade terminates spontaneously. Ca2+ should not be used to hasten the recovery of neuromuscular function for two reasons: the antagonism it produces is not sustained, and it may prevent the antibacterial effect of the antibiotics.  Temperature Hypothermia prolongs the duration of action of nondepolarizing NMBDs.244-246 The force of contraction of the adductor pollicis decreases by 10% to 16% per degree Celsius decrease in muscle temperature lower than 35.2°C.247,248 To maintain the muscle temperature at or higher than 35.2°C, the central temperature must be maintained above 36.0°C.244 The mechanical response recovery to 10% twitch height with 0.1 mg/kg of vecuronium increases from 28 minutes at a mean central temperature of 36.4°C to 64 minutes at 34.4°C.244 The mechanism or mechanisms underlying this prolongation may be pharmacodynamic or pharmacokinetic, or both.246 They include diminished renal and hepatic excretion, changing volumes of distribution, altered local diffusion receptor affinity, changes in pH at the neuromuscular junction, and the net effect of cooling on the various components of neuromuscular transmission.244,249 Hypothermia decreases the plasma clearance and prolongs the duration of action of rocuronium and vecuronium.246 Temperature-related differences in the pharmacodynamics of vecuronium have also been reported. The ke0 decreases (0.023/min/°C) with lower temperature, a finding suggesting slightly delayed equilibration of drug between the circulation and the neuromuscular junction during hypothermia.246 The Hofmann elimination process of atracurium is slowed by a decrease in pH and especially by a decrease in temperature.250 In fact, atracurium’s duration

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27 • Pharmacology of Neuromuscular Blocking Drugs

of action is markedly prolonged by hypothermia.245 For instance, the duration of action of a dose of 0.5 mg/kg atracurium is 44 minutes at 37°C but 68 minutes at 34.0°C when evoked mechanical responses are monitored. Changes in temperature also affect the interpretation of the results of monitoring neuromuscular blockade. For example, the duration of action of vecuronium measured in an arm cooled to a skin temperature of 27°C is prolonged, and monitoring by PTC in that arm is unreliable.251 In the same patient, TOF responses are different if the arms are at different temperatures, and the correlation of responses in the two arms becomes progressively poorer as the temperature difference between the arms increases.252 The efficacy of neostigmine is not altered by mild hypothermia.253-255 Hypothermia does not change the clearance, maximum effect, or duration of action of neostigmine in volunteers.255 Mild hypothermia prolonged sugammadex reversal of deep rocuronium block by 46 seconds, a prolongation considered clinically acceptable.255a 

Interactions With Magnesium and Calcium Magnesium sulfate, given for treatment of preeclampsia and eclamptic toxemia, potentiates the neuromuscular blockade induced by nondepolarizing NMBDs.256,257 After a dose of 40 mg/kg of magnesium sulfate, the ED50 of vecuronium was reduced by 25%, the onset time was nearly halved, and the recovery time nearly doubled.257 Neostigmine-induced recovery is also attenuated in patients treated with magnesium.256 The mechanisms underlying the enhancement of nondepolarizing block by magnesium probably involve both prejunctional and postjunctional effects. High magnesium concentrations inhibit Ca2+ channels at the presynaptic nerve terminals that trigger the release of acetylcholine.16 Further, magnesium ions have an inhibitory effect on postjunctional potentials and cause decreased excitability of muscle fiber membranes. In patients receiving magnesium, the dose of nondepolarizing NMBDs must be reduced and carefully titrated using an objective monitor to ensure adequate recovery of neuromuscular function prior to tracheal extubation. The interaction between magnesium and succinylcholine is controversial, with some reports suggesting that magnesium antagonizes the block produced by succinylcholine.258 Ca2+ triggers the release of acetylcholine from the motor nerve terminal and enhances excitation-contraction coupling in muscle.16 Increasing Ca2+ concentrations decreased the sensitivity to dTc and pancuronium in a muscle-nerve model.259 In hyperparathyroidism, hypercalcemia is associated with decreased sensitivity to atracurium and thus a shortened time course of neuromuscular blockade.260  Interactions With Lithium Lithium is used for treatment of bipolar affective disorder (manic-depressive illness). The lithium ion resembles Na+, K+, magnesium, and Ca2+ ions, and therefore may affect the distribution and kinetics of all these electrolytes.261 Lithium enters cells via Na+ channels and tends to accumulate within the cells. By its activation of K+ channels, lithium inhibits neuromuscular transmission presynaptically and muscular contraction postsynaptically.262 The combination of lithium and pipecuronium results in a synergistic inhibition of neuromuscular transmission, whereas the combination

819

of lithium and succinylcholine results in additive inhibition.262 Prolongation of neuromuscular blockade was reported in patients taking lithium carbonate and receiving both depolarizing and nondepolarizing NMBDs.263 Only one report did not demonstrate prolongation of recovery from succinylcholine in patients receiving lithium.264 In patients who are stabilized on lithium therapy and undergoing surgery, NMBDs should be administered in incremental and reduced doses and titrated to the degree of blockade required. 

Interactions With Local Anesthetic and Antidysrhythmic Drugs Local anesthetics act on the presynaptic and postsynaptic part of the neuromuscular junction. In large intravenous doses, most local anesthetics block neuromuscular transmission; in smaller doses, they enhance the neuromuscular blockade produced by both nondepolarizing and depolarizing NMBDs.265 The ability of neostigmine to antagonize a combined local anesthetic–neuromuscular blockade has not been studied. Procaine also inhibits butyrylcholinesterase and may augment the effects of succinylcholine and mivacurium by decreasing their hydrolysis by the enzyme. In small intravenous doses, local anesthetics depress posttetanic potentiation, and this is thought to be a neural prejunctional effect.266 With larger doses, local anesthetics block acetylcholine-induced muscular contractions, a finding suggesting that local anesthetics have a stabilizing effect on the postjunctional membrane.267 Procaine displaces Ca2+ from the sarcolemma and thus inhibits caffeine-induced contracture of skeletal muscle.268 Most of these mechanisms of action probably apply to all local anesthetics. Several drugs used for the treatment of dysrhythmias augment the blockade induced by NMBDs. Single-fiber electromyography found that verapamil and amlodipine impair neuromuscular transmission in subjects without neuromuscular disease.269 Clinical reports suggested potentiation of neuromuscular block with verapamil270 and impaired reversal of vecuronium in a patient receiving disopyramide.271 However, the clinical significance of these interactions is probably minor.  Interactions With Antiepileptic Drugs Anticonvulsants have a depressant action on acetylcholine release at the neuromuscular junction.272,273 Patients receiving long-term anticonvulsant therapy demonstrated resistance to nondepolarizing NMBDs (except mivacurium274 and probably atracurium as well273), as evidenced by accelerated recovery from neuromuscular blockade and the need for increased doses to achieve complete neuromuscular blockade. Vecuronium clearance is increased two-fold in patients receiving long-term carbamazepine therapy.275 Other investigators, however, attribute this resistance to the increased binding (i.e., decreased free fraction) of the NMBDs to α1-acid glycoproteins or to upregulation of neuromuscular acetylcholine receptors (or to both mechanisms).276 The latter could also explain the hypersensitivity seen with succinylcholine.277 The slight prolongation of succinylcholine’s action in patients taking anticonvulsants has few clinical implications. Conversely, the potential hyperkalemic response to succinylcholine in the presence of receptor upregulation is of concern. 

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SECTION II  •  Anesthetic Physiology

Interactions With Diuretics Early results showed that in patients undergoing renal transplantation, the intensity and duration of dTc neuromuscular blockade was increased after a dose of furosemide (1 mg/kg intravenously).278 Furosemide reduced the concentration of dTc required to achieve 50% twitch tension depression in the indirectly stimulated rat diaphragm and intensified the neuromuscular blockade produced by dTc and succinylcholine.279 Furosemide appears to inhibit the production of cyclic adenosine monophosphate. In addition, the breakdown of adenosine triphosphate is inhibited, resulting in reduced output of acetylcholine. Acetazolamide antagonized the effects of anticholinesterases in the rat phrenic-diaphragm preparation.280 However, in one report, 1 mg/kg of furosemide facilitated recovery of the evoked twitch response after pancuronium.281 Long-term furosemide treatment had no effect on either dTcor pancuronium-induced neuromuscular blockade.282 In contrast, mannitol appears to have no effect on a nondepolarizing neuromuscular blockade. Increasing urine output by the administration of mannitol or other osmotic or tubular diuretics has no effect on the rate at which dTc and presumably other NMBDs are eliminated in the urine.283  Interactions With Other Drugs Dantrolene, a drug used for the treatment of malignant hyperthermia, prevents Ca2+ release from the sarcoplasmic reticulum and blocks excitation-contraction coupling. Although dantrolene does not block neuromuscular transmission, the mechanical response to stimulation is depressed, resulting in potentiation of nondepolarizing neuromuscular blockade.284 Azathioprine, an immunodepressant drug that is used in patients undergoing renal transplantation, has a minor antagonistic action on muscle relaxant–induced neuromuscular blockade.285 Steroids antagonize the effects of nondepolarizing NMBDs in both humans286 and animals.287 Possible mechanisms for this interaction include facilitation of acetylcholine release because of the effect of steroids on the presynaptic motor nerve terminal.288 Other reports, however, described a noncompetitive inhibition and channel blockade of the nAChR.289 Endogenous steroids act noncompetitively on nAChRs.290 Prolonged treatment with a combination of corticosteroids and NMBDs can result in prolonged weakness in patients receiving critical care (see the later section on NMBDs and weakness syndromes in critically ill patients). Antiestrogenic drugs such as tamoxifen appear to potentiate the effects of nondepolarizing NMBDs.291 

Special Populations PEDIATRIC PATIENTS The development of the neuromuscular junction is not complete at birth.16 In humans, maturation of neuromuscular transmission occurs after the first 2 months of age, although immature junctions have been found up to 2 years of age. The main evolution during the first months of life is that the fetal receptors located outside the neuromuscular junction will disappear and will be replaced by mature receptors with ε

subunits instead of γ subunits. These changes suggest that that the neonate’s neuromuscular junction may exhibit evidence of its immaturity by changes in response to NMBDs, although NMBDs can be used safely in term and preterm infants. The routine administration of succinylcholine to healthy children should be discontinued. In apparently healthy children, intractable cardiac arrest with hyperkalemia, rhabdomyolysis, and acidosis may develop after succinylcholine administration, particularly in patients with unsuspected muscular dystrophy of the Duchenne type292 (see the section on complications of succinylcholine). Significant age-related differences in the potency of nondepolarizing NMBDs exist in infants and children when compared with adults. Children require higher doses of nondepolarizing NMBDs than any other age group of patients. In infants less than 1 year old, the ED95 at the adductor pollicis is approximately 30% less than in older children. It is not apparent from older studies whether the neonate is more sensitive than adults to nondepolarizing NMBDs,293 although most of the studies showed a wider range of dosage requirement in the neonate. These apparent discrepancies have been explained in studies by Fisher and associates on the pharmacokinetics and pharmacodynamics of NMBDs in infants, children, and adults.294-296 Neonates and infants are more sensitive than adults to the neuromuscular blocking effects of dTc.294 Plasma concentrations required to achieve a desired level of neuromuscular blockade are 57% and 32% lower in neonates and infants, respectively, when compared with children. However, the dosage should not be decreased as much because neonates and infants have a larger volume of distribution at steady state. This increased volume of distribution results from the increase in extracellular fluid volume during the first months of life. This increase, in association with a lower elimination clearance, contributes to a longer elimination half-life.294,297 In infants, less frequent dosing (longer dosing intervals) of nondepolarizing NMBDs may be required than in older children. Atracurium, vecuronium, cisatracurium, rocuronium, and mivacurium are commonly administered to children because many surgical procedures are of short duration in children and are compatible with the duration of action of a single intubating dose. Onset time of neuromuscular block is faster in infants (30%) and children (40%) when compared with adults. This age-related effect is probably caused by circulatory factors such as the relative decrease in cardiac output and increase in circulation time with age. As for long-acting NMBDs, the sensitivity of infants to vecuronium is greater than that of children (ED95 0.047 mg/kg vs. 0.081 mg/kg, respectively).298,299 An increased duration of action in infants is most likely secondary to the increased volume of distribution of vecuronium because its clearance is unchanged.295,297 An age-dependent prolongation of action has been demonstrated in infants. A dose of 0.1 mg/kg of vecuronium produces almost a complete neuromuscular block of approximately 60 minutes’ duration in infants but of only 20 minutes’ duration in children and adults. Vecuronium therefore acts as a long-acting muscle NMBD in the neonate.295,297 In contrast, the duration of action of atracurium is not significantly different in the pediatric patient from that in the adult.300 As with vecuronium and dTc, the volume of distribution is increased in infants.296 However, the clearance of

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27 • Pharmacology of Neuromuscular Blocking Drugs

atracurium is also more rapid.296 Therefore the same dose (0.5-0.6 mg/kg) can be used in infants, children, and adults for tracheal intubation without any major differences among the three groups in the drug’s duration of action. Atracurium recovery from neuromuscular blockade is little affected by age in pediatric patients more than 1 month old. Histamine release and the occurrence of untoward reactions caused by atracurium are less frequent in children than in adults. In children, a dose of 0.1 μg/kg of cisatracurium has an onset just longer than 2 minutes and a clinical duration of approximately 30 minutes during balanced or halothane anesthesia.301 The calculated ED95 doses of cisatracurium in infants and children are 43 and 47 μg/kg, respectively.302 The mean infusion rate necessary to maintain 90% to 99% neuromuscular blockade is also similar in infants and children.302 Rocuronium in adults is an intermediate-acting NMBD with a faster onset of action than other nondepolarizing NMBDs, and this is also true in infants and children.303,304 The ED95 is approximately 0.4 mg/kg in children; it is approximately 20% to 30% greater than that in adults, but its onset is faster in adults.304 In children, 0.6 mg/kg of rocuronium produces better conditions for rapid tracheal intubation (approximately 60 seconds) than does 0.1 mg/kg of vecuronium (approximately 100 seconds) or 0.5 mg/kg of atracurium (approximately 180 seconds).303 Evidence indicates that, even during sevoflurane induction in infants, the addition of 0.3 mg/kg rocuronium significantly improves intubating conditions and significantly decreases the frequency of respiratory adverse events such as desaturation because of laryngospasm during induction.305 As with adults, for rapid sequence induction and intubation (60 seconds) in the presence of a full stomach, a 1.2 mg/kg dose of rocuronium is suggested to provide rapid, excellent intubating conditions in pediatric patients. The rate of recovery of intermediate- or short-acting NMBDs is faster than that of long-acting drugs in children. A neostigmine dose of 30 μg/kg in children is quite comparable to the usual dose of 40 μg/kg in adults and provides satisfactory antagonism of nondepolarizing NMBD. Neostigmineassisted recovery is dependent on age and is more rapid in children than either infants or adults.305a Several studies have demonstrated that when children’s tracheas were extubated using clinical criteria of recovery, the TOF ratio did not exceed 0.50 to 0.60, whereas a TOF ratio greater than 0.90 is required to guarantee full recovery from neuromuscular block. These results highlight the need for objective (quantitative) assessment of neuromuscular block, even in infants and children, because of their sensitivity and variability in their responsiveness to nondepolarizing NMBDs. 

OLDER PATIENTS The pharmacodynamics of NMBDs may be altered in older patients. Physiologic changes such as decreases in total body water and lean body mass, increases in total body fat, decreases in hepatic and renal blood flow and hepatic enzyme activity, and decreases in glomerular filtration rate (≈20%/year in adults) typically accompany the aging process. These changes may account for the altered responses of older adults to NMBDs. Some physiologic and anatomic changes at the neuromuscular junction also occur with aging. These include an increase in the distance between the junctional axon and the motor end plate, flattening of

821

the folds of the motor end plate, decreased concentration of acetylcholine receptors at the motor end plate, decrease in the amount of acetylcholine in each vesicle in the prejunctional axon, and decreased release of acetylcholine from the preterminal axon in response to a neural impulse.16 Several studies found no differences in the initial dose requirement for nondepolarizing muscle relaxants in older adults. The dose-response curves of atracurium, pancuronium, and vecuronium were shifted slightly to the right of the curves for the younger adult subjects; however, no significant differences were noted. After a bolus dose of pancuronium, no significant difference was observed in any of the plasma concentrations corresponding to a fixed degree of neuromuscular block. Such results confirm that nondepolarizing muscle relaxants are as potent in older as in young adult patients. The onset of neuromuscular block can be delayed and can be correlated with age.306 This agerelated effect is probably caused by circulatory factors such as the decrease in cardiac output and increase in circulation time in older adults. These factors induce slower biophase equilibration with plasma. The onset of rocuronium neuromuscular block was prolonged to 3.7 from 3.1 minutes in older adults. Similarly, the onset of cisatracurium is delayed approximately 1 minute in this age group. A prolongation of the duration of action of nondepolarizing muscle relaxants and a decrease in dose requirements for the maintenance of neuromuscular block have been observed with several currently available muscle relaxants in older adults. These results are explained by pharmacokinetic changes in this population. The distribution and elimination may be altered by any of the multitude of physiologic changes that accompany the aging process. The effect of aging alone, as opposed to disease states often associated with the aging process, may be difficult to distinguish in identifying mechanisms of altered NMBD action in older adults. Pancuronium,307 vecuronium,295,308 and rocuronium177 depend on the kidney or the liver (or both) for their metabolism and elimination. Therefore they all show altered pharmacodynamics and pharmacokinetics in older patients. Pancuronium has delayed recovery in older adults because of decreased plasma clearance secondary to delayed urinary excretion. Vecuronium dose requirements to maintain a constant neuromuscular block are decreased by approximately 36% in patients older than 60 years, and spontaneous recovery is significantly longer in older patients.25 Plasma clearance is reduced by more than 50% and elimination half-life prolonged by 60% in older patients.308 The prolongation of vecuronium action appears to be secondary to decreased drug elimination consistent with age-associated decreases in hepatic and renal blood flows. The duration of action of rocuronium and the recovery index are also increased in older adults. The prolongation of action can be explained by a 27% decrease in plasma clearance. In the case of drugs whose elimination is independent of hepatic or renal blood flow, pharmacokinetics and pharmacodynamics should not be altered significantly by age. Atracurium has multiple routes of elimination. Degradation by Hofmann elimination and ester hydrolysis is independent of the liver and the kidney and is not affected by age. The only pharmacokinetic change is a slight increase of the volume of distribution at steady state leading to a modestly increased

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822

SECTION II  •  Anesthetic Physiology

elimination half-life. Consequently, the duration of action, the recovery index, and the dose requirement during a continuous infusion are independent of age. Cisatracurium is mainly eliminated by Hofmann elimination, and unlike atracurium, cisatracurium does not undergo hydrolysis by specific esterases. It exhibits a slightly delayed onset of effect in older patients because of slower biophase equilibration. Clearances are not decreased in patients of advanced age. The slight prolongation of the elimination half-life of the drug in older adults is secondary to an increased volume of distribution at steady state (+10%). These minor pharmacokinetic changes are not associated with changes in the recovery profile in older patients. Butyrylcholinesterase activity in older adults, although still in the normal range, is approximately 26% lower than that in young adults.309 Because mivacurium is metabolized by butyrylcholinesterase, its clearance is likely to be slightly reduced in older patients, thus resulting in a 20% to 25% longer duration of action,310 as well as a decreased infusion requirement to maintain a stable depth of block. Succinylcholine metabolism is unaffected by these changes. In general, when maintaining neuromuscular blockade with nondepolarizing NMBDs in older patients, one can expect that, with the exception of atracurium and cisatracurium, the dosing interval will be increased to maintain the desired depth of neuromuscular blockade. The choice of drug and monitoring the depth of blockade are exceptionally important in this population because recovery of neuromuscular function is generally delayed in older patients. Inadequate or incomplete recovery of muscle strength after the use of pancuronium is associated with an increased incidence of perioperative pulmonary complications in this patient population.129 The clear relationship between incomplete recovery from neuromuscular block and occurrence of critical respiratory events in the PACU highlights the need for objective monitoring to ensure recovery of neuromuscular block in older patients. 

OBESE PATIENTS The level of plasma pseudocholinesterase activity and the volume of extracellular fluid, which are the main determinants of the duration of action of succinylcholine, are increased in obese patients. For complete neuromuscular paralysis and predictable intubating conditions, a 1-mg/kg dose based on total-body weight (TBW) is recommended.311 Initial studies showed that obese subjects needed significantly more pancuronium than nonobese patients to maintain a constant 90% depression of twitch height. However, when corrected for body surface area (BSA), no significant difference was noted in dose requirement to maintain neuromuscular block. The use of NMBDs with an intermediate duration of action should be preferred. Vecuronium doses based on TBW induce a prolonged duration of action in obese patients, although vecuronium pharmacokinetics is unaltered by obesity. The prolonged recovery in obese patients can be explained by the larger total dose of vecuronium administered to these patients. With larger doses, when administration is based on TBW, recovery occurs during the elimination phase when plasma concentration decreases more slowly than during the distribution phase.312 The

pharmacokinetics of rocuronium is not altered by obesity. In the same way, the duration of action of rocuronium is significantly prolonged when the dose is calculated according to TBW. In contrast, when rocuronium is dosed according to ideal body weight (IBW), the clinical duration is less than half.313,314 A correlation exists between the duration of action of atracurium and TBW when the dose is given as milligrams per kilogram of TBW. The clinical duration of action is doubled when the drug is given based on TBW versus IBW. There is little difference between obese and normal-weight patients in atracurium elimination half-life (19.8 vs. 19.7 minutes), volume of distribution at steady state (8.6 vs. 8.5 L), and total clearance (444 vs. 404 mL/min).315 The finding that IBW avoids prolonged recovery of atracurium-induced blockade can be explained by an unchanged muscle mass and an unchanged volume of distribution in morbidly obese patients compared with normal-weight patients.316 The duration of cisatracurium is also prolonged in obese patients when the drug is given on the basis of TBW versus IBW. In summary, nondepolarizing NMBDs should be given to obese patients on the basis of IBW rather than on their actual body weight, to ensure that these patients are not receiving relative overdoses and to avoid prolonged recovery. When using maintenance doses, objective monitoring is strongly recommended to avoid accumulation. 

SEVERE RENAL DISEASE NMBDs contain quaternary ammonium groups that make them very hydrophilic. They are therefore usually completely ionized at a pH of 7.4 and are poorly bound to plasma proteins. The predominant pathway of elimination of steroidal muscle relaxants is ultrafiltration by the glomeruli before urinary excretion. Renal failure influences the pharmacologic characteristics of nondepolarizing NMBDs by producing either decreased renal elimination of the drug or its metabolites. Only atracurium, cisatracurium, and, to some extent, vecuronium are independent of renal function. Succinylcholine elimination is mainly independent of kidney function. However, succinylcholine is metabolized by plasma cholinesterases, and concentrations may be slightly decreased in patients with severe renal failure (Table 27.11). The decrease in plasma cholinesterase activity is always moderate (30%) and does not result in prolongation of succinylcholine-induced neuromuscular block. Succinylcholine induces a transient increase in plasma K+ concentration (90%), may have other autoimmune disorders (e.g., Sjögren syndrome, autoimmune thyroid disease, limited cutaneous scleroderma, rheumatoid arthritis), and can progress to end-stage liver disease. Primary sclerosing cholangitis is characterized by bile duct destruction that can progress to cirrhosis and end-stage liver disease. The disease mainly affects males and may be idiopathic or associated with inflammatory bowel disease (i.e., ulcerative colitis, Crohn disease).  Unexpected Elevated Liver Function Tests Elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentration reflect hepatocyte damage. Bilirubin concentration measures the liver’s ability to conjugate and excrete bile salts. Alkaline phosphatase (ALP) rises with impaired hepatic excretion, whereas albumin and INR measure the synthetic function of the liver. Routine preoperative laboratory screening may identify about 1 in 700 surgical patients as having unexpected liver diseases, most of which are not severe.316 Nonetheless, if abnormal liver function test values are unexpectedly found, further testing or referral may be necessary in some cases. Elevated AST or ALT concentrations should prompt hepatitis screening with hepatitis A IgM antibody, hepatitis B antigens (surface and core), hepatitis B surface antibody, and hepatitis C antibody. Elevated concentrations of ALP or bilirubin, especially in association with normal or mild to moderate increased transaminase levels, may indicate obstruction in the biliary system. In these cases, abdominal ultrasound, computed tomography scans, or endoscopic retrograde cholangiopancreatography may establish a diagnosis. 

963

Cirrhosis Cirrhosis is defined as irreversible liver fibrosis and is the end result of most hepatotoxic conditions. This fibrosis leads to portal hypertension, impaired synthetic function (i.e., synthesis of proteins such as clotting factors), and impaired metabolic functions (i.e., clearance of toxins and drugs). Portal hypertension can lead to splenomegaly, esophageal varices, ascites, dependent edema, and pleural effusions. Patients with ascites may also develop spontaneous bacterial peritonitis, which is associated with increased perioperative mortality. Other complications include hepatic encephalopathy, bleeding, thrombocytopenia, low albumin concentrations, and prolonged INR. Hepatopulmonary syndrome may develop, resulting in hypoxemia and pulmonary hypertension because of pulmonary shunts. Jaundiced patients in particular are at risk for developing hepatorenal syndrome, which is renal insufficiency associated with hepatic disease but without any primary renal disease. The condition may be related to renal hypoperfusion. Patients with end-stage liver disease also develop a high–cardiac output state, characterized by decreased systemic vascular resistance. The Child-Turcotte-Pugh classification can predict perioperative morbidity and mortality, with especially high risks in patients assigned to class C (see Table 31.16). The MELD score also predicts perioperative risks, perhaps better than the Child-Turcotte-Pugh classification,317 with scores exceeding 14 indicative of increased perioperative risk. 

HEMATOLOGIC DISORDERS Anemia Anemia is a very common preoperative hematologic disorder with multifactorial etiology. It is strictly defined as a reduced number of circulating red blood cells (RBCs), however, more commonly it is defined based on the value of reduced hemoglobin concentration or reduced hematocrit. For example, the World Health Organization defines anemia as a hemoglobin level less than 130 g/L in adult men and less than 120 g/L in adult women. Anemia can be classified based on the underlying mechanisms as being related to decreased RBC production (e.g., bone marrow disorders, nutritional deficiencies), increased RBC destruction (e.g., hemolytic anemia, intravascular hemolysis), and blood loss (e.g., gastrointestinal blood loss). Anemia may also be classified morphologically based on the associated RBC size, which is itself characterized by the mean corpuscular volume (MCV). Based on this approach, anemia can be classified as microcytic (MCV < 80 femtoliter [fL]), macrocytic (MCV > 100 fL), or normocytic (MCV between 80 and 100 fL). Common causes of microcytic anemia are iron deficiency (including chronic blood loss), thalassemia minor, and anemia associated with inflammatory disease. Common causes of macrocytic anemia include alcoholism, liver disease, hypothyroidism, and vitamin B12 deficiency. Common causes of normocytic anemia are CKD, heart failure, and cancer. Preexisting anemia is a consistently recognized risk factor for postoperative death and complications, including AKI, stroke, and infections.318 Furthermore, this risk is proportional to the degree of anemia and independent of

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964

SECTION III  •  Anesthesia Management

the patient’s other comorbidities.101,102,319 Nonetheless, there are some important caveats for consideration. First, it remains unclear whether anemia is the causal mechanism for these complications, or instead simply a marker of a high-risk patient. The limited available perioperative data generally suggest that anemia treatment strategies (e.g., erythropoiesis-stimulating agents) can improve hemoglobin concentrations and reduce transfusion requirements, but without convincing evidence for the prevention of death or complications.320-322 These perioperative data are also generally consistent with findings in nonsurgical populations, such as patients with heart failure.323-327 Second, there is no consistent hemoglobin concentration threshold that defines elevated perioperative risk. While data from noncardiac surgery performed in Jehovah’s Witness patients suggest that risk increases substantially once preoperative hemoglobin concentrations fall below 100 g/L (especially in the presence of concomitant IHD),328 simply increasing hemoglobin concentrations to this threshold with RBC transfusion is not consistently beneficial. Importantly, transfusion itself has also been associated with poor outcomes in observational studies.329 In a multicenter randomized trial of 2016 patients undergoing hip fracture surgery, a strategy of transfusing in response to a 100 g/L threshold in hemoglobin concentration was not superior to a strategy of transfusing in response to a 80 g/L threshold or symptoms of anemia.330 Similarly, in a multicenter randomized trial of 5243 patients undergoing cardiac surgery, a strategy of transfusing in response to a 75 g/L threshold was noninferior to a strategy of transfusing in response to a 95 g/L threshold.331 These data suggest that the optimal perioperative hemoglobin concentration threshold varies between 75 g/L and 100 g/L across individuals, with interindividual differences largely explained by comorbid conditions (e.g., cardiopulmonary disease). During the preoperative evaluation of known or suspected anemia, the overarching goals are to determine its etiology, duration, stability, related symptoms, and therapy. Thus, it is important to inquire about any history of anemia (including family history of anemia), colon cancer, gastrointestinal bleeding, genitourinary bleeding, menorrhagia, chronic infections, inflammatory diseases, nutritional deficiencies, and prior weight reduction procedures (e.g., bariatric surgery). The anesthesiologist should also consider the type of surgical procedure, anticipated blood loss, and comorbid conditions that may either affect oxygen delivery or be affected by decreased oxygen delivery (i.e., pulmonary, renal, hepatic, cerebrovascular, cardiovascular disease). In addition, an accurate determination of the patient’s medications is helpful, especially because anemia has implications for the risk-to-benefit profile of some perioperative medications, such as β-adrenergic blockers.103,104 Patients with anemia or suspected anemia must have a CBC. In general, collaboration with a primary care physician or hematologist is helpful for further evaluation of newly diagnosed anemia. Usual initial studies include peripheral smear and MCV; subsequent studies, such as iron studies (i.e., ferritin, transferrin saturation), vitamin B12, or folate levels, are guided by findings on the smear and the MCV.332 The MCV is high and the vitamin B12 or folate levels are low in macrocytic anemia associated with these deficiencies. Low values in MCV, ferritin (48% in females and >49% in males) and hemoglobin concentration (>160 g/L in females and > 165 g/L in males). Polycythemia can be a primary disorder (i.e., polycythemia vera) or secondary to conditions typically associated with chronic hypoxia (e.g., COPD, high altitude, cyanotic congenital heart disease). A steep increase in blood viscosity occurs once the hematocrit increases to more than 50%, resulting in an increased thrombogenic risk. High hematocrits are associated with increased atherosclerosis (e.g., carotid

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stenosis, stroke) and cardiac disease (e.g., heart failure, myocardial infarction). Reports on whether polycythemia increases perioperative risk are contradictory. For example, a hematocrit more than 51% was associated with increased postoperative mortality in a retrospective cohort study of more than 310,000 patients.102 Conversely, a previous smaller study of 200 patients did not find an increased rate of perioperative complications in individuals with secondary polycythemia.347 The preoperative evaluation should focus on the pulmonary and cardiovascular systems. On physical examination, the anesthesiologist should examine for cyanosis, clubbing, wheezing, murmurs, and oxygen saturation (via pulse oximetry). Useful laboratory tests include an ECG, arterial blood gases, and chest radiograph. An unexpected finding of polycythemia should prompt an investigation for possible causes, which if not readily apparent, should raise the possibility of polycythemia vera. In such cases, elective surgery should be postponed pending a consultation by a hematologist.  Venous Thromboembolic Disorders. VTE is an important potential risk in hospitalized patients, including surgical patients.348 Primary VTE prophylaxis is beyond the scope of this chapter and is covered extensively in specialty society practice guidelines.11,12 Nonetheless, patients should be stratified preoperatively for their risks of perioperative VTE to inform the appropriate selection of prophylactic measures. The expected risk of postoperative VTE depends on both patient-related (e.g., inflammatory bowel disease, acute illness, smoking, malignant disease, obesity, increased age, prior VTE, estrogen use, hypercoagulable state, inherited thrombophilia) and procedure-related (e.g., invasiveness, trauma, immobilization) factors. A reasonable approach for estimating perioperative VTE risk is to use a validated clinical prediction index, a widely used example being the Modified Caprini Risk Assessment Model (Box 31.12).11,349 A Caprini score of zero indicates very low VTE risk (0.5% risk in the absence of thromboprophylaxis), scores of 1 to 2 indicate low VTE risk (1.5% risk in the absence of thromboprophylaxis), scores of 3 to 4 indicate moderate VTE risk (3.0% risk in the absence of thromboprophylaxis), and scores of 5 or more indicate high VTE risk (6.0% risk in the absence of thromboprophylaxis). Some subgroups of patients are at considerably higher risk for perioperative VTE, namely those with very recent VTE (i.e., within prior 3 months) and those with a history of VTE associated with a high-risk inherited thrombophilia.350 For individuals with a very recent VTE episode, elective surgery should be delayed until 3 or more months have elapsed since the episode (during which time they should be anticoagulated).351 Specifically, the risk of recurrent VTE is highest during the first 3 to 4 weeks after the initial episode; this risk then decreases over the next 2 months. Hereditary high-risk thrombophilias include Factor V Leiden, antithrombin III deficiency, protein C deficiency, protein S deficiency, prothrombin gene mutation, and antiphospholipid antibodies. Factor V Leiden and prothrombin gene mutations are the most common causes, together comprising up to 60% of cases.352

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968

SECTION III  •  Anesthesia Management

BOX 31.12  Modified Caprini Risk Assessment Model for Venous Thromboembolism 1 Point Each

2 Points Each

Age 41–60 years Minor surgery BMI > 25 kg/m2 Swollen legs Varicose veins Pregnancy or postpartum History of unexplained or recurrent spontaneous abortion Oral contraceptives or hormone replacement Sepsis (72 h) Immobilizing plaster cast Central venous access

3 Points Each

5 Points Each

Age ≥ 75 years History of VTE Family history of VTE Factor V Leiden mutation Prothrombin 20210A mutation Lupus anticoagulant Anticardiolipin antibodies Elevated serum homocysteine Heparin-induced thrombocytopenia Other congenital or acquired thrombophilia

Stroke (7 drinks per week on average) for all females and males 65 or more years of age. Addictive disease should be considered permanent even in patients who have had long periods of abstinence. Some patients in the process of recovery from addiction may be receiving specific medications to maintain recovery. For example, previous opioid abusers may be receiving methadone (long-acting opioid agonist), buprenorphine (partial μ-agonist), or naltrexone (opioid antagonist). Substance abuse disorders are risk factors for poor outcomes in the perioperative setting. For example, individuals with histories of alcohol misuse experience elevated rates of postoperative complications.72,400-402 In addition, they are at risk for postoperative withdrawal, acute intoxication, and altered tolerance of anesthetic or opioid medications. Consequently, it is worthwhile to incorporate screening for substance abuse disorders into the preoperative evaluation. Several simple validated screening questionnaires for alcohol abuse disorders are available, including the four-item CAGE questionnaire,403 the threeitem AUDIT-C questionnaire,404 and the U.S. National Institute on Alcohol Abuse and Alcoholism 2- and 4-question tests (NIAAA-2Q/4Q).405 These screening tools appear to be more sensitive when administered through a computer-based self-assessment questionnaire than during an in-person interview with a nurse or anesthesiologist.406 The accuracy of these questionnaires can be further augmented with additional screening laboratory tests, namely gamma gluteryl transferase and carbohydrate-deficient

transferrin.6,407 The preoperative evaluation is also an opportunity to obtain a detailed history of known addiction (drug type, routes of administration) and recovery (periods of abstinence, pharmacotherapy for addiction). The dosage of any pharmacotherapy should be documented and verified. Patients in recovery may also have heightened anxiety regarding upcoming surgical procedures because of concerns about relapse into addiction, and inadequate pain treatment (given their history of addiction). Such concerns may be appropriate. Patients receiving opioid substitution therapy do experience normal pain responses to nociceptive stimuli but require additional analgesia for control of postprocedural pain.408 These patients should therefore be reassured that anxiety and pain will be adequately treated. The clinicians performing preoperative evaluation may have prejudicial attitudes and lack the educational background to formulate appropriate perioperative pain management plans. For example, pain medication may be under dosed and inappropriately restricted because of concerns about provoking relapses. Early involvement of the acute pain service and addiction specialists to assist in the management of these at-risk patients may be helpful. The preoperative period should be used to develop appropriate management plans based on the types of abused drugs. All pertinent preoperative information and management plans should be transmitted to members of the perioperative team. Individuals addicted to alcohol, sedatives, or hypnotics may require stabilization with benzodiazepines, whereas heroin addicts may require substitution with methadone. It is important to document the dosage of opioids consumed by individuals abusing these drugs, especially to help guide postoperative pain management. To avoid inadequate analgesia (which could potentially activate addiction) in these patients, the preoperative evaluation should be used to discuss and plan the optimal use of nonopioid analgesics and regional techniques. Patients actively abusing cocaine and amphetamines are at especially high risk during anesthesia because of the potential for intraoperative hemodynamic instability. Urine testing may be helpful to rule out abused substances in such patients, but the results should be interpreted based on drug pharmacokinetics. For example, the half-life of cocaine is about 1.5 hours but its inactive metabolites may still be detectable in the urine for 14 days after consumption.409 A history of intravenous drug use should prompt an evaluation for cardiovascular, pulmonary, neurologic, and infectious complications such as endocarditis, abscesses, osteomyelitis, hepatitis, and HIV infection. Opioid (including heroin) users have a tolerance to narcotics. Patients with alcoholism are at risk for delirium tremens, a potentially life-threatening form of withdrawal characterized by autonomic instability and hyperpyrexia. These patients may also have liver disease (alcoholic hepatitis, cirrhosis, portal hypertension, end-stage liver disease), alcohol-induced cardiomyopathy, arrhythmias, seizures, neuropathies, dementia, WernickeKorsakoff syndrome (ataxia and cognitive dysfunction secondary to thiamine deficiency), macrocytic anemia, and coagulopathies (from hepatic dysfunction or vitamin K deficiency). Cocaine and amphetamine addicts can develop cerebrovascular accidents, cardiomyopathy, and arrhythmias. Additionally, cocaine and amphetamines inhibit the uptake of sympathomimetic neurotransmitters, thereby

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31 • Preoperative Evaluation

increasing risks for hypertension, tachycardia, paranoia, anxiety, seizures, and myocardial ischemia. Long-term use can result in ventricular hypertrophy, myocardial infarction, and nasal septal perforation. Solvents can cause cardiac dysrhythmias, pulmonary edema, cerebral edema, diffuse cortical atrophy, and hepatic failure. Hallucinogens, such as lysergic acid diethylamide, can cause autonomic dysregulation and paranoia. Ecstasy, or more specifically 3,4-methylenedioxymethamphetamine, can cause excessive thirst that results in hyponatremia, pulmonary edema, or cerebral edema. Acute marijuana use can cause tachycardia, vasodilatation, and increased cardiac output. The risk of pulmonary complications in patients who smoke marijuana is similar to that of individuals who smoke tobacco.410 During the preoperative evaluation interview, patients who abuse alcohol or drugs may not give a reliable history. The subsequent physical examination should include careful measurement of vital signs, including temperature. For example, cocaine and amphetamines may cause hypertension and tachycardia, whereas acute opioid use may result in a slow respiratory rate. Acute opioid use may also manifest as lethargy and pinpoint pupils, and recent alcohol consumption can often be detected by smell. Especially in individuals suspected of being intravenous drug abusers, it is important to examine venous access sites for signs of abscesses and infections. In addition, careful auscultation for murmurs is essential because of the risk of bacterial endocarditis. Cocaine or alcohol abusers can also exhibit findings in their cardiovascular examination consistent with heart failure or arrhythmias. Long-term alcohol abuse may manifest with physical findings of chronic liver disease. In addition to identifying the presence of substance abuse and its related complications, clinicians should ascertain whether, and for how long, patients can stop consuming alcohol or addictive drugs. If patients do stop consumption occasionally, it is especially important to determine what complications, if any, occur. When an alcoholic patient reports previously interrupting drinking for several days, the interviewer should inquire whether agitation, seizures, delirium tremens, or other signs of withdrawal developed. Any testing is largely informed by findings on the preoperative clinical evaluation, as well as the specific drug being abused. For example, an ECG may be warranted to assess for previous myocardial infarction in an individual with a history of cocaine abuse or in an individual receiving methadone (which prolongs the QT interval). Ideally, patients with drug or alcohol dependence should be drug free well before elective surgical procedures. The availability of randomized trial data is limited and suggest that preoperative alcohol cessation programs can help prevent postoperative complications.411 Preanesthesia clinic staff should therefore be prepared to refer patients to addiction specialists or to prescribe medications to prevent withdrawal in the preoperative period if patients agree to abstinence. For example, benzodiazepines can be useful in preventing or treating alcohol withdrawal symptoms. Some medications used to manage withdrawal or facilitate recovery have specific perioperative considerations.412 Patients taking methadone should continue maintenance doses in the perioperative period. Patients who are taking disulfiram because of a history of alcohol abuse may

983

have an altered response to sympathomimetic drugs; some authors therefore suggest that disulfiram be discontinued 10 days before the surgical procedure.412 If disulfiram is continued, users can experience flushing, nausea, and tachycardia in response to small amounts of alcohol, such as amounts encountered in skin preparations or medications. For patients taking naltrexone for a history of alcohol abuse, consideration should be given to discontinuing it 3 days preoperatively.412 Naltrexone alters responses to opioid analgesics and may make postoperative pain management very challenging. Buprenorphine-containing medications (i.e., Suboxone), which are used to treat opioid addiction (as well as chronic pain), also alter responses to opioid analgesics. In the case of relatively minor surgery with minimal levels of anticipated postoperative pain, it is reasonable to continue buprenorphine perioperatively and maximize the use of nonopioid analgesic approaches (e.g., regional anesthesia, NSAIDs). In other cases, the perioperative management of buprenorphine should be coordinated with the patient’s addiction specialist. 

BREASTFEEDING PATIENTS There are limited data to help guide recommendations for the safety of anesthetics and medications in babies of breastfeeding mothers who receive these agents. For elective surgery, women should be advised to pump and store milk preoperatively; this milk can be used in the first 24 hours after anesthesia administration, or for the duration of breast milk exposure to potentially harmful agents. The mother should discard milk produced within the first 24 hours after anesthesia, and then generally resume breastfeeding after this period. Very young or premature babies, especially those susceptible to apnea, may be at risk if the mothers continue to take opioid or sedating drugs. Mothers should be advised to discuss the safety of breastfeeding while taking medications with their child’s pediatrician. 

PATIENTS WITH DO NOT RESUSCITATE ORDERS Some patients scheduled for procedures have advance directives or a do-not-resuscitate (DNR) status.413 The ASA adopted guidelines for the care of these patients and updated them in 2013 (Box 31.14).414 Frequently, in circumstances with DNR orders, care providers are focused on a procedure-directed approach (i.e., do not intubate, do not administer resuscitative drugs). This approach is problematic in the perioperative period because much of anesthesia care involves such procedures. Within the context of anesthesia care, a better approach is to discuss DNR status in a goal-directed approach (i.e., from the perspective of the patient’s values and objectives, such as quality-of-life concerns).415 The ideal time to have this emotional and complex discussion is during the preoperative evaluation. Short discussions in the preoperative clinic have been shown to foster dialogue among patients, their proxies, and physicians regarding advance directives concerning end-of-life care, as demonstrated by a randomized trial of patients at a preoperative evaluation clinic.416 In this trial, individuals who received the information session were significantly more likely to complete a durable power-of-attorney (27%

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SECTION III  •  Anesthesia Management

BOX 31.14  Do-Not-Resuscitate Orders in the Perioperative Period Policies automatically suspending DNR orders or other directives that limit treatment before procedures involving anesthetic care may not sufficiently address a patient’s rights to self-determination in a responsible and ethical manner. Such policies, if they exist, should be reviewed and revised, as necessary, to reflect the content of these guidelines. 1. Full Attempt at Resuscitation: The patient or designated surrogate may request the full suspension of existing directives during the anesthetic and immediate postoperative period, thereby consenting to the use of any resuscitation procedures that may be appropriate to treat clinical events that occur during this time. 2. Limited Attempt at Resuscitation Defined With Regard to Specific Procedures: The patient or designated surrogate may elect to continue to refuse certain specific resuscitation procedures (for example, chest compressions, defibrillation or tracheal intubation). The anesthesiologist should inform the patient or designated surrogate about which procedures are (1) essential to the success of the anesthesia and the proposed procedure, and (2) which procedures are not essential and may be refused. 3. Limited Attempt at Resuscitation Defined With Regard to the Patient’s Goals and Values: The patient or designated surrogate may allow the anesthesiologist and surgical team to use clinical judgment in determining which resuscitation procedures are appropriate in the context of the situation and the patient’s stated goals and values. For example, some patients may want full resuscitation procedures to be used to manage adverse clinical events that are believed to be quickly and easily reversible, but to refrain from treatment for conditions that are likely to result in permanent sequelae, such as neurologic impairment or unwanted dependence upon life-sustaining technology. DNR, Do-not-resuscitate. Modified from Committee on Ethics, American Society of Anesthesiologists: Ethical guidelines for the anesthesia care of patients with do-not-resuscitate orders or other directives that limit treatment, 2013. Available at http://www.asahq.org/For-Members/StandardsGuidelines-and-Statements.aspx.

vs. 10%) and discuss end-of-life care with their proxy decision makers (87% vs. 66%). 

Preoperative Laboratory and Diagnostic Studies The value of preoperative diagnostic testing is a central issue in delivering cost-effective health care to surgical patients. The role of preoperative testing to screen for disease and evaluate patients’ fitness for surgery has been extensively studied. This research has largely concluded that routine preoperative testing in all surgical patients (i.e., without consideration for their demographics or comorbidities) cannot be justified. Routine preoperative testing in asymptomatic healthy patients has very poor diagnostic yield, provides little to no additional prognostic information, and has not shown any beneficial effect on outcomes.274,417-420 Unnecessary testing is also expensive, and may lead to costly evaluation of borderline or false-positive test abnormalities. Aside from potentially causing operating room delays or cancellations, these unnecessary follow-up tests

may pose risks to patients that are attributable to followup tests and any associated interventions. Therefore, the targeting of testing in appropriate patients has both clinical and economic benefits. At some hospitals where surgeons and primary care physicians order all preoperative tests, the common practice has been to order tests without any diagnostic focus, other than speculation that the anesthesiologist may “require them” for surgery to proceed without delay or cancellation. Other justifications offered for nonselective ordering of tests include routine screening for disease states, establishment of a diagnostic baseline, personal habit (e.g., “standard” testing checklist for all patients), physician reassurance, and a perceived medicolegal necessity “not to miss anything.” This pattern of practice has led to a plethora of preoperative testing practices that are costly, highly variable across hospitals, and largely unrelated to patients’ perioperative risk profiles.421-423 For example, in 2011, almost half of Medicare beneficiaries (aged ≥ 65 years) in the United States underwent preoperative laboratory testing before cataract surgery, which is considered a very lowrisk procedure.423 Preoperative diagnostic tests should be selectively ordered based on the patient’s medical history, planned surgery, and expected degree of intraoperative blood loss. Testing should be for the detection of specific clinical indications that may increase perioperative risk. Randomized trials have demonstrated that such a shift in strategy from nonselective to selective preoperative testing in low-risk surgical procedures can reduce costs while preserving patients’ safety.418,419 As experts in perioperative medicine, anesthesiologists are in a unique position to appropriately select the preoperative laboratory tests needed to guide perioperative care. Indeed, anesthesiologist-led preoperative evaluation has been shown to result in more selective ordering of laboratory tests than evaluation led by surgeons or primary care physicians.14-17 Thus, by educating and providing specific guidance to surgeons and other physician specialists on the appropriate ordering of preoperative tests, anesthesiologists can expedite patient care, reduce healthcare costs, and improve the delivery of perioperative medicine. A framework for ordering preoperative diagnostic tests based on patients’ medical history is presented in Table 31.18. These disease-specific recommendations are not intended as absolute, especially since many hospitals and regional jurisdictions (e.g., Ontario Pre-Operative Testing Grid)424 have developed their own preoperative testing recommendations. In addition, the NICE in the United Kingdom published updated 2016 guidelines for preoperative testing following an extensive systematic review of the literature.274 The NICE guidelines consider both patients’ preoperative medical status and the extensiveness of the planned surgery to determine when preoperative testing is warranted. In these guidelines, surgical procedures are graded as minor (e.g., skin lesion excision), intermediate (e.g., inguinal hernia repair, varicose vein excision, tonsillectomy, knee arthroscopy), and major (e.g., total abdominal hysterectomy, transurethral prostate resection, lumbar spine discectomy, thyroidectomy, total joint replacement, lung operations, colon resection, radical neck dissection). Although the most recent 2012 ASA “Practice Advisory for Preanesthesia Evaluation” does recommend against routine preoperative testing,5 it does

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TABLE 31.18  Framework for Preoperative Diagnostic Testing Based on Patients’ Medical History Preoperative Diagnosis

ECG

CXR

CBC

Electrolytes

X

±

Creatinine

Glucose

Coagulation

LFTs

Drug Levels

Ca

Cardiac disease IHD

X

HF

X

±

HTN

X

±

Chronic atrial fibrillation

X

PAD

X

Valvular heart disease

X

±

X

±

X*

X X†

Pulmonary disease COPD

X‡

X

Asthma§ Diabetes mellitus

X

±

X

X

Liver disease Infectious hepatitis

X

X

Alcohol/drug induced

X

X

X

X

Tumor infiltration Renal disease

X

Hematologic disorders

X

Coagulopathies

X

X

X

X

CNS Disorders Stroke

X

X

X

X

X

Seizures

X

X

X

X

X

Tumor

X

X

Vascular/aneurysms

X

X

Malignancy

X

Hyperthyroidism

X

X

X

Hypothyroidism

X

X

X

X

Cushing disease

X

X

X

Addison disease

X

X

X

X

X

X

X

X

Hyperparathyroidism

X

Hypoparathyroidism

X

Morbid obesity

X

Malabsorption/poor nutrition

X

±

X X

X

X

X

Select Drug Therapies Digoxin Anticoagulants

X

±

X

X

X

Phenytoin

X

Phenobarbital

X

Diuretics

X

Corticosteroids

X

Chemotherapy

X

X X ±

Aspirin/NSAID Theophylline

X

*If the patient is taking diuretics. †If the patient is taking digoxin. ‡If the patient is taking theophylline. §Only test for consideration is pulmonary function testing if clinically indicated. X, obtain; ±, consider. Ca, Calcium; CBC, complete blood count; HF, heart failure; CXR, chest x-ray; ECG, electrocardiogram; HTN, hypertension; IHD, ischemic heart disease; LFTs, liver function tests; NSAID, nonsteroidal antiinflammatory drug; PAD, peripheral artery disease. Downloaded for alex arman davidson ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on October 21, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.

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not make explicit recommendations about which tests should be ordered for specific clinical conditions. The practice advisory states that the indications for testing should be “based on information obtained from medical records, patient interview, physical examination, and type and invasiveness of the planned procedure.” In addition, it describes patient-related and surgery-related factors that anesthesiologists should consider when deciding whether to order a specific laboratory test.5 Conversely, the updated 2018 ESA guidelines on preoperative evaluation do make some specific recommendations for when preoperative laboratory testing should be performed.6 The following subsections discuss specific preoperative laboratory tests. In general, testing does not have to be repeated during the preoperative evaluation of healthy patients (i.e., ASA-PS class 1 or 2) if similar testing has already been performed within the 2 months preceding surgery and there has been no major interval change in the patient’s medical status (e.g., recent chemotherapy).425

COMPLETE BLOOD COUNT, HEMOGLOBIN, AND HEMATOCRIT The proposed surgery, associated potential blood loss, and individualized patient-level clinical indications should determine the requirement for a preoperative CBC. Typical clinical indications include a history of increased bleeding, hematologic disorders, CKD, chronic liver disease, recent chemotherapy or radiation treatment, corticosteroid therapy, anticoagulant therapy, and poor nutritional status. The NICE guidelines recommend routine CBC testing only in ASA-PS class 3 or 4 patients undergoing intermediate grade procedures, and all patients undergoing major procedures.274 

RENAL FUNCTION TESTING Renal function tests assess renal tubular function and glomerular filtration. Primary clinical indications include diabetes mellitus, hypertension, cardiac disease, potential dehydration (e.g., vomiting, diarrhea), anorexia, bulimia, fluid overload states (e.g., heart rate, ascites), known renal disease, liver disease, relevant recent chemotherapy (e.g., cisplatin, carboplatin), and renal transplantation. The NICE guidelines recommend routine renal function testing in ASA-PS class 3 or 4 patients undergoing intermediate procedures, and ASA-PS class 2, 3, or 4 patients undergoing major procedures.274 If patients are deemed to be at risk for perioperative AKI, testing may also be considered in ASA-PS class 3 or 4 patients undergoing minor procedures, and ASA-PS class 2 patients undergoing intermediate procedures.274 

LIVER FUNCTION TESTING The ordering of liver function tests should be based on a history of liver injury and physical examination findings. Primary clinical indications include a history of hepatitis (viral, alcohol, drug-induced, autoimmune), jaundice,

cirrhosis, portal hypertension, biliary disease, gallbladder disease, hepatotoxic drug exposure, tumor involvement of the liver, and bleeding disorders. 

COAGULATION TESTING Routine preoperative coagulation testing is not indicated (even in patients undergoing regional procedures) unless a known or suspected coagulopathy is identified on preoperative evaluation. Primary clinical indications for testing include a known bleeding disorder, hepatic disease, and anticoagulant use.5 The 2016 NICE guidelines state that coagulation testing should only be considered in patients who are (1) ASA-PS class 3 or 4; (2) undergoing intermediate, major, or complex surgical procedures; and (3) known to take anticoagulant medications or have chronic liver disease.274 

URINALYSIS There is no indication for routine preoperative urinalysis.274 Primary clinical indications include a suspected urinary tract infection and unexplained fever or chills. 

PREGNANCY TEST Pregnancy testing is often determined by hospital-specific protocols. It can also be based on clinical indications such as sexual activity, birth control use, and date of the last menstrual period. Another important factor that should be considered is the potential for the planned surgical procedure harming a fetus, based on direct injury (e.g., uterine surgery), reduction in blood flow (e.g., major cardiac or vascular surgery), and exposure to teratogenic agents (e.g., x-rays). The 2012 ASA “Practice Advisory for Preanesthesia Evaluation” suggests offering pregnancy testing to female patients of childbearing age when the result would alter the patient’s management. It also recommends that informed consent be obtained for such testing, or that there be a full discussion of the risks, benefits, and alternatives related to preoperative pregnancy testing. The NICE guidelines recommend that all women of childbearing potential be asked whether there is any possibility they could be pregnant, and that any women who could possibly be pregnant be made aware of the risks of anesthesia and surgery to a fetus. The guidelines also recommend documenting all discussions about whether or not to carry out pregnancy testing, and to conduct pregnancy testing with patient consent if there is any doubt about pregnancy status.274 

SICKLE CELL TEST Individuals at risk for sickle cell disease include those of African, Caribbean, Eastern Mediterranean, and Middle Eastern origin. Even in at-risk populations, routine preoperative screening for sickle cell disease has a very low yield,426 especially in regions with newborn screening programs for sickle cell disease.427 Consistent with this evidence, 2016 NICE guidelines recommend against routine preoperative testing for sickle cell disease or sickle cell trait.274

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31 • Preoperative Evaluation

A reasonable approach is to consider testing in previously untested patients who have at-risk ethnic backgrounds and clinical indicators. These indicators include patientrelated (e.g., family history of sickle cell disease, sickle cell symptoms) and surgery-related (e.g., deliberate hypothermia, cardiopulmonary bypass, intrathoracic procedures, intraabdominal procedures, orthopedic procedures with tourniquet use) factors. 

ELECTROCARDIOGRAM The ECG can help detect a prior myocardial infarction, cardiac rhythm disturbances, ischemia, chamber hypertrophy, and electrolyte disorders. Nonetheless, when combined with usual clinical examination, the preoperative ECG may not provide additional prognostic information to identify individuals at risk for postoperative cardiac complications.100 Primary clinical indications for preoperative ECGs include a history of IHD, hypertension, diabetes mellitus, heart failure, chest pain, palpitations, abnormal valvular murmurs, peripheral edema, syncope, dizziness, dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, and CVD. The 2014 ESC/ESA guidelines suggest preoperative ECGs in patients with risk factors for IHD or suspicious symptoms, especially if they are undergoing intermediaterisk or high-risk surgery.9 The 2014 ACC/AHA guidelines are fairly consistent in that they support preoperative ECGs for patients who are undergoing intermediate-risk or high-risk surgery, and who have known IHD, significant arrhythmia, PAD, CVD, or other significant structural heart disease.7 The guidelines also recommend against routine preoperative ECGs (see Box 31.2), especially in asymptomatic patients without known cardiovascular disease or risk factors.7 The NICE guidelines recommend routine preoperative ECGs in ASA-PS class 3 or 4 patients undergoing intermediate grade procedures, and ASA-PS class 2, 3, or 4 patients undergoing major procedures.274 If patients have cardiovascular disease, CKD, or diabetes mellitus, testing may also be considered in ASA-PS class 2 patients undergoing intermediate procedures.274 

CHEST RADIOGRAPH Routine preoperative chest radiographs do not provide prognostically important information for assessing perioperative risk.428 Preoperative chest radiographs should therefore not be ordered routinely,274 but rather selectively based on abnormalities identified by preoperative evaluation. These indications include advanced COPD, bullous lung disease, suspected pulmonary edema, suspected pneumonia, suspected mediastinal masses, and suspicious findings on physical examination (e.g., rales, tracheal deviation). 

Preoperative Risk Assessment A critical component of the preanesthesia evaluation is assessment of a patient’s risk for undergoing anesthesia and surgery. This assessment improves patients’ understanding of the inherent perioperative risks and better informs healthcare providers’ clinical decision making.

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TABLE 31.19  American Society of Anesthesiologists Physical Status Classification Category*

Definition

ASA-PS 1

A normal, healthy patient

ASA-PS 2

A patient with mild systemic disease

ASA-PS 3

A patient with severe systemic disease

ASA-PS 4

A patient with severe systemic disease that is a constant threat to life

ASA-PS 5

A moribund patient who is not expected to survive without the operation

ASA-PS 6

A declared brain-dead patient whose organs are being removed for donor purposes

*The addition of “E” to the classification category indicates emergency surgery. ASA-PS, American Society of Anesthesiologists physical status.

For example, these risk assessments might help identify individuals who warrant enhanced levels of postoperative monitoring, consideration for alternative nonoperative or less invasive treatment options for their underlying condition, or initiation of interventions intended to decrease perioperative risk. An anesthesiologist’s designation of a surgical patient as being high-risk is clinically important. Specifically, when the initial preanesthesia evaluation deems that a patient is at unacceptably high risk for anesthesia and surgery, adherence to the anesthesiologist’s recommendations for further perioperative management is associated with lower postoperative complication rates.429 In addition, accurate risk assessments facilitate fairer comparisons of perioperative outcomes; specifically, estimates of patients’ risks are required by statistical methods that adjust for case-mix differences across providers and hospitals. The most commonly used method by anesthesiologists to assess overall perioperative risk is the ASA-PS classification system (Table 31.19). This classification system, which was developed in 1941, was originally intended to facilitate collection and comparison of statistical data in anesthesia.430 The ASA-PS classification system seeks to describe a patient’s preoperative medical status, but it does not consider risks inherent to the planned surgical procedure. Although not intended to guide estimation of patients’ risks for anesthesia and surgery, the ASA-PS is often used for this purpose, especially given its simplicity of use. Indeed, several studies have shown a correlation of ASA-PS scores with postoperative mortality and major complications.97,218,431-433 An important limitation to the classification system is its inherent subjectivity; consequently, previous research has shown only fair to modest interrater agreement when different individuals attempt to assign an ASA-PS category to the same patient.432,434-436 In addition to patients’ preoperative medical status, which is described by the ASA-PS system, the operative procedure is an important determinant of perioperative risk.437-439 Overall perioperative risk is necessarily a function of both the risk associated with the specific operative procedure and the risk associated with a patient’s underlying medical status. For example, ambulatory surgical procedures are very

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SECTION III  •  Anesthesia Management

TABLE 31.20  Johns Hopkins Surgery Risk Classification System Category

Description

1

Minimal risk to the patient independent of anesthesia. Minimally invasive procedure with little or no blood loss. Procedures are often done in an office setting, with the operating room used principally for anesthesia and monitoring.

2

Minimal to moderately invasive procedure, with expected blood loss not exceeding 500 mL. Mild risk to patient independent of anesthesia.

3

Moderately to significantly invasive procedure, with expected blood loss of 500-1500 mL. Moderate risk to patient independent of anesthesia.

4

Highly invasive procedure, with expected blood loss exceeding 1500 mL. Major risk to patient independent of anesthesia.

5

Highly invasive procedure, with expected blood loss exceeding 1500 mL. Critical risk to patient independent of anesthesia. Usually requires postoperative critical care unit stay with invasive monitoring.

From Paternak LR, Johns A. Ambulatory gynaecological surgery: risk and assessment. Best Pract Res Clin Obstet Gynaecol. 2005;19:663–679.

safe with respect to risks of postoperative mortality and major adverse events,440-442 as evidenced by a 7-day postoperative mortality rate of only 41 per 100,000 procedures in a large cohort of Medicare beneficiaries 65 years old or older.440 Thus, although older patients with an increased burden of comorbidity do have increased relative risks of mortality and morbidity following ambulatory surgery, their absolute risks remain very low. Classification schemes have been proposed for assessing operative risk, such as the Johns Hopkins risk classification system (Table 31.20), elevated surgical risk category in the RCRI (see Table 31.5), and the strata employed by the ESA/ESC cardiovascular evaluation guidelines.9,439 Importantly, individual operative procedures within broad categories (e.g., intraabdominal surgery) vary with respect to their perioperative risk.107 As a consequence, there is a need to balance the desire to ensure that clinical prediction tools sufficiently capture the variability in operative risk across different procedures, against the need to ensure that these tools are sufficiently simple for straightforward clinical use. Several commonly used and methodologically sound clinical indices can predict mortality and major morbidity after cardiac surgery with reasonable accuracy, such as the EuroSCORE,443 Society of Thoracic Surgeons risk models,444 and Cleveland Clinic AKI risk score.269 A variety of prediction tools have also been developed for use in noncardiac surgery.445 For example, the ACS NSQIP risk calculator is available on the Internet (http://riskcalculator.f acs.org) and provides an estimate of risk based on patients’ comorbidities and proposed surgical procedures.32 Highquality validated indices have been developed for predicting specific major complications of noncardiac surgery, such as cardiovascular events (e.g., RCRI)97,106 and respiratory complications (e.g., ARISCAT).257,261 Other examples including the Surgical Risk Scale,446 the Preoperative Score to Predict Postoperative Mortality (POSPOM),99 and large

multinational prospective epidemiologic studies of surgical patients (which included accurate capture of perioperative characteristics and outcomes),77,78 will likely help lead to the development of other high-quality predictive indices.

ROLE OF SPECIALIZED TESTING IN PREOPERATIVE RISK ASSESSMENT Based on an initial preoperative clinical evaluation, anesthesiologists may order subsequent specialized tests to help address diagnostic questions (e.g., “Does this patient have aortic stenosis?”) or determine perioperative risk more accurately. Examples of such tests include noninvasive cardiac stress tests (see section on “Ischemic Heart Disease”), coronary angiography (see section on “Ischemic Heart Disease”), echocardiography, CPET, and PFTs (see section on “Pulmonary Disorders”). Resting echocardiography can provide information related to valvular lesions, pulmonary hypertension, fixed wall motion abnormalities, and ventricular function. Especially in cases of a suspicious murmur or other clinical indication, a preoperative echocardiogram can help diagnose prognostically important valvular or other cardiac lesions, such as aortic stenosis or pulmonary hypertension.447,448 An echocardiogram can also identify fixed wall motion abnormalities consistent with a previous myocardial infarction. Although these findings can help support a diagnosis of IHD, fixed wall motion abnormalities are not themselves indicative of increased perioperative cardiac risk.122 Similarly, while systolic ventricular dysfunction identified on echocardiography is associated with increased cardiac risk161,162 this finding may not provide additional prognostic information when it is combined with routine preoperative clinical evaluation.161 Thus, the overall role of echocardiography is to address focused diagnostic questions identified in usual clinical preoperative evaluation (e.g., suspicious systolic murmurs), not to provide important prognostic information pertaining to perioperative risk. Current guidelines therefore largely recommend preoperative echocardiography to assess dyspnea of unknown origin or recent altered clinical status in an individual with known heart failure (see Box 31.3).7 In addition, repeat echocardiography is reasonable in clinically stable patients with known ventricular dysfunction who have not been tested in the previous year.7 Conversely, routine preoperative echocardiography is discouraged.7,8 CPET is a noninvasive global assessment of exercise capacity; it involves a patient exercising on a bicycle or treadmill for 8 to 12 minutes while undergoing continuous measurement of respiratory gas exchange (i.e., oxygen uptake and carbon dioxide production).449 Poor exercise capacity during CPET, based on either a low peak oxygen consumption or a low anaerobic threshold, is associated with increased risks of postoperative morbidity.29,36,450 Thus, the test can help improve the accuracy of preoperative risk stratification. In some geographic settings,451 CPET is a commonly used preoperative test. In these settings, it is used to aid preoperative risk assessment for major surgery, and to inform decisions on the appropriateness of planned major surgical procedures. The role of PFTs for guiding preoperative assessment in the setting of specific comorbidities was discussed earlier in this chapter. These tests have an established and important role for assessing perioperative risk in lung resection surgery

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31 • Preoperative Evaluation

(see section on “Patients Scheduled for Lung Resection” and Chapter 53).219 PFTs also play an important diagnostic role. For example, they help differentiate between pulmonary and cardiac causes of dyspnea of unknown origin. Aside from these specific circumstances, the prognostic value of preoperative PFTs is limited. Practice guidelines from the American College of Physicians recommend against routine preoperative spirometry for estimating risks for pulmonary complications after noncardiothoracic surgery.10 Research has not found a consistent link between poor PFT results and increased risks for perioperative pulmonary complications, with older studies being generally limited by important methodologic flaws.218 Furthermore, there does not seem to be a critical PFT threshold below which patients should not be offered surgery. For example, in a previous cohort study, individuals with severe obstructive findings (i.e., FEV1 < 50% of predicted and FEV1/ FVC ratio < 0.7) had reasonably acceptable risks of postoperative death (5.6%) and respiratory failure (5.6%).452 

Preoperative Medication Management The patient’s comorbidities and planned procedure must inform medication management during the perioperative

989

period. Some medications have beneficial effects during surgical procedures, whereas others may be detrimental. In some cases, abrupt withdrawal of medications can have a negative effect. Management of specific preoperative medications has been discussed in the previous sections of this chapter. These recommendations are outlined again in Box 31.15. Although issues pertaining to many drugs are covered in other sections of this chapter, several issues merit special mention. NSAIDs have reversible antiplatelet effects; hence, once the drugs have been eliminated, platelet function returns to normal. Concomitant NSAID use does not appear to increase the risk of spinal hematoma with neuraxial anesthesia.196 Preoperative discontinuation of NSAIDs may be of value in patients at risk for perioperative AKI. Typically, NSAIDs are discontinued 24 to 72 hours preoperatively. Earlier discontinuation does not increase safety, and it may be burdensome to many patients with significant arthritis or chronic pain. COX-2 inhibitors (e.g., celecoxib) have minimal effect on platelet function and can usually be continued in the perioperative period. However, the longterm COX-2 inhibitor use in the nonoperative setting does increase the risk of cardiac events, in comparison with placebo or naproxen.453 Conversely, COX-2 inhibitors have a cardiac risk profile similar to that of ibuprofen or diclofenac.453 In general, no clear evidence indicates increased

BOX 31.15  Preoperative Management of Medications Instruct patients to take these medications with a small sip of water, even if fasting. 1. Antihypertensive medications Continue on the day of surgery, except for ACEIs and ARBs 2. Cardiac medications (e.g., β-blockers, digoxin) Continue on the day of surgery. 3. Antidepressants, anxiolytics, and other psychiatric medications Continue on the day of surgery. 4. Thyroid medications Continue on the day of surgery. 5. Oral contraceptive pills Continue on the day of surgery. 6. Eye drops Continue on the day of surgery. 7. Heartburn or reflux medications Continue on the day of surgery. 8. Opioid medications Continue on the day of surgery. 9. Anticonvulsant medications Continue on the day of surgery. 10. Asthma medications Continue on the day of surgery. 11. Corticosteroids (oral and inhaled) Continue on the day of surgery. 12. Statins Continue on the day of surgery. 13. Aspirin Continue aspirin in patients with prior percutaneous coronary intervention, high-grade IHD, and significant CVD. Otherwise, discontinue aspirin 3 days before surgery. 14. P2Y12 inhibitors (e.g., clopidogrel, ticagrelor, prasugrel, ticlopidine) Patients having cataract surgery with topical or general anesthesia do not need to stop taking thienopyridines. If reversal of platelet inhibition is necessary, the time interval for discontinuing these medications before surgery is 5–7 days for clopidogrel, 5–7 days for ticagrelor, 7–10 days for prasugrel, and 10

days for ticlopidine. Do not discontinue P2Y12 inhibitors in patients who have drug-eluting stents until they have completed 6 mo of dual antiplatelet therapy, unless patients, surgeons, and cardiologists have discussed the risks of discontinuation. The same applies to patients with bare metal stents until they have completed 1 month of dual antiplatelet therapy. 15. Insulin For all patients, discontinue all short-acting (e.g., regular) insulin on the day of surgery (unless insulin is administered by continuous pump). Patients with type 2 diabetes should take none, or up to one half of their dose of long-acting or combination (e.g., 70/30 preparations) insulin, on the day of surgery. Patients with type 1 diabetes should take a small amount (usually one third) of their usual morning long-acting insulin dose on the day of surgery. Patients with an insulin pump should continue their basal rate only. 16. Topical medications (e.g., creams and ointments) Discontinue on the day of surgery. 17. Non-insulin antidiabetic medications Discontinue on the day of surgery (exception: SGLT2 inhibitors should be discontinued 24 hours before elective surgery) 18. Diuretics Discontinue on the day of surgery (exception: thiazide diuretics taken for hypertension, which should be continued on the day of surgery). 19. Sildenafil (Viagra) or similar drugs Discontinue 24 h before surgery. 20. COX-2 inhibitors Continue on the day of surgery unless the surgeon is concerned about bone healing. 21. Nonsteroidal antiinflammatory drugs Discontinue 48 hours before the day of surgery. 22. Warfarin (Coumadin) Discontinue 5 days before surgery, except for patients having cataract surgery without a bulbar block. 23. Monoamine oxidase inhibitors Continue these medications and adjust the anesthesia plan accordingly.

ACEI, Angiotensin converting enzyme inhibitors; ARB, angiotensin receptor blocker; COX-2, cyclooxygenase-2; CVD, cerebrovascular disease; IHD, ischemic heart disease; P2Y12, adenosine diphosphate receptor; SGLT2, sodium-glucose cotransporter 2 inhibitors. Downloaded for alex arman davidson ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on October 21, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.

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cardiac risk from short-term perioperative administration of COX-2 inhibitors. The exception is valdecoxib (now withdrawn from the market), which caused an excess of cardiac events in patients undergoing cardiac surgery,454 Postmenopausal hormone replacement therapies that contain estrogen increase the risk of thromboembolic events.455 It may therefore be reasonable to discontinue these medications before operations. Estrogens must be stopped approximately 4 weeks preoperatively for coagulation function to return to baseline. Most modern oral contraceptives contain low doses of estrogen. Nonetheless, these medications are still associated with some elevation in thrombotic risk.456 Since the risk of unanticipated pregnancy may outweigh the benefits of discontinuing oral contraceptives preoperatively, it is reasonable to continue oral contraceptives in most patients during the perioperative period. In patients who are deemed to be a high risk for postoperative VTE (see section on “Venous Thromboembolic Disorders”), consideration may be given to stopping oral contraceptives 4 weeks before surgery (and temporarily switching to other forms of contraception). This decision should be made collaboratively with the patient and must balance the risk of VTE versus the risk of unwanted pregnancy. Most medications for psychiatric and psychological problems should be continued into the preoperative period. Thus, most antidepressants, antipsychotics, and benzodiazepines are best maintained to avoid exacerbations of symptoms. Historically, monoamine oxidase inhibitor (MAOI) antidepressants were discontinued preoperatively; however, elimination of the risks associated with many of these drugs required drug discontinuation at least 3 weeks before surgery. This long withdrawal period is specifically applied to MAOIs that cause irreversible inhibition of MAO. Some newer agents, such as moclobemide, cause reversible enzyme inhibition and have effects lasting less than 24 hours. Preoperative withdrawal of these drugs has potential risks. Specifically, case reports of suicides or severe depression following discontinuation of MAOIs have been reported. Thus, the safest approach may be to continue these drugs and adjust the anesthetic plan accordingly (e.g., avoid meperidine and indirect-acting vasopressors such as ephedrine). If this approach is taken, it is critical that details of a patient’s MAOI use must be clearly communicated to healthcare providers on the day of surgery. Patients receiving tricyclic antidepressants require a preoperative ECG, given the potential for a prolonged QT interval. Because tricyclic antidepressants block the reuptake of norepinephrine and serotonin, high doses may also result in augmented responses to vasopressor drugs, with the potential for exaggerated hemodynamic changes. Patients taking lithium require evaluation of electrolyte and creatinine concentrations. Discontinuation of lithium has also been associated with suicide. Continued perioperative use of selective serotonin reuptake inhibitors (SSRIs) are associated with increased surgical bleeding,457,458 whereas abrupt discontinuation of SSRIs can also cause dizziness, chills, muscle aches, and anxiety. Overall, it is still reasonable to continue SSRI perioperatively in most patients, aside from those undergoing procedures where bleeding could have significant postoperative sequalae (e.g., intracranial surgery). Complementary and alternative medications may interact with anesthetic drugs, alter effects of prescription

medications, and increase bleeding. In addition, many patients do not consider these drugs “medications,” and may not list them among their medications unless specifically asked. The perioperative management of complementary and alternative medications is discussed in further detail in Chapter 33. 

Planning for Anesthesia PREOPERATIVE FASTING STATUS The overarching goal of preoperative fasting recommendations has been to reduce the risk of pulmonary aspiration. The ASA published practice guidelines pertaining to preoperative fasting in nonlaboring individuals undergoing elective procedures.459 The recommended fasting period following clear fluids for all patients is 2 hours. In general, the volume of liquid ingested is less important than the type of liquid ingested. For neonates and infants, the recommended fasting period is 4 hours following breast milk, and 6 hours following formula, non-human milk, and solids. For patients other than infants, a fasting period of 6 hours after a light meal is recommended; this period may have to be increased to 8 or more hours if the meal includes fried or fatty foods. In addition to implementing these fasting intervals, the guidelines recommend that the preoperative evaluation include assessment of the potential for difficult airway management, as well as factors that may increase the risk for aspiration (e.g., gastrointestinal motility disorders, diabetes). 

PLANNING FOR POSTOPERATIVE PAIN MANAGEMENT A preoperative evaluation should always include baseline pain assessment. Standardization of pain measurement is difficult because of the subjective nature of the variable. It is therefore helpful to incorporate standardized pain measurement scales into the preoperative evaluation process. The scales may either be single-dimension scales, such as visual analog and numeric rating scales, or multidimensional scales such as the McGill pain questionnaire,460 and Modified Brief Pain Inventory—Short Form.461 Although multidimensional scales are longer, they capture a broader range of important details. For example, the 9-item Modified Brief Pain Inventory—Short Form captures details on the pain intensity, pain location, adequacy of analgesic treatment, and pain-related interference in activities. Consistent use of the same scale during the perioperative episode of care allows comparison when reassessments are performed after surgery. The preoperative evaluation provides an important opportunity to discuss and plan for the management of acute postoperative pain, for several reasons. First, adequacy of perioperative pain control is a frequent concern for patients during preoperative evaluation.462,463 Second, intensive preoperative pain instructions may help improve postoperative pain control in surgical patients.464 Third, preoperative anesthesia consultation is associated with improved patient acceptance of perioperative regional techniques,19 which can help improve the quality of postoperative analgesia.465 Fourth, preoperative evaluation

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facilitates planning the perioperative care of patients with chronic pain conditions, who often present significant challenges with respect to managing postoperative analgesia. Specific issues include their tolerance to usual doses of opioid analgesics and the potential for acute withdrawal reactions if they receive insufficient doses of opioids postoperatively. The preoperative consultation should therefore be used to carefully document their usual baseline opioid requirements (to ensure adequate postoperative dosing), facilitate early involvement of an acute pain service or transitional pain specialist,466 encourage regional analgesic techniques, and plan adjunct analgesic medications (e.g., NSAIDs, gabapentin, pregabalin, clonidine). Patients with preexisting chronic pain should be encouraged to develop reasonable goals for adequacy of postoperative pain control. They should be informed that although care providers will do everything possible to maintain comfort postoperatively, patients should not expect to have no pain at all. In general, patients should not be weaned from pain medications before surgery. If instructed by their surgeons to temporarily discontinue NSAIDs or COX-2 analgesics, they may have to be transitioned to alternative analgesics before surgery. Patients should be instructed to take their usual morning dose of pain medication, including continued use of any transdermal medications. 

Regulatory Issues Providers must be aware of various governmental regulatory requirements, which often differ by individual municipalities and countries. These requirements may be driven by quality regulations, such as those developed by The Joint Commission or by payment requirements as set by the Centers for Medicare and Medicaid Services (CMS) in the United States. For example, the CMS has determined that a comprehensive anesthesia evaluation can be done within 30 days, and a focused update is required within 48 hours of a procedure requiring anesthesia services. The evaluation should be performed by a practitioner qualified to provide anesthesia. At a minimum, the preanesthesia evaluation must include the following:    □  Notation of anesthesia risk (e.g., ASA-PS classification) □  Review of the medical, anesthesia, drug, and allergy history □  Interview and examination of the patient □  Potential anesthesia problems (e.g., difficult airway, limited intravascular access) □  Additional evaluation, if deemed necessary (e.g., stress tests, specialist consultation) □  Development of a plan for anesthesia, including the type of medications for induction, maintenance, and postoperative care □  Discussion of the risks and benefits of anesthesia with the patient or the patient’s representative 

Preoperative Evaluation Clinic Many anesthesiology groups and medical centers have developed preoperative evaluation programs and outpatient

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clinics, with the objectives of improving patient care and operating room efficiency.14,22,467 Although these programs may differ with respect to staffing, structure, financial support, and daily operations, they all share a common goal of preventing delays, last-minute cancellations, and adverse patient outcomes that could have been addressed before the day of surgery. The decision to develop a preoperative evaluation clinic depends on several key factors. They include the anticipated daily volume of surgical patients, the predominant level of medical acuity among these patients, the availability of clinic facilities, relevant patient demographics (e.g., average travel distances from patients’ homes to the clinic), and requisite support from the anesthesia department, perioperative staff, and hospital administration. If the decision to implement a preoperative evaluation program is made, anesthesiologists must play a key role in its leadership and management. When this role is instead undertaken by other specialties, such as internal medicine, anesthesiologists’ expertise in perioperative patient management often becomes secondary. This shift to a secondary role can result in interdepartmental conflicts concerning patients’ preoperative evaluation, risk stratification, and fitness to proceed with anesthesia and surgery. These conflicts can, in turn, result in unplanned delays or cancellations of planned surgical procedures, despite the completion of an assessment in an outpatient preoperative evaluation clinic. Such conflicts often relate to surgeons’ interpretation of a nonanesthesia specialist’s judgment that a patient is “cleared for surgery” as evidence that the patient is fit for anesthesia. Unfortunately, this “clearance” is frequently made with limited knowledge of factors critical to the responsible anesthesiologist in the operating room, such as current anesthesia practice and intraoperative patient management. Indeed, previous research has shown that preoperative histories, physical examinations, and assessments performed by medical specialists often fail to address specific anesthesia-related concerns.468 As the specialist who makes the final determination of whether a patient is fit to proceed with anesthesia and surgery, the responsible anesthesiologist is a critical “end-user” of any assessment performed in a preoperative evaluation clinic. Consequently, a reliance on nonanesthesia specialists can result in preoperative assessments that are deemed inadequate by the responsible anesthesia providers and that lead to potential last-minute surgical delays and cancellations, with associated significant frustration among both patients and surgeons. Conversely, preoperative-to-intraoperative communication is likely significantly improved when anesthesiologists are responsible for most outpatient preanesthesia evaluations, as confirmed by previous studies showing fewer last-minute case cancellations,14,20,22,469 shorter durations of hospitalization,22,469,470 lower hospital costs,469 and possibly reduced postoperative mortality,471 with institution of anesthesia-led preoperative evaluation programs. Awareness of the local hospital context is critical if a preoperative evaluation program is to have good outcomes. In a hospital with limited resources that has mostly healthy outpatient and same-day-admission surgical patients, the anesthesia group may be unable to evaluate all patients preoperatively in a clinic before the day of surgery. In this situation, the preoperative program must develop a means

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for accurate screening and triage of patients based on their current health status. An accurate triage process helps target the use of preoperative clinic visits only among selected higher-risk patients without compromising patients’ quality of care and outcomes.24 An example of such a triage process may involve having patients initially complete an anesthesia screening questionnaire in their surgeons’ office. This questionnaire can be a Web-based online document or even a paper version that would then be faxed to the anesthesia group before the date of surgery. The anesthesia group can develop local context-specific screening questionnaires, or adopt published instruments developed for this purpose.472,473 In the case of a patient with a questionable medical history, a telephone call by the anesthesiologist could clarify any issues of concern. This opportunity to review a patient’s medical history before the day of surgery helps reduce unresolved or unexpected medical concerns on the day of surgery. It also helps determine whether a patient requires formal preoperative consultation in advance of the surgical procedure, as opposed to evaluation on the day of surgery itself. Conversely, anesthesia departments at hospitals with many medically complex surgical patients may benefit from the establishment of a formal preoperative evaluation facility with multiple examination rooms, dedicated staffing, and a full-time operational system. The establishment of a successful preoperative evaluation clinic requires commitment, collaboration, and support from several hospital disciplines.14 At a minimum, the departments of anesthesia, surgery, nursing, and hospital administration must agree that such a clinic has value for the hospital, and they must commit to support its operational goals.

COLLABORATION, COMMITMENT, AND TEAMWORK The preoperative evaluation clinic is a partnership among the departments of anesthesia, surgery, nursing, and hospital administration to achieve common goals. This collaboration conveys the important theme that the new clinical program is an integrated enterprise that requires shared obligation, endeavor, and financial responsibility. Although these clinics are best led by anesthesiologists,14,20,22,469 collaborative engagement with medical specialists (e.g., cardiologists, geriatricians) and hospitalists remains important to the success of any preoperative program. These nonanesthesia specialties provide unique expertise in the preoperative management of selected medically complex patients; furthermore, they can facilitate enhanced postoperative monitoring of high-risk patients through, for example, the comanagement model of postoperative care (see section on “Role of the Medical Consultant in Preoperative Evaluation”). Surgeons may be initially reluctant to send their patients to a newly established anesthesia-led preoperative evaluation clinic. This reluctance often stems from an unclear understanding of the benefits of outpatient preoperative anesthesia evaluation. Consequently, the surgeons’ hesitation can be reduced by clearly identifying the specific advantages of an integrated anesthesia-led preoperative evaluation program. First, the proven benefits of anesthesiology-led preoperative evaluation should be highlighted.14,20,22,469-471

Second, anesthesiologists should emphasize the important practical advantages of an integrated assessment of medically complex surgical patients. Specifically, when relevant medical concerns are identified before the surgical procedure, the preoperative program can acquire all relevant prior medical data, coordinate any additional workup or consultation, prearrange any required specialized postoperative monitoring, and discuss the case beforehand with the surgeon and responsible anesthesiologist. This approach ensures that when such a patient presents for the operation, the responsible anesthesia provider is satisfied to proceed with the surgical procedure, and the perioperative team has all required medical information to manage the patient optimally during the hospitalization. This integration of the preoperative evaluation with the entire perioperative episode of care is an integral component of the Perioperative Surgical Home model.1 Third, informal assurances should be made to the surgical services that, if a patient is managed by the preoperative evaluation program, surgery will proceed without cancellation or delay by the assigned anesthesiologist unless an intervening illness or adverse medical event occurs between the outpatient evaluation and the scheduled operation. Because cancellations and delays on the day of surgery can be a prominent source of aggravation for surgeons and patients, these informal assurances would be viewed as a key strength of the newly developed preoperative program. Such assurances depend heavily on the anesthesia department’s addressing relevant clinical practice variations. Specifically, issues that are subject to important interpractitioner differences, such as what fasting blood glucose level or degree of preoperative hypertension would merit cancelling a surgical case, must be discussed to achieve a departmental consensus standard. The absence of consensus standards can lead to situations in which half the anesthesia providers may proceed with a higher-risk surgical case, whereas the other half would cancel it instead. Wide inconsistency in practice will foster a lack of support among surgeons and will lead to reluctance to have their patients evaluated. Such a preoperative evaluation program is unlikely to be successful. 

ROLE OF THE MEDICAL CONSULTANT IN PREOPERATIVE EVALUATION Use of preoperative medical consultation varies across hospitals, likely depending on the expertise in perioperative medicine among the clinicians performing preanesthesia assessments. Since exposure to preoperative evaluation is inadequate at many anesthesia residency programs,474 some anesthesia departments may prefer that medical specialists take primary responsibility for preoperative evaluations at their centers. Conversely, when anesthesiologists involved with preoperative evaluation develop improved comfort with interpreting ECGs, cardiac stress tests, or other specialized tests, rates of medical consultations can be substantially reduced.17 Medical consultants have a clear role in the preoperative care of selected surgical patients. For example, these consultations can help manage unstable medical conditions (e.g., unstable angina), optimize poorly controlled medical diseases (e.g., asthma exacerbation), or facilitate clinically

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31 • Preoperative Evaluation

indicated diagnostic workups (e.g., coronary angiography following high-risk cardiac stress test results). Preoperative consultation by medical specialists or hospitalists can also help facilitate postoperative comanagement by these same individuals.475 The comanagement model for postoperative care of surgical patients is increasingly common,476 although its benefits with respect to clinical outcomes and healthcare costs remain uncertain.477-482 Multidisciplinary collaboration with medical consultants can be especially helpful for perioperative management of complex or uncommon medical disorders. Indeed, some clinical practice guidelines recommend such multidisciplinary team management for patients with known cardiac disease undergoing high-risk noncardiac surgery,9 as well as patients with significant pulmonary hypertension or adult congenital heart disease undergoing noncardiac surgery.7 Despite these theoretical benefits, preoperative medical consultation has shown a variable effect on postoperative outcomes. A randomized trial of outpatient preoperative evaluation demonstrated fewer last-minute surgical cancellations but no difference in hospital length of stay, as well as an increase in consultations.483 In other nonrandomized studies, medical consultation was associated with increases in specialized testing, costs, hospital length of stay, and mortality.484,485 Conversely, a transition from an anesthesiologist-led to a hospitalist-led preoperative assessment clinic was associated with reduced hospital length of stay in high-risk patients,486 while preoperative geriatric consultation was associated with improved postoperative 90-day outcomes (i.e., survival, hospital length of stay, need for supported discharge, hospital readmission) in elderly patients (≥65 years) undergoing major elective noncardiac surgery.487 Potential reasons for this variable effect may be the absence of recommendations or new interventions resulting from many medical consultations,488,489 as well as disagreements among medical specialists, anesthesiologists, and surgeons on the intended purpose of these consultations.468 In addition, increased burden of comorbidity is a very small determinant of whether patients are referred for preoperative medical consultations,490-492 a finding suggesting poor patient selection during referral to medical specialists. Thus, during preoperative evaluation, the anesthesiologist should ensure that any referrals to medical specialists before surgery involve appropriate matching of patient profiles to specialist expertise. For example, patients with high-risk IHD should be referred to a cardiologist, while frail elderly patients should be referred to a geriatrician. 

STRUCTURES AND ACTIVITIES OF THE PREOPERATIVE EVALUATION CLINIC The daily operations of a preoperative evaluation clinic vary based on the patient volume, the general level of medical complexity among surgical patients, the type of available clinic facilities, and staffing resources. Nonetheless, a general operational structure can be proposed based on examination of several preoperative clinic models currently in practice. Centers with large surgical case volumes should have their patients formally scheduled in the clinic before the day of evaluation, to allow for medical records and relevant

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outside information to be acquired and collated. The surgeon’s office should schedule this clinic appointment at the same time that it books the operating room case. To ensure timely patient access and flow through the facility, these appointments should be booked using an efficient clinic scheduling system. Ideally, appointments should be scheduled to allow sufficient time between the clinic visit and the scheduled surgical procedure, to facilitate any additional preoperative testing, consultations, or interventions. Some degree of flexibility in the clinic schedule is also needed, especially to accommodate patients who have urgent indications for surgery. One approach for incorporating some flexibility is to include a few open appointment slots in the daily clinic schedule that can be used as needed for last-minute patient referrals. Such flexibility is required for individuals residing in rural and remote areas, who have been reported to have reduced rates of access to preoperative evaluation clinic facilities.493 Anesthesiologists at some centers have also adopted telemedicine technology (defined as healthcare delivery and sharing of medical knowledge over a distance using telecommunications systems)494 so that patients residing at remote locations can undergo preanesthesia consultations without traveling long distances to the clinic.495 At the clinic, a clinician interviews and examines the patient, obtains historical medical information and outside records, and determines whether (and which) additional laboratory tests, ECGs, radiographs, or other diagnostic tests are required. Phlebotomy, ECG, and hospital admitting and insurance registration services are typically available in the preoperative clinic facility. The ECGs are assessed during the clinic visit itself, whereas laboratory test results are evaluated at the end of each clinic day, with follow-up of abnormal findings as needed. In this manner, significant abnormalities can be addressed immediately; thus, any required delays or cancellations of surgical cases can occur well in advance of the scheduled day of surgery. This centralization of multiple services is also a significant convenience for patients, who no longer have to visit multiple hospital locations to complete their preoperative requirements. This arrangement should also centralize all medical data relevant to the scheduled hospital admission into a single chart, which remains in the preoperative evaluation clinic area until the date of surgery. In addition to addressing medical aspects relevant to the scheduled surgery, the preoperative evaluation program plays an important role in educating surgical patients. Typically, both the clinician performing the preoperative assessment and a specifically trained nurse educator discuss the forthcoming perioperative process with each patient and family members. By increasing patients’ awareness of important components pertaining to their scheduled hospital admission (e.g., analgesic options, risks of anesthesia), this education process can decrease patients’ anxiety,18 as well as increase their willingness to receive regional analgesia.19 The types of clinicians who perform the preanesthesia assessment include anesthesiologists and specially trained nurse practitioners. Some authors have questioned whether the responsible anesthesiologist in the operating room would be satisfied with preanesthesia assessments performed by another individual.496 Patients themselves often report a preference for having the same anesthesiologist in both the preoperative

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clinic and the operating room.497 Nonetheless, it is simply not feasible for all patients in the preoperative clinic to be evaluated by their eventual anesthesia providers. Furthermore, a large Dutch cohort study of about 21,000 surgical patients demonstrated that responsible anesthesia providers were satisfied with 95% of outpatient preanesthesia assessments performed by other anesthesiologists or trained nurses.498 Preoperative programs must adopt several strategies to ensure that anesthesia providers in the operating room will be satisfied with the quality of outpatient preoperative assessments. First, the anesthesia department must develop consensus standards for determining when patients should have scheduled surgery cancelled for medical reasons. Second, the documentation required for all preanesthesia assessments in the clinic should be standardized. This standardization helps prevent situations in which an assessment does not contain information needed by the anesthesia provider in the operating room to determine a patient’s fitness for surgery or to develop an anesthetic management plan. Some national anesthesiology groups have initiated work on consensus-based documentation standards for all preanesthesia assessments.23 Strategies for improving the consistency of documentation across preanesthesia assessments include the use of checklists, as well as structured electronic or paper-based forms for documenting preanesthesia assessments. Third, all nurse practitioners or other nonanesthesia clinicians assessing patients in the clinic should undergo an intensive and ongoing education in preoperative assessment. Anesthesiologists with strong interest and expertise in preoperative evaluation should lead this education program. Previous research has shown that well-trained nurses do perform effectively in both screening and evaluating patients in preoperative clinics.499-501 

IMPACT ON OPERATING ROOM EFFICIENCY AND OUTCOMES Anesthesia-led preoperative assessment clinics have had positive impact on operating room efficiency and outcomes (see the earlier section “Goals and Benefits of Preanesthesia Evaluation”). The demonstrated benefits of these clinics include fewer case cancellations on the day of surgery,14,20,22,469 shorter duration of hospitalization,22,469,470 and a possible reduction in postoperative mortality.471 Other mechanisms whereby preoperative evaluation clinics reduce healthcare costs include more selective ordering of preoperative laboratory tests and specialist referrals.14,16,17 Thus, although preoperative evaluation programs do incur costs (e.g., facility development costs, staff salaries), they can still lead to an overall reduction in hospital costs as a result of these associated cost savings.469 

should be considered. They include being assessed by the same anesthesiologist who will administer anesthesia in the operating room, shorter wait times in the clinic, and good quality of communication from the clinic staff.497,502,503 Because it is simply not feasible to have all patients in the clinic seen by their eventual anesthesia providers, the major focus should be on improving wait times and the quality of communication. Changes in appointment booking systems,504 process flows, and clinic operations can decrease wait times,499 which in turn can substantially improve patients’ satisfaction.499 In addition, preoperative programs can ensure that patients receive an accurate estimate of average waiting times before their scheduled clinic visit, and use any encountered wait times to conduct other clinic-related activities (e.g., physical therapy instructions, video-based preoperative education). 

Conclusion The practice of anesthesiology has changed. The expanding role of the anesthesiologist outside the operating room will redefine the specialty’s contribution to high-quality patient care in the healthcare system. Within the context of preoperative evaluation, anesthesiologists must be knowledgeable and adept at assessing patients of highly varying medical complexity, whether in an outpatient preoperative evaluation clinic before the day of the surgical procedure or at the bedside immediately before induction of anesthesia. Anesthesiologists must be familiar with the impact of a broad range of chronic and acute medical conditions on patients’ risks for anesthesia and surgery. In addition, this role entails awareness of multiple practice guidelines, regulatory requirements, and approaches for efficient management of outpatient clinics. Despite this evolving and expanding role of anesthesiologists in preoperative care, the primary purpose of preoperative evaluation will never change. It is the clinical foundation for guiding perioperative patient management, and it has the potential to reduce perioperative morbidity and enhance patient outcome.

Acknowledgment The editors, publisher, and Dr. Duminda Wijeysundera would like to thank Dr. Bobbie-Jean Sweitzer for her contribution to this chapter in the prior edition of this work. It has served as the foundation for the current chapter. Complete references available online at expertconsult.com.

References

PATIENT SATISFACTION WITH PREOPERATIVE EVALUATION CLINICS In addition to addressing perioperative efficiencies and clinical outcomes, preoperative programs should also consider the experience and satisfaction of patients attending their clinics. During development of strategies to improve patient satisfaction, the underlying determinants of improved satisfaction















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469. Pollard JB, et al. Anesth Analg. 1997;85(6):1307–1311. 470.  Wijeysundera DN, et al. Cochrane Database Syst Rev. 2009;(4): CD004126. 471. Blitz JD, et al. Anesthesiology. 2016;125(2):280–294. 472. Hilditch WG, et al. Anaesthesia. 2003;58(9):874–877. 473. Vetter TR, et al. Anesth Analg. 2016;123(6):1453–1457. 474. Tsen LC, et al. Anesthesiology. 2000;93:1134. 475. Salerno SM, et al. Arch Intern Med. 2007;167:271. 476. Sharma G, et al. Arch Intern Med. 2010;170:363. 477. Grigoryan KV, et al. J Orthop Trauma. 2014;28(3):e49–55. 478. Auerbach AD, et al. Arch Intern Med. 2004;170:2010. 479. Huddleston JM, et al. Ann Intern Med. 2004;141:28. 480. Kammerlander C, et  al. Osteoporos Int. 2010;21(suppl 4):S637– S646. 481. Rohatgi N, et al. Ann Surg. 2016;264(2):275–282. 482. Batsis JA, et al. J Hosp Med. 2007;2(4):219–225. 483. Macpherson DS, Lofgren RP. Med Care. 1994;32:498. 484. Wijeysundera DN, et al. Arch Intern Med. 2010;170:1365. 485. Auerbach AD, et al. Arch Intern Med. 2007;167:2338. 486. Vazirani S, et al. J Hosp Med. 2012;7:697–701. 487. McIsaac DI, et al. J Am Geriatr Soc. 2017;65(12):2665–2672. 488. Katz RI, et al. Can J Anesth. 2005;52:697. 489. Groot MW, et al. Neth Heart J. 2017;25(11):629–633. 490. Wijeysundera DN, et al. Anesthesiology. 2012;116:25. 491. Thilen SR, et al. JAMA Intern Med. 2014;174(3):380–388. 492. Thilen SR, et al. Anesthesiology. 2013;118(5):1028–1037. 493. Seidel JE, et al. BMC Health Serv Res. 2006;6:13. 494. Strode SW, et al. JAMA. 1999;281:1066. 495. Wong DT, et al. Anesthesiology. 2004;100:1605. 496. Down MP, et al. Can J Anesth. 1998;45:802. 497. Soltner C, et al. Br J Anaesth. 2011;106:680. 498. van Klei WA, et al. Br J Anaesth. 2010;105:620. 499. Harnett MJ, et al. Anesthesiology. 2010;112:66. 500. Vaghadia H, Fowler C. Can J Anesth. 1999;46:1117. 501. van Klei WA, et al. Anaesthesia. 2004;59:971. 502. Edward GM, et al. Br J Anaesth. 2008;100:322. 503. Hepner DL, et al. Anesth Analg. 2004;98:1099. 504. Dexter F. Anesth Analg. 1999;89:925.

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998.e12 References 472. Hilditch WG, Asbury AJ, Jack E, McGrane S. Validation of a preanaesthetic screening questionnaire. Anaesthesia. 2003;58(9):874– 877. 473. Vetter TR, Boudreaux AM, Ponce BA, Barman J, Crump SJ. Development of a preoperative patient clearance and consultation screening questionnaire. Anesth Analg. 2016;123(6):1453–1457. 474. Tsen LC, Segal S, Pothier M, Bader AM. Survey of residency training in preoperative evaluation. Anesthesiology. 2000;93(4):1134– 1137. 475. Salerno SM, Hurst FP, Halvorson S, Mercado DL. Principles of effective consultation: an update for the 21st-century consultant. Arch Intern Med. 2007;167(3):271–275. 476. Sharma G, Kuo YF, Freeman J, Zhang DD, Goodwin JS. Comanagement of hospitalized surgical patients by medicine physicians in the United States. Arch Intern Med. 2010;170(4):363–368. 477. Grigoryan KV, Javedan H, Rudolph JL. Orthogeriatric care models and outcomes in hip fracture patients: a systematic review and metaanalysis. J Orthop Trauma. 2014;28(3):e49–55. 478. Auerbach AD, Wachter RM, Cheng HQ, et al. Comanagement of surgical patients between neurosurgeons and hospitalists. Arch Intern Med. 2010;170(22):2004–2010. 479. Huddleston JM, Long KH, Naessens JM, et al. Medical and surgical comanagement after elective hip and knee arthroplasty: a randomized, controlled trial. Ann Intern Med. 2004;141(1):28–38. 480. Kammerlander C, Roth T, Friedman SM, et  al. Ortho-geriatric service--a literature review comparing different models. Osteoporos Int. 2010;21(suppl 4):S637–S646. 481. Rohatgi N, Loftus P, Grujic O, Cullen M, Hopkins J, Ahuja N. Surgical comanagement by hospitalists improves patient outcomes: a propensity score analysis. Ann Surg. 2016;264(2):275–282. 482. Batsis JA, Phy MP, Melton LJ, et al. Effects of a hospitalist care model on mortality of elderly patients with hip fractures. J Hosp Med. 2007;2(4):219–225. 483. Macpherson DS, Lofgren RP. Outpatient internal medicine preoperative evaluation: a randomized clinical trial. Med Care. 1994;32(5):498–507. 484. Wijeysundera DN, Austin PC, Beattie WS, Hux JE, Laupacis A. Outcomes and processes of care related to preoperative medical consultation. Arch Intern Med. 2010;170(15):1365–1374. 485. Auerbach AD, Rasic MA, Sehgal N, Ide B, Stone B, Maselli J. Opportunity missed: medical consultation, resource use, and quality of care of patients undergoing major surgery. Arch Intern Med. 2007;167(21):2338–2344. 486. Vazirani S, Lankarani-Fard A, Liang LJ, Stelzner M, Asch SM. Perioperative processes and outcomes after implementation of a hospitalist-run preoperative clinic. J Hosp Med. 2012;7(9):697–701. 487. McIsaac DI, Huang A, Wong CA, Wijeysundera DN, Bryson GL, van Walraven C. Effect of preoperative geriatric evaluation on outcomes after elective surgery: a population-based study. J Am Geriatr Soc. 2017;65(12):2665–2672. 488. Katz RI, Cimino L, Vitkun SA. Preoperative medical consultations: impact on perioperative management and surgical outcome. Can J Anaesth. 2005;52(7):697–702.

489. Groot MW, Spronk A, Hoeks SE, Stolker RJ, van Lier F. The preoperative cardiology consultation: indications and risk modification. Neth Heart J. 2017;25(11):629–633. 490. Wijeysundera DN, Austin PC, Beattie WS, Hux JE, Laupacis A. Variation in the practice of preoperative medical consultation for major elective noncardiac surgery: a population-based study. Anesthesiology. 2012;116(1):25–34. 491. Thilen SR, Treggiari MM, Lange JM, Lowy E, Weaver EM, Wijeysundera DN. Preoperative consultations for medicare patients undergoing cataract surgery. JAMA Intern Med. 2014;174(3):380–388. 492. Thilen SR, Bryson CL, Reid RJ, Wijeysundera DN, Weaver EM, Treggiari MM. Patterns of preoperative consultation and surgical specialty in an integrated healthcare system. Anesthesiology. 2013;118(5):1028–1037. 493. Seidel JE, Beck CA, Pocobelli G, et al. Location of residence associated with the likelihood of patient visit to the preoperative assessment clinic. BMC Health Serv Res. 2006;6:13. 494. Strode SW, Gustke S, Allen A. Technical and clinical progress in telemedicine. JAMA. 1999;281(12):1066–1068. 495. Wong DT, Kamming D, Salenieks ME, Go K, Kohm C, Chung F. Preadmission anesthesia consultation using telemedicine technology: a pilot study. Anesthesiology. 2004;100(6):1605–1607. 496. Down MP, Wong DT, McGuire GP. The anaesthesia consult clinic: does it matter which anaesthetist sees the patient? Can J Anaesth. 1998;45(8):802–808. 497. Soltner C, Giquello JA, Monrigal-Martin C, Beydon L. Continuous care and empathic anaesthesiologist attitude in the preoperative period: impact on patient anxiety and satisfaction. Br J Anaesth. 2011;106(5):680–686. 498. van Klei WA, Peelen LM, Kruijswijk JE, van Wolfswinkel L. Feedback system to estimate the quality of outpatient preoperative evaluation records: an analysis of end-user satisfaction. Br J Anaesth. 2010;105(5):620–626. 499. Harnett MJ, Correll DJ, Hurwitz S, Bader AM, Hepner DL. Improving efficiency and patient satisfaction in a tertiary teaching hospital preoperative clinic. Anesthesiology. 2010;112(1):66–72. 500. Vaghadia H, Fowler C. Can nurses screen all outpatients? Performance of a nurse based model. Can J Anaesth. 1999;46(12):1117– 1121. 501. van Klei WA, Hennis PJ, Moen J, Kalkman CJ, Moons KG. The accuracy of trained nurses in pre-operative health assessment: results of the OPEN study. Anaesthesia. 2004;59(10):971–978. 502. Edward GM, de Haes JC, Oort FJ, Lemaire LC, Hollmann MW, Preckel B. Setting priorities for improving the preoperative assessment clinic: the patients’ and the professionals’ perspective. Br J Anaesth. 2008;100(3):322–326. 503. Hepner DL, Bader AM, Hurwitz S, Gustafson M, Tsen LC. Patient satisfaction with preoperative assessment in a preoperative assessment testing clinic. Anesth Analg. 2004;98(4):1099–1105; table of contents. 504. Dexter F. Design of appointment systems for preanesthesia evaluation clinics to minimize patient waiting times: a review of computer simulation and patient survey studies. Anesth Analg. 1999;89(4):925–931.

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32

Anesthetic Implications of Concurrent Diseases JESSE KIEFER, MONTY MYTHEN, MICHAEL F. ROIZEN, and LEE A. FLEISHER

KEY POINTS

◼ ◼ ◼

◼ ◼

◼

◼ ◼ ◼

◼ ◼

◼ ◼ ◼

T he history and physical examination most accurately predict the risks of anesthesia and the likelihood of required changes in monitoring or therapy. For diabetic patients, end-organ dysfunction and the degree of glucose control in the perioperative and periprocedural periods are the critical issues with regard to risk. The keys to managing blood glucose levels in diabetic patients perioperatively are to set clear goals and then monitor blood glucose levels frequently enough to adjust therapy to achieve these goals. Obesity is associated with multiple comorbid conditions, including diabetes, hyperlipidemia, and cholelithiasis, but the primary concern is derangements of the cardiopulmonary system. Obstructive sleep apnea is important to recognize because of the increased sensitivity to and the consequence of the depressing effects of hypnotics and opioids on airway muscle tone and respiration, as well as the difficulty with laryngoscopy and mask ventilation. Although no controlled, randomized prospective clinical studies have been performed to evaluate the use of adrenergic receptor blocking drugs in patients undergoing resection of pheochromocytoma, the preoperative use of such drugs is generally recommended. For patients with hypertension, the routine administration of all drugs preoperatively is recommended, except angiotensin-converting enzyme inhibitors and angiotensin II antagonists. Evaluation of a patient with cardiovascular disease depends on clinical risk factors, the extent of surgery, and exercise tolerance. In patients with pulmonary disease, the following should be assessed: dyspnea, coughing and the production of sputum, recent respiratory infection, hemoptysis, wheezing, previous pulmonary complications, smoking history, and physical findings. In patients with pulmonary disease, several strategies have been suggested, including cessation of smoking 8 weeks or more preoperatively. Risk factors for perioperative renal dysfunction include advanced age, congestive heart failure, previous myocardial revascularization, diabetes, and increased baseline blood creatinine concentration. One of the primary objectives for a patient with renal disease is ensuring that the renal dysfunction is not augmented and thereby increasing the chance for renal failure, coma, and death. Mild perioperative anemia may be clinically significant only in patients with ischemic heart disease. Careful management of long-term drug administration should include questions about the effects and side effects of alternative as well as prescription drugs.

This chapter reviews many conditions requiring special preoperative and preprocedure evaluation, intraoperative or intraprocedure management, or postprocedure care. Patients undergoing surgical procedures move through a continuum of medical care to which a primary care physician, an internist or pediatrician, an anesthesiologist, and a surgeon, gastroenterologist, radiologist, or obstetrician-gynecologist contribute to ensure the best outcome possible. It may also involve comanagement with a hospitalist. No aspect of medical care requires greater cooperation among physicians than does performance of a surgical operation or a complex procedure involving multiple specialists and the perioperative care of a patient. Moreover, nowhere else can counseling make so huge a difference

in so many lives. The preoperative evaluation also represents a time when education on tobacco cessation, physical inactivity, brain health, and poor food choices can be discussed. The importance of integrating physicians’ expertise is even greater within the context of the increasing life-span of our population. As the number of older adults and very old adults (those >85 years old) grows, so does the need of surgical patients for preoperative consultation to help plan for comorbidity, frailty, and multiple drug regimens, the knowledge of which is crucial to successful patient management. At a time when medical information is encyclopedic, it is difficult, if not impossible, for even the most conscientious anesthesiologist to keep abreast of the medical issues relevant to every aspect of perioperative 999

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SECTION III  •  Anesthesia Management

or periprocedure patient management. This chapter reviews such issues with primary emphasis on the anesthesiologist providing preoperative evaluation and care, rather than transferring these responsibilities to other providers. As with “healthy” patients, the history and physical examination most accurately predict not only the associated risks but also the likelihood of whether a monitoring technique, change in therapy, or “prehabilitation” will be beneficial or necessary for survival. This chapter emphasizes instances in which specific information should be sought in history taking, physical examination, or laboratory evaluation. Although controlled studies designed to confirm that optimizing a patient’s preoperative or preprocedure physical condition would result in a less frequent rate of morbidity have not been performed for most diseases, it is logical to assume that such is the case. That such preventive measures would cost less than treating the morbidity that would otherwise occur is an important consideration in a cost-conscious environment. Minimally invasive procedures such as cataract extraction, magnetic resonance imaging (MRI), or diagnostic arthroscopy, performed in conjunction with the best current anesthetic practices, may pose no greater risk than daily living and thus may not be considered an opportunity for special evaluation. Nevertheless, the preoperative evaluation may identify conditions that could change perioperative management and that may improve both throughput of surgery and the speed of recovery. Examples include the following: ensuring the administration of long-term medications such as a β-adrenergic blocking drug, aspirin for patients with coronary stents, or a statin (or any combination); administering a histamine type 2 (H2) antagonist 1 to 2 hours before entry into the operating room; ensuring the availability of equipment to measure blood glucose levels; obtaining a history of the patient’s diabetic course and treatment from the primary care physician, as well as from the patient; and performing a fiberoptic laryngoscopic examination or procuring additional skilled attention. The following conditions are discussed in this chapter:   

1. Diseases involving the endocrine system and disorders of nutrition (discussed first because of its increasing importance to care) 2. Diseases involving the cardiovascular system 3. Disorders of the respiratory and immune system 4. Diseases of the central nervous system (CNS), neuromuscular diseases, and mental disorders 5. Diseases involving the kidney, infectious diseases, and disorders of electrolytes 6. Diseases involving the gastrointestinal (GI) tract or the liver 7. Diseases involving hematopoiesis and various forms of cancer 8. Diseases of aging or those that occur more commonly in older adults, as well as chronic and acute medical conditions requiring drug therapy

Role of the Primary Care Physician or Consultant The roles of the primary care physician or consultant are not to select and suggest anesthetic or surgical methods but

BOX 32.1  Guidelines for Consultation Practice □ □ □ □ □ □ □

 omplete a prompt, thorough, generalist-oriented evaluation. C Respond specifically to the question or questions posed. Indicate clearly the perioperative importance of any observations and recommendations outside the area of initial concern. Provide focused, detailed, and precise diagnostic and therapeutic guidance. Emphasize verbal communication with the anesthesiologist and surgeon, particularly to resolve complex issues. Avoid chart notations that unnecessarily create or exacerbate regulatory or medicolegal risk. Use frequent follow-up visits in difficult cases to monitor clinical status and compliance with recommendations.

From American College of Physicians. Medical consultation. Medical Knowledge Self-Assessment Program IX. Part C. Book 4. Philadelphia: American College of Physicians; 1992: 939.

rather to optimize the patient’s preoperative and preprocedure status regarding conditions that increase the morbidity and mortality associated with surgery and to alert the anesthesia care team about these conditions. Within the context of shared decision making, the primary care physician may also be involved in the decision to proceed with surgery. Quotations and a box in a Medical Knowledge SelfAssessment Program published by the leading organization representing internists, the American College of Physicians, highlight this role for the consultant1: Effective interaction with colleagues in other specialties requires a thorough grounding in the language and science of these other disciplines as well as an awareness of basic guidelines for consultation [Box 32.1]. The consulting internists’ role in perioperative care is focused on the elucidation of medical factors that may increase the risks of anesthesia and surgery. Selecting the anesthetic technique for a given patient, procedure, surgeon, and anesthetist is highly individualized and remains the responsibility of the anesthesiologist rather than the internist. Optimizing a patient’s preoperative and preprocedure condition and, in settings with a preoperative clinic, counseling a patient about needed future lifestyle changes such as exercise, food choices, and tobacco cessation are cooperative ventures between the anesthesiologist and the internist, pediatrician, surgeon, or family physician. If available, the primary care physician should affirm that the patient is in the very best physical state attainable (for that patient), or the anesthesiologist and primary care physician should do what is necessary to optimize that condition. Although not yet definitively proven, prehabilitation prior to surgery has been advocated by many groups. Primary care physicians can prepare and treat a patient to provide optimal conditions for daily life. The preoperative clinic should collaborate with the primary care physician to start the process of preparing the patient for the needs of surgery or complex procedures. Although such education is more readily available and of better quality than in previous decades, and although cardiologic organizations have provided considerable data on the importance of this aspect of care,2-4 the primary care physician’s training, knowledge,

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32 • Anesthetic Implications of Concurrent Diseases

and ability may not include an in-depth understanding of the perioperative evaluation. Without understanding the physiologic changes that occur perioperatively, appropriate therapy is difficult to prescribe. It is therefore part of the anesthesiologist’s job to guide the patient’s consultants about the type of information needed from the preoperative and preprocedure consultation. 

Diseases Involving the Endocrine System and Disorders of Nutrition PANCREATIC DISORDERS Preoperative and Preprocedure Diabetes Mellitus Diabetes mellitus is a heterogeneous group of disorders that have the common feature of a relative or absolute insulin deficiency. The disease is characterized by a multitude of hormone-induced metabolic abnormalities, diffuse microvascular lesions, and long-term end organ complications. The diagnosis of diabetes is made with a fasting blood glucose level greater than 110 mg/dL (6.1 mmol/L), and impaired glucose tolerance is diagnosed if the fasting glucose level is less than 110 mg/dL (6.1 mmol/L) but greater than 100 mg/ dL (5.5 mmol/L). Diabetes can be divided into two very different diseases that share the same long-term end-organ complications. Type 1 diabetes is associated with autoimmune diseases and has a concordance rate of 40% to 50% (i.e., if one of a pair of monozygotic twins had diabetes, the likelihood that the other twin would have diabetes is 40%-50%). In type 1 diabetes, the patient is insulin deficient, principally from autoimmune destruction of the pancreatic β cells, and susceptible to ketoacidosis if insulin is withheld. Type 2 diabetes has a concordance rate approaching 80% (i.e., genetic material is both necessary and sufficient for the development of type 2 diabetes).4a How markedly the aging and end-organ effects of these genes are expressed is based on lifestyle choices of food and physical activity. These patients are not susceptible to the development of ketoacidosis in the absence of insulin, and they have peripheral insulin resistance through multiple defects with insulin action and secretion. Patients with non–insulin-dependent (type 2) diabetes account for the majority (>90%) of the diabetic patients in Europe and North America. These individuals tend to be overweight, relatively resistant to ketoacidosis, and susceptible to the development of a hyperglycemic-hyperosmolar nonketotic state. Plasma insulin levels are normal or increased in type 2 diabetes but are relatively low for the level of blood glucose. This hyperinsulinemia by itself is postulated to cause accelerated cardiovascular disease. Gestational diabetes develops in more than 3% of all pregnancies and increases the risk of developing type 2 diabetes by 17% to 63% within 15 years. Type 1 and type 2 diabetes differ in other ways as well. Contrary to long-standing belief, a patient’s age does not allow a firm distinction between type 1 and type 2 diabetes; type 1 diabetes can develop in an older person, and clearly, type 2 diabetes can develop in overweight children. Type 1 diabetes is associated with a 15% prevalence of other autoimmune diseases, including Graves disease, Hashimoto thyroiditis, Addison disease, and myasthenia gravis. Over the next decade, the prevalence of diabetes is expected to increase by 50%. This growth is primarily the

1001

result of the increase in type 2 diabetes caused by excessive weight gain in adults and now also in the pediatric population. Large clinical studies show that long-term, strict control of blood glucose levels and arterial blood pressure, along with regular physical activity, results in a major delay in microvascular complications and perhaps indefinite postponement of type 2 diabetes in patients.5,6 The common administered drugs can be classified into eight major groups: acarbose, biguanides (e.g., metformin), dipeptidyl peptidase-4 inhibitors (e.g., sitagliptin, saxagliptin, vildagliptin), glucagon-like peptide-1 receptor agonists (e.g., albiglutide, dulagutide, or exenatide), meglitinide (e.g., repaglinide or nateglinide), sodium-glucose transport protein 2 inhibitors (e.g., canagliflozin or empagliflozin), sulfonylureas (e.g., glibenclamide, glipizide, glimepiride, gliquidone), and thiazolidinediones (e.g., pioglitazone or rosiglitazone).6a Patients with insulin-dependent diabetes tend to be younger, nonobese, and susceptible to the development of ketoacidosis. Plasma insulin levels are low or un-measurable, and therapy requires insulin replacement. Patients with insulin-dependent diabetes experience an increase in their insulin requirements in the post-midnight hours, which may result in early morning hyperglycemia (dawn phenomenon). This accelerated glucose production and impaired glucose use reflect nocturnal surges in secretion of growth hormone (GH). Physiologically normal patients and diabetic patients taking insulin have steady-state levels of insulin in their blood. Absorption of insulin is highly variable and depends on the type and species of insulin, the site of administration, and subcutaneous blood flow. Nevertheless, attainment of a steady state depends on periodic administration of the preparations received by the patient. Thus it seems logical to continue the insulin combination perioperatively that the patient had been receiving after assessing previous blood glucose control.6b The major risk factors for diabetic patients undergoing surgery are the end-organ diseases associated with diabetes: cardiovascular dysfunction, renal insufficiency, joint collagen tissue abnormalities (limitation in neck extension, poor wound healing), inadequate granulocyte production, neuropathies, and infectious complications.7-15 Thus a major focus of the anesthesiologist should be the preoperative and preprocedure evaluation and treatment of these diseases to ensure optimal preoperative and preprocedure conditions. Poor preoperative glucose control, as measured by the hemoglobin A1C (glycosylated hemoglobin) level, is an independent predictor of worse perioperative outcome.16-18 

Glucotoxicity Long-term tight control of blood glucose has been motivated by concern for three potential glucotoxicities, in addition to the results from major randomized outcome studies involving diabetic patients.5-13   

1. Glucose itself may be toxic because high levels can promote nonenzymatic glycosylation reactions that lead to the formation of abnormal proteins. These proteins may weaken endothelial junctions and decrease elastance, which is responsible for the stiff joint syndrome (and difficult intubation secondary to fixation of the atlantooccipital joint), as well as decrease wound-healing tensile strength.

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SECTION III  •  Anesthesia Management

2. Glycemia also disrupts autoregulation. Glucose-induced vasodilation prevents target organs from protecting against increases in systemic blood pressure. A glycosylated hemoglobin level of 8.1% is the threshold at which the risk for microalbuminuria increases logarithmically. A person with type 1 diabetes who has microalbuminuria of greater than 29 mg/day has an 80% chance of experiencing renal insufficiency. The threshold for glycemic toxicity differs for various vascular beds. For example, the threshold for retinopathy is a glycosylated hemoglobin value of 8.5% to 9.0% (12.5 mmol/L or 225 mg/dL), and that for cardiovascular disease is an average blood glucose value of 5.4 mmol/L (96 mg/dL). Thus different degrees of hyperglycemia may be required before different vascular beds are damaged. Another view is that perhaps severe hyperglycemia and microalbuminuria are simply concomitant effects of a common underlying cause. For instance, diabetic patients in whom microalbuminuria develops are more resistant to insulin, insulin resistance is associated with microalbuminuria in first-degree relatives of patients with type 2 diabetes, and persons who are normoglycemic but subsequently have clinical diabetes are at risk for atherogenesis before the onset of disease.   

Diabetes itself may not be as important to perioperative outcome as are its end-organ effects. Epidemiologic studies segregated the effects of diabetes itself on the organ system from the effects of the complications of diabetes (e.g., cardiac, nervous system, renal, and vascular disease) and the effects of old age and the accelerated aging that diabetes causes. Even in patients requiring intensive care unit (ICU) management, long-standing diabetes does not appear to be as important an issue as the end-organ dysfunction that exists and the degree of glucose control in the perioperative or periprocedure and ICU periods.6b,8-13 The World Health Organization’s surgical safety checklist bundle suggests control with a target perioperative blood glucose concentration of 6 to 10 mmol/L (acceptable range, 4-12 mmol/L) or 100 to 180 mg/dL.19 Poor perioperative glycemic control has a significant impact on the risk of postoperative infection across a variety of surgical specialities.20 Different regimens permit almost any degree of perioperative control of blood glucose levels, but the tighter the control desired, the greater the risk of hypoglycemia. Therefore, debate regarding optimal control during the perioperative period has been extensive. Tight control retards all these glucotoxicities and may have other benefits in retarding the severity of diabetes itself.5-13,21 Management of intraoperative glucose may be influenced by specific situations, such as the following: the type of operation, pregnancy,22 expected global CNS insult, the bias of the patient’s primary care physician, or the type of diabetes. Much of the research on perioperative control is derived from studies in the ICU, as opposed to the operating room. The first major trial demonstrating the benefit of tight glucose control was in medical ICU patients in Leuven, Belgium.23 The most recent trial was from the NICE-SUGAR (Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation) group.24 In this randomized controlled trial, the investigators examined the associations between moderate and severe hypoglycemia

(blood glucose, 41-70 mg/dL [2.3-3.9 mmol/L] and ≤40 mg/dL [2.2 mmol/L], respectively) and death among 6026 critically ill patients in ICUs. Intensive glucose control leads to moderate and severe hypoglycemia, both of which are associated with an increased risk of death. The association exhibits a dose-response relationship and is strongest for death from distributive shock. The optimal perioperative management has been reviewed elsewhere.25 Guidelines have been developed on the use of insulin infusions in the critical care unit to achieve these goals (Table 32.1).26 

Diabetes and Accelerated Physiologic Aging Adverse perioperative outcomes have repeatedly and substantially correlated with the age of the patient,2,3,27-30 and diabetes does cause physiologic aging. When one translates the results of the Diabetes Control and Complications Trials into age-induced physiologic changes, a patient with type 1 diabetes who has poor control of blood glucose ages approximately 1.75 years physiologically for every chronologic year of the disease and 1.25 years if blood glucose has been controlled tightly.27-29 A patient with type 2 diabetes ages approximately 1.5 years for every chronologic year of the disease and approximately 1.06 years with tight control of blood glucose and blood pressure.6,27-29,31 Thus when providing care for a diabetic patient, one must consider the associated risks to be those of a person who is much older physiologically; the physiologic age of a diabetic patient is considerably older than that person’s calendar age just by virtue of having the disease.1 Obesity and lack of physical exercise seem to be major contributors to the increasing prevalence of type 2 diabetes. As with type 1 diabetes, tight control of blood glucose, increased physical activity, and reduction in weight appear to reduce the accelerated aging associated with type 2 diabetes, and possibly delay the appearance of the disease and aging from it substantially.27-29,31 Although such a reduction in aging should reduce the perioperative risk for diabetic patients, no controlled trials have confirmed this theory. The key to managing blood glucose levels perioperatively in diabetic patients is to set clear goals and then monitor blood glucose levels frequently enough to adjust therapy to achieve these goals.31a  Other Conditions Associated With Diabetes Diabetes is associated with microangiopathy (in retinal and renal vessels), peripheral neuropathy, autonomic dysfunction, and infection. Diabetic patients are often treated with angiotensin-converting enzyme (ACE) inhibitors, even in the absence of gross hypertension, in an effort to prevent the effects of disordered autoregulation, including renal failure.5,6,32 Preoperatively, assessment and optimization of treatment of the potential and potent end-organ effects of diabetes are at least as important as assessment of the diabetic patient’s current overall metabolic status. The preoperative evaluation of diabetic patients is also discussed in Chapter 31. The presence of autonomic neuropathy likely makes the operative period more hazardous and the postoperative period crucial to survival. Evidence of autonomic neuropathy may be routinely sought before the surgical procedure. Patients with diabetic autonomic neuropathy are at increased risk for gastroparesis (and consequent aspiration

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32 • Anesthetic Implications of Concurrent Diseases

1003

TABLE 32.1  Recommended Glucose Target Ranges for Intensive Care Patients and Related Subgroups

Society, Guideline

Patient Group

Trigger Blood Glucose Value to Start Insulin Infusion (mM [mg/dL])

Society of Critical Care Medicine’s ­clinical practice guideline26

General recommendation

8.3 (150)

Cardiac surgical patients

American Diabetes Association guidelines446

American Association of Clinical Endocrinologists447

Target range, (mM [mg/dL]) 5.6-8.3 (100-150) 20 μg/kg) opioid technique is used. The hemodynamic effects of fentanyl at a dose of 25 μg/kg with pancuronium given to infants in the postoperative period after operative repair of a congenital heart defect include no change in LAP, pulmonary artery pressure, PVR, and cardiac index and a small decrease in SVR and mean arterial pressure.90 Because of its cardiovascular effects, pancuronium was an ideal neuromuscular blocking drug for pediatric heart surgery, but it is no longer available for clinical use. Therefore, either vecuronium or rocuronium are most often used. Larger doses of fentanyl at 50 to 75 μg/kg with rocuronium or vecuronium compared to doses of fentanyl at 50 to 75 μg/kg with pancuronium result in a slightly larger decrease in arterial blood pressure and heart rate in infants undergoing repair for complex congenital heart defects.91 Despite the wide safety margin exhibited by this opioid, a selected population of infants and children with marginally compensated hemodynamic function sustained by endogenous catecholamines may manifest more extreme cardiovascular changes with these doses. Fentanyl also has been shown to block stimulus-induced pulmonary vasoconstriction and contributes to the stability of the pulmonary circulation in neonates after congenital diaphragmatic hernia repair.92 Thus, the use of fentanyl may be

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78 • Anesthesia for Pediatric Cardiac Surgery

TABLE 78.7  Sufentanil Pharmacokinetics in Pediatric Cardiovascular Patients Age Group

t½ α (min)

1-30 days

23 ± 17

t½ β (min)

Clearance (mL/kg/min) Vdss (L/kg)

737 ± 346

6.7 ± 6.1

4.2 ± 1.0

1-24 months 16 ± 5

214 ± 41

18.1 ± 2.7

3.1 ± 1.0

2-12 years

20 ± 6

140 ± 30

16.9 ± 2.2

2.7 ± 0.5

12-18 years

20 ± 6

209 ± 23

13.1 ± 0.4

2.7 ± 0.5

All values are mean ± standard deviations (see Forbess et al.386). t½ α, Slow distribution half-life; t½ β, elimination half-life; Vdss, volume of distribution at steady state. 20 Sufentanil clearance (mL/kg/min)

extrapolated to the operating room, where stabilizing pulmonary vascular responsiveness in newborns and young infants with reactive pulmonary vascular beds is crucial to weaning from CPB and stabilizing shunt flow. Fentanyl in the 8 to 12 μg/kg dose range should provide sufficient analgesia, but still allow adequate ventilation efforts to allow for intraoperative extubation with stable hemodynamics during the procedure. Children receiving sufentanil for induction of anesthesia as a single dose of 5 to 20 μg/kg have a stable preintubation period.93,94 Intubation and other stimuli such as sternotomy do not produce clinically significant alterations in hemodynamics, although changes are more than with equipotent doses of fentanyl. The use of fentanyl as an infusion (1-2 μg/kg/h) produces fewer alterations in heart rate and blood pressure. This is particularly important in infants, in whom significant hemodynamic changes are poorly tolerated. For neonates with critical CHD, sufentanil anesthetic and postoperative infusion reduce morbidity after cardiac surgery when compared with a halothane anesthetic and routine morphine postoperatively.95 The blunting of the stress response observed in this study probably accounted for the differences in morbidity; no comparison group representing a more typical dose of a phenylpiperidine opioid (e.g., fentanyl, 0-75 μg/kg) was included to permit conclusions as to whether such large opioid doses are optimal. In contrast to other opioids, remifentanil, an ultra– short-acting opioid, offers the unique advantage of metabolism by nonspecific and tissue esterases, thereby limiting the potential for accumulation related to protracted elimination.96 Remifentanil may provide advantages in the selected group of patients for whom the blunting of endogenous responses is desirable intraoperatively but potentially deleterious at the end of the procedure. A randomized controlled trial comparing equipotent doses of alfentanil and remifentanil for outpatient pediatric surgery revealed delayed emergence, requiring naloxone only in the alfentanil group.97 In both adults and children, remifentanil is associated with qualitative hemodynamic changes similar to those with other opioids, a variable tendency to bradycardia, and a small decrease in arterial blood pressure.98-101 Because of the widespread use of the opioids for pediatric cardiac surgery and the availability of invasive monitoring, the pharmacokinetics and pharmacodynamics of these drugs have been well studied.93,99 In general, the clinical pharmacology of fentanyl and sufentanil share the same age-related pharmacokinetic and pharmacodynamic features. For example, sufentanil has an increased clearance in patients 1 month to 12 years of age, comparable to adult clearance in adolescents (12-16 years of age), and a decreased clearance during the neonatal period (newborn to 1 month of age) (Table 78.7).84,88 Furthermore, sequential sufentanil anesthetics in neonates with CHD show marked increases in clearance and elimination between the first week and the third or fourth week of life (Fig. 78.8).101 The latter observation is most likely attributable to maturational changes in hepatic microsomal activity and improved hepatic blood flow from closure of the ductus venosus. The variability in clearance and elimination, coupled with limited cardiovascular reserve in the neonate during the first month of life, makes opioid dosing difficult in this age group.

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10

Patient 1 Patient 2 Patient 3

0 0

10 20 Age in days

30

Fig. 78.8  Sequential sufentanil clearance during the first month of life in three neonates with congenital heart disease.  Clearance of sufentanil increases above adult rates within the neonatal period. (Data from Greeley WJ, de Bruijn NP. Changes in sufentanil pharmacokinetics within the neonatal period. Anesth Analg. 1988;67:86–90.)

Careful titration of fentanyl 5 to 10 μg/kg or sufentanil 1 to 2 μg/kg or a continuous infusion technique provides the most reliable method of achieving hemodynamic stability and an accurate dose response. CPB, different institutional anesthetic practices, and individual patient differences influence pharmacokinetic and pharmacodynamic disposition of the opioids in ways that are not predictable. Even certain disease states such as TOF or pathophysiologic conditions such as increased intraabdominal pressure alter pharmacokinetic processes.90,91 Intraoperative use of methadone is an alternative pain control strategy introduced as an answer to counter acute tolerance to fentanyl infusions in the postoperative period. Adult data suggest that intraoperative use of methadone as the primary opioid in CPB cases significantly reduced the use of other opioids in the postoperative period, improved pain scores, and enhanced patient-perceived quality of pain management.102 There is no pharmacokinetic data in children having CPB surgery, but available data show that the pharmacokinetic parameters in children and neonates are similar to those reported in adults, and that there is no clearance maturation with age.103 For non-CPB cases, a dose of 0.2 mg/kg is suggested; we have used total doses of 0.3 to 0.4 mg/kg in CPB cases and extubated intraoperatively. Other strategies to address opioid tolerance include alternating opioid drugs, instituting opioid holidays, the addition of benzodiazepines on an as-needed basis, and the use of dexmedetomidine infusions.

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SECTION V  •  Pediatric Anesthesia

Dexmedetomidine is an α2-agonist approved by the U.S. Food and Drug Administration for sedation in adults. It has been used in pediatric anesthesia as part of a balanced technique preoperatively and intraoperatively for sedation, anxiolysis, and analgesia, and postoperatively for prevention of emergence delirium and sedation.104 Dexmedetomidine has significant analgesic and antiinflammatory effects, attenuates the neuroendocrine response to surgery, and has no neurotoxic effects; it is a crucial adjunct to a balanced anesthetic as it reduces the need for other analgesics and hypnotics.105-107 The pharmacodynamic effects of dexmedetomidine when used as an infusion are generally well tolerated.108 The clinical effects are predictable and usually insignificant with slight lowering of both heart rate and arterial blood pressure compared to baseline.109 However, when administered as a rapid bolus, the first physiologic effect noted is hypertension along with heart rate slowing, lasting approximately 2 to 5 minutes before arterial blood pressure decreases.110 Dexmedetomidine demonstrates cardiac conduction effects, via both direct depression of the sinus and AV nodes in the heart, and decreased sympathetic tone in the locus coeruleus.111 Clinically, this translates into a significant reduction of the incidence of junctional ectopic tachycardia post-CPB.112 However, some studies and case reports, mostly in the adult literature, have documented clinically significant bradycardia, hypotension, and even asystole with its use. It is necessary to remain vigilant and titrate dexmedetomidine carefully. Dexmedetomidine should be used with particular caution in children at risk for bradycardia or sinus or AV node dysfunction, and possibly in patients who have had a heart transplant.113 At our institution, dexmedetomidine is used in almost every case, with an infusion of 0.2 μg/ kg/h in neonates and 0.5 μg/kg/h in all other cases initiated postinduction. The infusion is continued throughout the surgery and into the postoperative period. This practice is particularly helpful in patients that are extubated intraoperatively and we will often increase the dose to 1 to 2 μg/kg/h after extubation to keep the child calm for transport to the ICU. 

TABLE 78.8  Differences Between Adult and Pediatric Cardiopulmonary Bypass Parameter

Adult

Pediatric

Hypothermic temperature

Rarely below 25°C -30°C

Commonly 15°C -20°C

Use of total circulatory arrest

Rare

Common

25%-33%

150%-300%

Pump prime   Dilution effects on blood volume   Additional additives in pediatric primes

Blood, albumin

Perfusion pressures

50-80 mm Hg

Influence of α-stat versus pH-stat management strategy

Minimal at moderate Marked at deep hypothermia hypothermia

Measured Paco2 differences

30-45 mm Hg

Glucose regulation  Hypoglycemia  Hyperglycemia

20-50 mm Hg

20-80 mm Hg

Rare—requires Common—reduced significant hepatic hepatic glycogen injury stores Frequent—generally Less common— easily controlled rebound hypoglywith insulin cemia may occur

DIFFERENCES BETWEEN ADULT AND PEDIATRIC CARDIOPULMONARY BYPASS

supplementation, cannula placement, presence of aortopulmonary collaterals, and patient age affect organ function during CPB. Adult patients are infrequently exposed to such biologic extremes; temperature is rarely lowered below 25°C, hemodilution is more moderate, perfusion pressure is generally maintained at 50 to 80 mm Hg, flow rates are maintained at 50 to 65 mL/kg/min, and pH management strategy is less consequential because of moderate hypothermic temperatures and rare use of circulatory arrest. Variables such as glucose supplementation rarely pose a problem in adult patients owing to large hepatic glycogen stores. Venous and arterial cannulas are less deforming of the atria and aorta, and their placement is more predictable. Although superficially similar, the conduct of CPB in children is considerably different from that in adults. Marked physiologic differences in the response to CPB in children can occur. Additionally, several modifiable intraoperative factors can influence neuropsychologic morbidity (Box 78.3).

The physiologic effects of CPB on neonates, infants, and children are significantly different from the effects on adults (Table 78.8). During CPB, pediatric patients are exposed to biologic extremes not seen in adults, including deep hypothermia (18°C), hemodilution (threefold to fivefold greater dilution of circulating blood volume), low perfusion pressures (20-30 mm Hg), wide variation in pump flow rates (ranging from total circulatory arrest to 200 mL/kg/min), and differing blood pH management techniques (α-stat, pH-stat, or both sequentially). These parameters deviate far from normal physiology and affect preservation of normal organ function during and after CPB. In addition to these prominent changes, subtle variations in glucose

Volume of Priming Solutions The priming solutions used in pediatric CPB take on great importance because of the disproportionately large priming volume–to–blood volume ratio in children. In adults, the priming volume is equivalent to 25% to 33% of the patient’s blood volume, whereas in neonates and infants the priming volume may exceed the patient’s blood volume by 200%. With contemporary low-volume bypass circuits (e.g., small volume oxygenators, smaller tubing), priming volume is not more than one blood volume in a small neonate. Care must be taken, therefore, to achieve a physiologically balanced priming solution and limit the volume as much as

Cardiopulmonary Bypass

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78 • Anesthesia for Pediatric Cardiac Surgery

BOX 78.3  Central Nervous System Injury and Potential Modifiable Intraoperative Factors Air or particulate embolus Rate and depth of core cooling (if used) Deep hypothermic circulatory arrest (if used) Reperfusion injury and inflammation Rate of core rewarming/hyperthermia Hyperglycemia Hyperoxia pH management during cardiopulmonary bypass Hematocrit management during cardiopulmonary bypass

possible. Most pediatric priming solutions, however, have quite variable levels of electrolytes, calcium, glucose, and lactate. Electrolytes, glucose, and lactate levels may be quite high if the solution includes large amounts of banked blood or quite low if a minimal amount of banked blood is added. Calcium levels are generally very low in pediatric priming solutions; this may contribute to the rapid slowing of the heart with the initiation of bypass. The main constituents of the priming solution include crystalloid, colloid, and, if necessary, banked blood to maintain a temperature-appropriate hematocrit. Other potential supplements are fresh frozen plasma, mannitol, a buffer (sodium bicarbonate or trishydroxymethylaminomethane [THAM]), and steroids. Low concentrations of plasma proteins have been shown experimentally to impair lymphatic flow and alter pulmonary function by increasing capillary leak.114 Although adding albumin to the pump prime has not been shown to alter outcome in adults during CPB, one study suggested that maintaining normal colloid osmotic pressure may improve survival in infants undergoing CPB.115,116 Whole blood, if available, is an alternative to adding both packed RBCs and fresh frozen plasma. Blood cells are added to the prime solution to maintain a postdilutional hematocrit of at least 20% to 25% (usually higher in patients with cyanotic CHD), and plasma restores levels of procoagulants. Low-volume bypass circuits enable perfusionists and anesthesiologists to share a single unit of whole blood, thereby limiting the donor. The addition of any blood products will cause a much higher glucose load in the priming solution. Hyperglycemia may increase the risk for neurologic injury if brain ischemia occurs. Mannitol is added to promote an osmotic diuresis and scavenge O2 free radicals from the circulation. Steroids are added to stabilize membranes and produce the theoretic advantage of reducing ion shifts during periods of ischemia, attenuating inflammation caused by CPB, decreasing low cardiac output states, and improving fluid balance in the postoperative period. Steroids, however, may raise glucose levels, which can be detrimental if there is a period of cerebral ischemia, and may suppress immune function. Steroids remain a controversial additive in priming solutions. Recent retrospective data suggest negative effects with its use and an association with decreased survival in neonates having the Norwood procedure.117 A number of prospective studies are ongoing to address the role of steroids in pediatric cardiac surgery. 

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Temperature Hypothermic CPB is used to preserve organ function during cardiac surgery. Three distinct methods of CPB are used: moderate hypothermia (25°-32°C), deep hypothermia (18°C), and DHCA. The choice of method of bypass is based on the required surgical conditions, patient size, type of operation, and potential physiologic impact on the patient. Moderate hypothermic CPB is the principal method of bypass employed for older children and adolescents. In these patients, venous cannulas are less obtrusive and the heart can easily accommodate superior and inferior vena cava cannulation. Bicaval cannulation reduces right atrial blood return and improves the surgeon’s ability to visualize intracardiac anatomy. Moderate hypothermia may also be chosen for less demanding cardiac repairs, such as an ASD or uncomplicated VSD. Most surgeons are willing to cannulate the inferior and superior venae cavae in neonates and infants. In these patients, however, this approach is technically more difficult and likely to induce brief periods of hemodynamic instability. Additionally, the pliability of the venae cavae and the rigidity of the cannulas may result in caval obstruction, impaired venous drainage, and elevated venous pressure in the mesenteric and cerebral circulation. Deep hypothermic CPB is generally reserved for neonates and infants requiring complex cardiac repair. However, certain older children with complex cardiac disease or severe aortic arch disease benefit from deep hypothermic temperatures. For the most part, deep hypothermia is selected to allow the surgeon to operate under conditions of low-flow CPB or total circulatory arrest. Low pump flows (50 mL/kg/ min) improve the operating conditions for the surgeon by providing a nearly bloodless field. DHCA allows the surgeon to remove the atrial or aortic cannula. If this technique is used, surgical repair is more precise because of the bloodless and cannula-free operative field. Arresting the circulation, even at deep hypothermic temperatures, introduces the concern of how well deep hypothermia preserves organ function, with the brain being at greatest risk. Three-region perfusion techniques may be an option to deep hypothermic CPB, but further studies are needed to assess feasibility and outcomes of this newer strategy.  Hemodilution Hemodilution is used during CPB to decrease homologous blood use and improve microcirculatory flow by reducing blood viscosity during periods of hypothermia. Although hemoconcentrated blood has an improved O2-carrying capacity, its viscosity reduces efficient flow through the microcirculation. With hypothermic temperatures, blood viscosity increases significantly and flow decreases. Hypothermia, coupled with the nonpulsatile flow of CPB, impairs blood flow through the microcirculation. Blood sludging, small vessel occlusion, and multiple areas of tissue hypoperfusion may result. Therefore, hemodilution is an important consideration during hypothermic CPB. The appropriate level of hemodilution for a given hypothermic temperature, however, is not well defined. Further, hemodilution reduces perfusion pressure; increases CBF, thereby potentially increasing the microembolic load to the brain; and reduces the O2-carrying capacity of blood.118 Using an animal model, one group of investigators found

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SECTION V  •  Pediatric Anesthesia

that extreme hemodilution to a hematocrit less than 10% resulted in inadequate O2 delivery, but with higher hematocrit levels of 30%, there was improved cerebral recovery after DHCA.119 Jonas and colleagues120 confirmed these findings in a randomized trial using two hemodilution protocols (20% vs. 30% hematocrit) in infants younger than 9 months of age. In the short term, the group with lower hematocrit values had lower nadirs of cardiac index, higher serum lactate levels 1 hour after CPB, and a greater increase in total body water on the first postoperative day. At 1 year of age, mental development index scores were similar but psychomotor development index scores were significantly lower in the group with lower hematocrit values. Also, infants in this group had psychomotor development scores that were 2 standard deviations below the mean. Because RBCs serve as the major reservoir of O2 during circulatory arrest, especially during rewarming, hematocrit values closer to 30% are generally preferred for deep hypothermia when this technique is contemplated. Currently, most centers maintain hematocrit levels approximately 25% to 30% during CPB, enhancing O2 delivery to vital organs such as the brain. Cerebral O2 delivery is an especially important consideration because cerebral autoregulation is impaired at deep hypothermic temperatures and after DHCA. To achieve a hematocrit level of 25% to 30% in neonates and infants, banked blood should be added to the priming solution. The mixed hematocrit level on CPB (the hematocrit level of the total priming volume plus the patient’s blood volume) can be calculated by the following formula: HctCPB = BVpt × HCTpt /BVpt + TPV where HctCPB is the mixed hematocrit (TPV + BVpt), BVpt is the patient’s blood volume (weight in kilograms × estimated blood volume in milliliters per kilogram), TPV is the total priming volume, and Hctpt is the starting hematocrit level of the patient. This calculation allows an estimate of the hematocrit level of the patient using an asanguinous priming solution and is therefore useful for older children and adolescents. In neonates and infants, the perfusionist must add blood to the pump prime to achieve a desired hematocrit level during hypothermic CPB. The following formula estimates the amount of packed RBCs in milliliters that must be added to the prime volume to achieve this hematocrit level: Added RBCs (mL) = (BVpt + TPV) (Hctdesired ) − (BVpt ) (Hctpt )

where BVpt is the patient’s blood volume, TPV is the total priming volume, Hctdesired is the desired hematocrit level on CPB, and Hctpt is the starting hematocrit level of the patient. Like in adults, the optimal hematocrit level after weaning from CPB is not clear for pediatric patients. Decisions concerning post-CPB hematocrit levels are made based on the patient’s post-repair function and anatomy. Neonates, patients with residual hypoxemia, and those with moderate-to-severe myocardial dysfunction benefit from the improved O2-carrying capacity of hematocrit levels of 40% or higher. Patients with a physiologic correction and excellent myocardial function may tolerate hematocrit levels of 25% to 30%.121 In children with mild-to-moderate myocardial dysfunction, accepting hematocrit values

between these levels seems prudent. Therefore, in patients with physiologic correction, moderately good ventricular function, and hemodynamic stability, the risks associated with blood and blood product transfusion should be strongly considered during the immediate postbypass period. 

BLOOD GAS MANAGEMENT The theoretic benefit of α-stat versus pH-stat blood gas management during hypothermic CPB has been a topic of great debate. Although the pH-stat strategy may not be optimal for adults in whom the principal risk for brain injury is microembolism, this risk is thought to be lower in infants because of the lack of atherosclerotic disease. With pH-stat management, the addition of CO2 to the inspired gas mixture during cooling on CPB increases CBF and may improve cerebral tissue oxygenation and outcomes. The controversial issue of pH management during CPB has been addressed in a large study from Boston Children’s Hospital. In this study, infants younger than 9 months of age were randomized to α-stat versus pH-stat during deep hypothermic CPB with excellent long-term followup.122,123 Neurodevelopmental outcomes were evaluated in infants undergoing biventricular repair for a variety of cardiac defects when younger than 9 months of age. The short-term benefits identified with the pH-stat strategy included a trend toward less postoperative morbidity and shorter recovery time to first electroencephalographic activity. In patients with TGA, there was a shorter duration of intubation and ICU stay in patients.122 However, the use of either the α-stat or pH-stat strategies was not consistently related to either improved or impaired neurodevelopmental outcomes at 2- and 4-year follow-up.123 

INITIATION OF CARDIOPULMONARY BYPASS Arterial and venous cannula placed in the heart before initiating CPB may result in significant problems in the peribypass period. A malpositioned venous cannula has the potential for vena cava obstruction. The problems of venous obstruction are magnified during CPB in the neonate because arterial pressures are normally low (20-40 mm Hg), and large, relatively stiff cannulas easily distort these very pliable venous vessels.114,116 A cannula in the inferior vena cava may obstruct venous return from the splanchnic bed, resulting in ascites from increased hydrostatic pressure or directly reduced perfusion pressure across the mesenteric, renal, and hepatic vascular beds. Significant renal, hepatic, and gastrointestinal dysfunction may ensue and should be anticipated in the young infant with unexplained ascites. Similar cannulation problems may result in superior vena cava obstruction. This condition may be more ominous during bypass. Under these circumstances, three problems may ensue: (1) cerebral edema, (2) a reduction in regional or global CBF, and (3) reduced proportion of pump flow reaching the cerebral circulation, causing inefficient brain cooling. In the operating room, superior vena cava pressures via an internal jugular catheter should be monitored by examining the patient’s head for signs of suffusion after initiating bypass. Discussions with the perfusionist regarding

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78 • Anesthesia for Pediatric Cardiac Surgery

adequacy of venous return and large cooling gradients between the upper and lower body should alert the anesthesiologist and the surgeon to potential venous cannulae problems. Patients with anomalies of the large systemic veins (persistent left superior vena cava or azygous continuation of an interrupted inferior vena cava) are at particular risk for problems with venous cannulation and drainage. Problems with aortic cannula placement can occur. The aortic cannula may slip beyond the takeoff of the innominate artery, with blood therefore selectively flowing to the right side of the cerebral circulation. Also, the position of the tip of the cannula may promote preferential flow down the aorta or induce a Venturi effect to steal flow from the cerebral circulation. This problem has been confirmed during CBF monitoring by the appearance of large discrepancies in flow between the right and left hemispheres after initiating CPB. The presence of large aortic-to-pulmonary collaterals, such as a large PDA, also may divert blood to the pulmonary circulation from the systemic circulation, thereby reducing CBF and the efficiency of brain cooling during CPB. The surgeon should gain control of the ductus either before or immediately after instituting CPB to eliminate this problem and, if possible, large aortopulmonary collaterals should be embolized in the cardiac catheterization laboratory before the operative procedure. Neonates with significant aortic arch abnormalities (e.g., aortic atresia, interrupted aortic arch) may require radical modifications of cannulation techniques, such as placing the arterial cannula in the main pulmonary artery and temporarily occluding the branch pulmonary arteries to perfuse the body via the PDA or even dual arterial cannulation of both the ascending aorta and main pulmonary artery. Such adaptations require careful vigilance to ensure effective, thorough perfusion and cooling of vital organs. Once the aortic and venous cannulas are positioned and connected to the arterial and venous limb of the extracorporeal circuit, bypass is initiated. The arterial pump is slowly started, and, once forward flow is ensured, venous blood is drained into the oxygenator. Pump flow rate is gradually increased until full circulatory support is achieved. If venous return is diminished, arterial line pressure is high, or mean arterial pressure is excessive, pump flow rates must be reduced. High line pressure and inadequate venous return are usually caused by malposition or kinking of the arterial and venous cannulae, respectively. The rate at which venous blood is drained from the patient is determined by the height difference between the patient and the oxygenator inlet and the diameter of the venous cannula and line tubing. Venous drainage can be increased by using vacuum-assisted drainage under certain circumstances. In neonates and infants, deep hypothermia is commonly used. For this reason, the pump prime is kept cold (18°22°C). When the cold perfusate contacts the myocardium during the institution of CPB, heart rate slows immediately and contraction is impaired. The contribution of total blood flow pumped by the infant’s heart rapidly diminishes. Therefore, to sustain adequate systemic perfusion at or near normothermic temperatures, the arterial pump must reach full flows quickly. CPB is initiated in neonates and infants by beginning the arterial pump flow first. Once aortic flow is ensured, the venous line is unclamped and blood is siphoned out

2481

of the RA into the inlet of the oxygenator. Flowing before unclamping the venous line prevents the potential problem of exsanguination if aortic dissection or misplacement of the aortic cannula occurs. Neonates and infants have a low blood volume–to–priming volume ratio, and intravascular volume falls precipitously if the venous drainage precedes aortic inflow. Once the aortic cannula position is verified, pump flow rates are rapidly increased to maintain effective systemic perfusion. Because coronary artery disease is rarely a consideration, the myocardium should cool evenly unless distortion caused by the cannulas compromises the coronary arteries. When a cold prime is used, caution must be exercised in using the pump to infuse volume before initiating CPB. Infusion of cold perfusate may result in bradycardia and impaired cardiac contractility before the surgeon is prepared to initiate CPB. Once CPB is initiated, appropriate circuit connections, myocardial perfusion, and optimal cardiac decompression should be confirmed. Ineffective venous drainage can rapidly result in ventricular distention. This is especially true in infants and neonates, in whom ventricular compliance is low and the heart is relatively intolerant of excessive preload augmentation. If ventricular distention occurs, pump flow must be reduced and the venous cannula repositioned. Alternatively, the heart may be decompressed by placing a cardiotomy suction catheter or small vent in the appropriate chamber. 

PUMP FLOW RATES Recommendations for optimal pump flow rates for children have historically been based both on the patient’s body mass and on evidence of efficient organ perfusion as determined by arterial blood gases, acid-base balance, and whole-body O2 consumption during CPB.124 At hypothermic temperatures, metabolism is reduced, and CPB flow rates can therefore be reduced and still meet or exceed the tissue’s metabolic needs (see the discussion of low-flow CPB in the following section). 

SPECIAL TECHNIQUES Deep Hypothermic Circulatory Arrest A certain subset of neonates, infants, and children with CHD require extensive repair of complex congenital heart defects using DHCA. This technique facilitates precise surgical repair under optimal conditions, with no blood or cannulae in the operative field and providing maximal organ protection and often resulting in shortened total CPB time. The scientific rationale for the use of deep hypothermic temperatures rests primarily on a temperature-mediated reduction of metabolism. Whole-body and cerebral O2 consumption during induced hypothermia decreases the metabolic rate for O2 by a factor of 2 to 2.5 for every 10°C reduction in temperature.125 These results are consistent with in-vitro models, which relate temperature reduction to a decrease in the rate constant of chemical reactions, as originally described by Arrhenius using the equation k = Ae − RT. The reduction in O2 supply during deep hypothermic low-flow CPB is associated with preferential increases in vital organ perfusion (e.g., to the brain) and increased extraction of O2.126 Therefore, to some extent, deep hypothermic low-flow CPB

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SECTION V  •  Pediatric Anesthesia

DCHA group

0.0 :0.2

*

:0.3

1.4

:0.4

1.2

*

:0.5

1.0 *

0.8

*

0.6

CMRO2

Cyt aa3

:0.1

0.4 *

I

*

IA II III IV Measurement intervals

0.2 0.0 V

Fig. 78.9  Bar graph of variations in cytochrome oxidase (cyt aa3) near-infrared spectroscopic signals and cerebral metabolic rate for oxygen (CMRo2) in subjects with deep hypothermic circulatory arrest (DHCA).  Each point of cyt aa3 represents mean ± SE in six subjects; CMRo2 values are mean ± SD. Negative values in cyt aa3 represent relative decreases in quantity of oxidized enzyme. *CMRo2 and cyt aa3 are significantly different from control, P ± .05.

exerts a protective effect by reducing the metabolic rate for O2, promoting preferential organ perfusion, and increasing tissue O2 extraction. The duration of the safe period for DHCA has not clearly been delineated.127 Although all organ systems are at risk for the development of ischemic and reperfusion injury, as manifested by lactate and pyruvate production during DHCA, the brain appears to be the most sensitive to and the least tolerant of these effects. Brainstem and cortical evoked potentials as well as processed electroencephalographs are altered after DHCA.127-129 The abnormalities in evoked potentials appear to be related to the duration of DHCA and are attributed to altered metabolism. During reperfusion after the arrest period, CBF and metabolism remain depressed in neonates and small infants (Fig. 78.9; also see Fig. 78.6).70 Importantly, during the use of these extremes of temperature, autoregulation is lost and cerebral perfusion becomes highly dependent on the extracorporeal perfusion and presumably postbypass hemodynamic performance. The potentially deleterious effects of prolonged DHCA in infants and neonates are well described. In general, it is agreed that very prolonged periods of uninterrupted DHCA may have adverse neurologic outcomes. However, considerable disagreement exists if a “safe” period of DHCA exists and whether patient-specific, procedure-specific, or postoperative management strategies may attenuate or promote CNS damage from DHCA. Cases have been reported of detrimental effects of DHCA on a variety of outcomes regarding the CNS, while others have described an inconsistent effect or no effect.122,130,131 Three issues have become clear over time: (1) the effects of short durations of DHCA are inconsistently related to adverse outcomes, (2) the effect of DHCA is not a linear phenomenon, and (3) the effects are most likely modified by other patient-related, preoperative, and postoperative factors.131-133 A large-scale study of 549 subjects undergoing the Norwood stage 1 procedure with DHCA found duration of greater than 45 minutes to be a risk factor for 30-day mortality.134 

Regional Cerebral Perfusion Some surgeons have developed innovative and challenging strategies to provide continuous cerebral perfusion during complex reconstruction of the aortic arch or intracardiac repair to avoid or minimize the use of DHCA. However, avoiding DHCA, the duration of CPB is necessarily lengthened, and longer durations of CPB have been shown to adversely affect both short- and long-term outcomes.51,52 The relative risks and benefits of longer CPB versus less (or no) DHCA remain a subject of continued controversy. In efforts to study this newer strategy, two recent studies have evaluated the technique of regional cerebral perfusion. In one non-randomized study, Wypij and colleagues135 followed 29 infants who underwent a stage 1 palliation, 9 of whom received regional cerebral perfusion at 30 to 40 mL/kg/min. The authors reported no difference in mental or psychomotor developmental indices at 1 year of age between the regional cerebral perfusion group and those who received DHCA as a primary strategy. A larger randomized trial of DHCA with or without regional cerebral perfusion at 20 mL/kg/min in patients with a functional single ventricle included 77 patients with similar survival to hospital discharge (88%) and at 1-year follow-up (75%).136 No significant difference was seen in either the psychomotor development index or the mental development index scores between the two groups at any time points, although the scores tended to be lower in the regional cerebral perfusion group. A further innovation to the previously described technique is a three-region perfusion strategy for aortic arch reconstruction in the Norwood procedure. This strategy involves direct perfusion of the coronaries via a proximal aortic cannula, splanchnic beds via a distal thoracic aorta cannula, and cerebral perfusion via an innominate cannula. The arch repair occurs from distal to proximal at warmer patient temperatures and with a beating heart. This theoretically provides the potential for decreased coronary and splanchnic ischemic times, decreasing the risk of cardiac dysfunction and abdominal organ damage, and mitigating the negative hypothermic effects on the hematological system.2,3 Larger, long-term studies are needed to assess the efficacy of this technique in improving cardiovascular, renal, and other outcomes.  Glucose Regulation The detrimental effects of hyperglycemia during complete, incomplete, and focal cerebral ischemia are well demonstrated.137,138 The role of glucose in potentiating cerebral injury appears to rest on two factors: adenosine triphosphate (ATP) usage and lactic acidosis.139,140 The anaerobic metabolism of glucose requires phosphorylation and the expenditure of two molecules of ATP before ATP production can occur. This initial ATP expenditure may result in a rapid depletion of ATP and may explain why hyperglycemia worsens neurologic injury. Lactic acidosis is also important in glucose-augmented cerebral injury, though its role may be as a glycolytic enzyme inhibitor: lactate slows anaerobic ATP production by inhibiting glycolysis immediately after ATP is consumed in the phosphorylation of glucose.141 Although the detrimental effects of hyperglycemia during ischemia are clear, very little evidence supports a relationship between a worsening neurologic outcome and

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78 • Anesthesia for Pediatric Cardiac Surgery

hyperglycemia during CPB or DHCA in children. A review of acquired neurologic lesions in patients undergoing the Norwood stage 1 procedure for HLHS suggested hyperglycemia as a significant associated finding in patients with extensive cerebral necrosis or intraventricular hemorrhage. A host of other potentially damaging factors (e.g., periods of hypoxia, low diastolic and systolic pressure, thrombocytopenia) were statistically associated with the observed neuropathology.142 Whether glucose directly contributes to neurologic injury or merely serves as a marker for a highrisk population that ultimately suffers neurologic insult as a result of other factors is not clear. Hypoglycemia is also a frequent concern in neonates during the perioperative period. Reduced hepatic gluconeogenesis coupled with decreased glycogen stores places the newborn at increased risk for hypoglycemic events. In newborns with CHD, reduced systemic perfusion (e.g., critical coarctation, HLHS, critical aortic stenosis) may result in worsening hepatic biosynthesis, further impairing glucose production. These patients may be fully dependent on exogenous glucose; therefore, it is not uncommon for them to require 20% to 30% dextrose infusions to maintain euglycemia in the prebypass period. Older children are not immune to hypoglycemic events and are therefore susceptible to hypoglycemiainduced neurologic injury. Patients with low cardiac output states (cardiomyopathies, pre-transplant patients, critically ill postoperative patients) requiring reoperation and when on substantial inotropic support are at high risk for reduced glycogen stores and intraoperative hypoglycemia.143 The impact of hypoglycemia during CPB is further complicated by the consequences of hypothermia, CO2 management, and other factors that may modify normal cerebrovascular responses during bypass. In a dog model, insulin-induced hypoglycemia to 30 mg/dL did not alter the electroencephalographic findings. However, after 10 minutes of hypocapnic hypoglycemia, the electroencephalogram became flat.144 The loss of electroencephalographic activity from hypoglycemia alone does not normally occur above glucose levels of 8 mg/dL.145 During deep hypothermic CPB and DHCA, CBF and metabolism are altered. The additive effect of hypoglycemia, even if mild, may cause alterations in cerebral autoregulation and culminate in increased cortical injury.142 The common practice of using hyperventilation to reduce PVR in neonates and infants during weaning from CPB and in the early postbypass period can further exacerbate hypoglycemic injury. Glucose monitoring and rigid maintenance of euglycemia are an important part of CPB management in the patient with CHD. 

Renal Effects After CPB, the combined effects of hypothermia, nonpulsatile perfusion, and reduced mean arterial pressure cause release of angiotensin, renin, catecholamines, and antidiuretic hormones.146-148 These circulating hormones promote renal vasoconstriction and reduce renal blood flow. However, despite the negative impact of CPB on renal function, low-flow, low-pressure, nonpulsatile perfusion has not been linked with postoperative renal dysfunction (Table 78.9).147 The factors that best correlate with

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TABLE 78.9  Sequelae of Pediatric Cardiopulmonary Bypass End-Organ Injury

Cause and Signs

Renal injury

Organ immaturity, preexisting renal disease Post–cardiopulmonary bypass low cardiac output, use of DHCA Renal dysfunction characterized by reduced GFR and ATN

Pulmonary injury

Endothelial injury, increased capillary leak, complement activation, and leukocyte degranulation Pulmonary dysfunction characterized by reduced compliance, reduced FRC, and increased A-a gradient

Cerebral injury after Loss of autoregulation, suppressed metaboDHCA lism and cerebral blood flow, cellular acidosis, and cerebral vasoparesis CNS dysfunction characterized by seizures, reduced developmental quotients, choreoathetosis, learning disabilities, behavioral abnormalities A-a, Alveolar-arterial; ATN, acute tubular necrosis; CNS, central nervous system; DHCA, deep hypothermic circulatory arrest; FRC, functional residual capacity; GFR, glomerular filtration rate.

postoperative renal dysfunction are preoperative renal dysfunction and profound reductions in post-CPB cardiac output. Preoperative factors include primary renal disease, low cardiac output, and dye-related renal injury after cardiac catheterization.148 Acute kidney injury after pediatric cardiac surgery has an incidence between 20% to 60% depending on criteria used.149 Multiple causative factors are involved, and the final common result is oliguria and an increased serum creatinine. Diuretics have been the mainstay of promoting urine flow after pediatric CPB. Furosemide in a dose of 1 to 2 mg/kg or ethacrynic acid 1 mg/kg every 4 to 6 hours, or both, induces diuresis and may reverse renal cortical ischemia associated with CPB. After DHCA, a 24-hour period of oliguria or anuria can occur that resolves over the next 12- to 24-hour period. The use of diuretics is effective only after spontaneous urine output has been initiated in these patients. Glomerular filtration rate, creatinine clearance, and medullary concentrating ability are substantially reduced in neonates and young infants. Therefore, the use of CPB in these patients results in greater fluid retention than is typically seen in older children and adult patients. The net result may be increased total body water, increased organ weight (e.g., lungs, heart), and greater difficulty with postoperative weaning from ventilatory support. The use of ultrafiltration during rewarming or after CPB is effective in reducing total body water, limiting the damaging effects of CPB, and decreasing the postoperative ventilation period.150,151 

Pulmonary Effects Cardioplegia protects the heart, but no parallel protection is afforded to the lungs during bypass. Pulmonary dysfunction is common after CPB, and its pathogenesis is poorly understood (see Table 78.9). In the broadest terms, lung injury is mediated in one of two ways: first, by an inflammatory

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SECTION V  •  Pediatric Anesthesia

response resulting from leukocyte and complement activation and, second, by a mechanical effect culminating in surfactant loss, atelectasis with resultant ventilation-perfusion mismatch, loss of lung volumes, and altered mechanics of breathing. Pulmonary function after CPB is characterized by reduced static and dynamic compliance, reduced functional residual capacity, surfactant deficiency, and an increased A-a gradient.152,153 Atelectasis and increased capillary leak due to hemodilution and hypothermic CPB are the most likely causes. Hemodilution reduces circulating plasma proteins, reducing intravascular oncotic pressure, and favors water extravasation into the extravascular space. Hypothermic CPB causes complement activation and leukocyte degranulation.154 Leukocytes and complement are important in causing capillary-alveolar membrane injury and microvascular dysfunction through platelet plugging and release of mediators, which increase PVR. The technique of MUF is highly effective in reducing lung water and pulmonary morbidity during the postoperative period. 

during CPB may be best accomplished by the continuous administration of an inhaled anesthetic via a vaporizer connected to the pump oxygenator, dexmedetomidine infusion, careful titration of incremental doses of opioids, or the precise administration of an opioid or opioid and benzodiazepine by a continuous infusion technique. Primary opioid anesthetic techniques result in reduced stress hormone release and decreased postoperative metabolic acidosis and lactate production compared with halothane anesthesia and may therefore be a preferred technique in complex CHD.95 If an adequate depth of anesthesia is accomplished by the administration of excessively large doses of opioids (e.g., fentanyl or sufentanil), postoperative mechanical ventilation will be necessary. By contrast, residual levels of inhaled anesthetics (e.g., halothane or isoflurane) can produce transient myocardial depression at the termination of CPB, complicating separation from CPB. Because of the improved surgical techniques coupled with the reduced morbidity of CPB, the use of high doses of an opioid anesthetic is infrequent in current practice. 

STRESS RESPONSE AND CARDIOPULMONARY BYPASS

DISCONTINUATION OF CARDIOPULMONARY BYPASS

The release of a large number of metabolic and hormonal substances, including catecholamines, cortisol, growth hormone, prostaglandins, complement, glucose, insulin, endorphins, and other substances, characterizes the stress response during hypothermic CPB.9,155 The likely causes of the elaboration of these substances include contact of blood with the nonendothelialized surface of the pump tubing and oxygenator, nonpulsatile flow, low perfusion pressure, hemodilution, hypothermia, and light anesthesia depth. Other factors that may contribute to elevations of stress hormones include delayed renal and hepatic clearance during hypothermic CPB, myocardial injury, and exclusion of the pulmonary circulation from bypass. The lung is responsible for metabolizing and clearing many of these stress hormones. The stress response generally peaks during rewarming from CPB. Strong evidence indicates that the stress response can be blunted by increasing the depth of anesthesia.9,155 The stress response in return can mediate undesirable effects such as myocardial damage (catecholamines), systemic and pulmonary hypertension (catecholamines, prostaglandins), pulmonary endothelial damage (complement, prostaglandins), and pulmonary vascular reactivity (thromboxane). The benefits of controlling the stress response with fentanyl in premature infants undergoing PDA ligation and with sufentanil in neonates with complex CHD have been demonstrated.95,156 Although blunting the stress response seems warranted, additional evidence suggests that the newborn stress response, especially the endogenous release of catecholamines, may be an adaptive metabolic response necessary for survival at birth.157 Thus, the complete elimination of an adaptive stress response may not be desirable. To what extent acutely ill neonates with CHD depend on the stress response for maintaining hemodynamic stability is currently unknown. A depth of anesthesia adequate to attenuate the stress response should be used, but to attempt to block the response altogether is likely not necessary. Acceptable anesthesia

In separating the patient from CPB, blood volume is assessed by direct visualization of the heart and monitoring right atrial or left atrial filling pressures. When filling pressures are adequate, the patient is fully warmed, acidbase status is normalized, heart rate is adequate, and sinus rhythm has been achieved, the venous drainage is stopped and the patient can be weaned from bypass. The arterial cannula is left in place so that a slow infusion of residual pump blood can be used to optimize filling pressures. Myocardial function is assessed by direct cardiac visualization and a transthoracic left or right atrial catheter, by a percutaneous internal jugular catheter, or by the use of intraoperative echocardiography. Pulse oximetry also can be used to assess the adequacy of cardiac output.158 Low systemic arterial saturation or the inability of the oximeter probe to register a pulse may be a sign of very low output and high systemic resistance.159 After the repair of complex congenital heart defects, the anesthesiologist and surgeon may have difficulty separating patients from CPB. Under these circumstances, a diagnosis must be made and includes (1) an inadequate surgical result with a residual defect requiring repair, (2) pulmonary artery hypertension, and (3) right or left ventricular dysfunction. Two general approaches are customarily used, either independently or in conjunction. An intraoperative “cardiac catheterization” can be performed to assess isolated pressure measurements from the various great vessels and chambers of the heart (i.e., catheter pullback measurements or direct needle puncture to evaluate residual pressure gradients across repaired valves, sites of stenosis and conduits, and O2 saturation data to examine for residual shunts).160 Alternatively, echo-Doppler imaging may be used to provide an intraoperative image of structural or functional abnormalities to assist in the evaluation of the postoperative cardiac repair.7,161 If structural abnormalities are found, the patient can be placed back on CPB and residual defects can be repaired before the patient leaves

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78 • Anesthesia for Pediatric Cardiac Surgery

A

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B

Fig. 78.10  (A) Two-dimensional echocardiogram in the short-axis view across the ventricles demonstrating the presence of intramyocardial air (arrow) in the ventricular septum and right ventricular wall. The intramyocardial air appears as a dense, “snowy” echogenic area. Note the associated wall motion abnormality appearing as flattening of the ventricular septum. (B) The patient was treated with phenylephrine, increasing systemic and coronary perfusion pressure, resulting in clearance of the air, normalization of the echogenic density, and restoration of normal left ventricular (LV) wall motion and configuration.

the operating room. Leaving the operating room with a significant residual structural defect adversely affects survival and increases patient morbidity (see Fig. 78.5).7,161 EchoDoppler imaging can rapidly identify right and left ventricular dysfunction and suggest the presence of pulmonary artery hypertension. In addition, echo-Doppler imaging can identify regional wall motion abnormalities caused by ischemia or intramyocardial air that will direct specific pharmacologic therapy and provide a means of assessing the results of these interventions (Fig. 78.10).162 

ULTRAFILTRATION Institution of CPB in neonates, infants, and young children results in a profound proinflammatory response and significant hemodilution. This may contribute to post-CPB morbidity and mortality resulting from poor organ function. The organ systems most affected by this are the heart, lungs, and brain. Although contact between the patient’s blood and the foreign surface of the bypass circuit is a potent stimulus to trigger the inflammatory cascade, other factors including ischemia, profound hypothermia, rewarming, and surgical trauma are also important in its genesis. These inflammatory mediators include complement anaphylatoxins, vasoactive amines, and cytokines (e.g., tumor necrosis factor-α [TNF-α]) that lead to an increase in vascular permeability.163 Hemodilution occurs at the onset of CPB despite the use of physiologically balanced priming solutions that include blood, crystalloid, albumin, and buffer and smaller volume circuits. Hemodilution may, however, be advantageous in patients in whom the surgery is performed under hypothermic conditions ranging from mild hypothermia to DHCA. Initiation of CPB will change the viscoelastic properties of blood, and these changes have been shown to continue into the post-CPB period.164 Although the mode of perfusion, cardiotomy suction, arterial roller pump type, and shear forces of the CPB circuit are important, it is the temperature and hematocrit of the

blood that play the most important role in changing viscoelasticity. It has been shown that low temperature with a high hematocrit leads to a higher viscosity.165 This elevated viscosity may lead to altered organ perfusion, particularly in the brain. Because of these alterations in blood viscosity, hemodilution is tolerated in the cooling phases of CPB. Although advantageous early, this hemodilution combined with the inflammatory response will lead to transudation of fluid into the extravascular space, which in turn leads to the potential for organ dysfunction as eluded to earlier. Prevention of organ dysfunction and improved oxygenation by the removal of excess fluid and inflammatory mediators are the rationale, therefore, in the use of ultrafiltration. The end result is removal of plasma water and low-molecularweight solutes across a semipermeable membrane. Essentially, five forms of ultrafiltration are used in modern perfusion practice, three of which are while the patient is on CPB. Prime ultrafiltration is used when packed RBCs are added to the prime solution and is performed in the prebypass phase; prime ultrafiltration aims to replace crystalloid prime with blood prime, adjust pH, alter electrolyte concentration to safer levels, and remove inflammatory mediators potentially present in the donor blood.166 Conventional ultrafiltration (CUF) involves the removal of fluid at any time while the patient is being supported by CPB. A common use for this method is removal of the volume of clear fluid equal to the volume of cardioplegia used. CUF can be performed during all phases of CPB. It involves the placement of an ultrafilter within the circuit and connected either to the venous line or the venous reservoir. The removal of an excess of ultrafiltrate will result in low reservoir volumes. In zero balance ultrafiltration, once fluid has been removed it is replaced with crystalloid to avoid inadequate reservoir volume, and thus there is no net removal of volume. The third method of on-bypass ultrafiltration is dilutional ultrafiltration, which is employed when the concentration of a given electrolyte (e.g., potassium) is deemed elevated.

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SECTION V  •  Pediatric Anesthesia

The method involves removal of ultrafiltrate with its replacement by half with normal saline, thus diluting the concentration of the given electrolyte to safer levels. All on-bypass ultrafiltration have similar end points—that is, attempted removal of excess clear fluid resulting in hemoconcentration, removal of inflammatory mediators, and manipulation of electrolyte concentrations to safe levels. MUF, first described by Naik and associates150 in 1991, involves filtration of blood once the patient has been weaned from bypass. This can be achieved either by a venovenous technique in which blood is removed and returned to the atrium once concentrated or by an arteriovenous technique in which blood is removed via the aortic cannula and returned via the venous line.150,167,168 In more detail, in this technique blood is removed in a retrograde fashion by the aortic cannula and passes through the ultrafilter along with remaining circuit volume from the venous reservoir and oxygenator. Flow through the ultrafilter is maintained by a roller pump at flows of between 10 and 30 mL/kg, with the slower rates resulting in a more gradual change in the intravascular fluid compartment and thus potentially better tolerated. A constant atrial pressure is maintained throughout the procedure by adding crystalloid into the venous reservoir as needed. Suction is applied to the filtrate port to achieve a maximal transmembrane pressure, thus allowing for ultrafiltration rates of between 100 and 150 mL/min. End points for the process of MUF are time (15-20 minutes) and reaching of a target hematocrit (usually 40%) once the circuit volume has been replaced by crystalloid or should the patient’s hemodynamics not tolerate the procedure. Cardiac surgeries in the very young may be complex with potentially protracted CPB and cross-clamp times. Therefore, myocardial performance is more commonly depressed after weaning from CPB. Although ultrafiltration is used during CPB in an attempt to remove excess body water, it appears from studies that it is the use of MUF that significantly improves myocardial performance (Fig. 78.11).169,170 Using echocardiographic measurements in a study of infants undergoing corrective surgery under nonhypothermic arrested conditions, Davies and associates171 found improvements in both systolic and diastolic function in the children studied. They found that the preload recruitable stroke work, which is load independent, improved after MUF and was thus a good indicator of improved systolic function. The same study showed that after MUF a decrease in the myocardial wall thickness and cross-sectional area occurred that was not present in the control group of patients who received no ultrafiltration. These reductions result in an increase in end-diastolic length and a fall in enddiastolic pressure, both of which are indicators of improved diastolic function. Although presumably it was the decrease in myocardial edema that was the cause for these improvements, increased hematocrit also was observed. Because these positive effects were not seen past 24 hours, the absolute benefit of MUF is not clear.171 Pulmonary dysfunction is one of the most common negative effects of CPB172; MUF is utilized to improve oxygenation, decrease the effects of inflammatory mediators on the alveolar capillary membrane, and decrease pulmonary vascular reactivity. Studies have demonstrated that in patients in whom ultrafiltration and MUF were used, improvements in pulmonary compliance, decreased airway resistance,

* 100

90 Systolic BP (mm Hg)

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80

70

60

50 MUF

No MUF

Weaned from CPB 15 min post wean *P .001

Fig. 78.11  Systolic blood pressure (BP) after separating from cardiopulmonary bypass (CPB) and 15 minutes after separating with and without modified ultrafiltration (MUF). Note the significant improvement in systolic BP with the use of MUF. (From Ungerleider RM. Effects of cardiopulmonary bypass and use of modified ultrafiltration. Ann Thorac Surg. 1998;65:S35; reprinted with permission from the Society of Thoracic Surgeons.)

pulmonary arterial reactivity, and improved oxygenation were demonstrated.172-175 It is therefore obvious why these methods have found such wide acceptance in pediatric cardiac surgery, particularly in patients in whom normal compliance with low PVR is vital (i.e., those with singleventricle physiology). Although these studies commonly find improvement in pulmonary function immediately after weaning from CPB and the completion of MUF, disagreement exists as to whether these effects result in improved function much beyond 6 hours, with some showing little if any benefit at 24 hours. A conclusion, however, from these studies is that combination of on-bypass ultrafiltration coupled with MUF has the best results in the early postbypass period. In a study performed on a piglet model of DHCA, the use of MUF after CPB improved hematocrit, cerebral O2 delivery, and cerebral O2 consumption, thus representing a potential reduction in cerebral injury. Further studies have made similar conclusions, demonstrating that four variables are of importance in improving cerebral oxygenation: PCO2, mean arterial pressure, hematocrit, and MUF flow rate.176,177 Increasing all except MUF flow rate improved O2 delivery. Increasing the flow rate appeared to cause a steal-like phenomenon in which apparent diastolic runoff occurred into the MUF circuit from the aortic cannula. Thus, although the process of MUF is important for recovery of normal cerebral function, care must be used not to negate the benefits by decreasing the time on MUF by increasing the flow rates (Fig. 78.12). Common to the improvement in cardiac and pulmonary function are the associated decrease in inflammatory mediators seen after ultrafiltration. Studies have shown

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78 • Anesthesia for Pediatric Cardiac Surgery

CMRO2 (mL/100 g/min)

3.5

*

3.0 2.5 2.0 1.5 1.0 CTL MUF TX

0.5 0 I

II Stage

III

Fig. 78.12 Cerebral metabolic rate for oxygen measurements (CMRO2) before and after deep hypothermic circulatory arrest.  Note the significant increase in CMRo2 in the MUF animals compared with the control and transfusion groups at stage 3. CTL, Control; MUF, modified ultrafiltration; TX, transfusion. (From Skaryak LA, Kirshbom PM, DiBernardo LR, et al. Modified ultrafiltration improves cerebral metabolic recovery after circulatory arrest. J Thorac Cardiovasc Surg. 1995;109:744–751.)

that the ultrafiltrate contains a wide variety of low-molecular-weight inflammatory mediators, including C3a, C5a, interleukin (IL)-6, IL-8, TNF, myocardial depressant factor, and endothelin.173,178,179 It is the removal of endothelin-1 after MUF that results in the improvement of pulmonary vascular reactivity, which is of great importance, particularly in infants younger than 4 to 6 months of age, when pulmonary vascular reactivity is high, and in patients who are having staged cavopulmonary reconstructions. TNF, a potent inflammatory mediator implicated in the development of capillary leak syndrome seen after CPB, has been shown to be removed best by MUF. Despite these positive effects of MUF, the literature does not give a clear advantage of one form of ultrafiltration over the other, and it may be the combination of these methods that once again shows the best potential results. Another important post-CPB issue is ongoing blood loss. The use of MUF will result in an elevation of the patient’s hematocrit secondary to the removal of the excess body water, as already discussed. This further results in decreased blood use and the observation that there is less postoperative bleeding.180 Indeed, in older children attempts can thus be made to avoid the use of donor blood altogether. Disadvantages to these techniques are noted. The addition of an ultrafilter to the CPB circuit adds a level of complexity to the circuitry and thus another potential area in which circuit-related complications may occur. Opponents of MUF note also the following potential problems: the potential for air entrainment into the arterial cannula, additional time in which the patient is anticoagulated, potential for hypovolemia as volume is drawn off from the patient, hypothermia because the filtered volume does not pass through the heater/oxygenator, and the potential for the increase in the plasma concentration of drugs (e.g., fentanyl).181 Another interesting complication potentially associated with ultrafiltration was the reduction in thyroid hormone. This acute hypothyroidism may lead to depressed function, manifesting as decreased contractility, heart rate, cardiac output, and elevated SVR, all of which will

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clearly affect the immediate post-CPB period.182 As with other techniques in medicine the benefit versus risk must be seriously considered, but from the presented evidence the use of ultrafiltration both on and off CPB is extremely beneficial and these methods are thus commonly used in modern pediatric cardiac surgery with good result and little complication.143,145,183,184 In the preceding paragraphs the discussion concluded that no clear advantage has been determined of one method of ultrafiltration over the other. Unfortunately, comparing a wide range of patients having different surgeries under different conditions is difficult, and thus it appears that from the articles referenced the best strategy would include both the use of on-CPB ultrafiltration and the use of MUF once the patient has been separated from bypass to achieve the goals of decreasing total-body water; removal of inflammatory mediators; improved hematocrit, and thus O2-carrying capacity; and preservation of vital organ function. With the miniaturization of CPB circuits and resultant reduced hemodilution, some institutions have stopped using MUF because it simplifies and decreases the volume of the CPB circuit. They believe there is an advantage to preventing hemodilution rather than reversing hemodilution with MUF. Significantly miniaturizing circuits is also not without safety concerns as it may limit the ability to increase CPB flow rates. At our institution we continue to use MUF for the many reasons previously described. 

SPECIFIC PROBLEMS ENCOUNTERED IN DISCONTINUING CARDIOPULMONARY BYPASS Left Ventricular Dysfunction The contractile state of the LV may be reduced after pediatric cardiac surgery, due to surgically induced ischemia during the repair, the preoperative condition of the myocardium, the effects of DHCA on myocardial compliance, and new, altered loading conditions on the LV caused by the repair.185,186 Left ventricular dysfunction can be treated by optimizing preload, increasing heart rate, increasing coronary perfusion pressure, correcting ionized calcium levels, and adding inotropic support. The neonate’s heart rate–dependent cardiac output, reduced myocardial compliance, and diminished response to calcium and catecholamines are factors influencing the need for inotropic support. Inotropic support usually begins with epinephrine 0.03 to 0.05 μg/kg/min or dopamine 3 to 10 μg/kg/min. Several studies suggest that the effect of dopamine in children is age dependent. After cardiac surgery in young children, dopamine increases cardiac output, which correlates more with elevations in heart rate than augmentation of stroke volume, whereas, in young adults, dopamine clearly increases stroke volume. Nonetheless, infants and neonates respond favorably to epinephrine and dopamine infusions with increased systemic arterial blood pressure and cardiac output and improved systemic perfusion. Calcium supplementation is important in augmenting cardiac contractility. Although calcium supplementation has fallen into some disfavor because of concerns over reperfusion injury, it remains an important therapy after pediatric cardiac surgery. Fluctuations in ionized calcium levels occur commonly in the immediate post-CPB period in children. This is most often due to the relatively large

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SECTION V  •  Pediatric Anesthesia

transfusions of citrate-rich and albumin-rich blood products, such as whole blood, fresh frozen plasma, platelets, and cryoprecipitate necessary for hemostasis, all of which bind calcium.187 Routine calcium supplementation during the early post-CPB period is especially helpful in patients with diminished left ventricular function. In patients with a slow sinus or junctional rate, calcium must be administered cautiously because marked slowing of AV conduction may occur. Epinephrine 0.02 to 0.2 μg/kg/min is useful in patients with significant left ventricular dysfunction who remain hypotensive with high left atrial filling pressures or echoDoppler imaging evidence of reduced contractility or regional ischemia.188 Milrinone, a potent phosphodiesterase-3 inhibitor, is also an effective inotrope-vasodilator in infants and children. Studies in neonates after open-heart surgery reveal significant reductions in SVR and PVR and increases in cardiac index, primarily as a result of larger stroke volume.189 Infants and children demonstrate a larger volume of distribution and clearance of milrinone than that in adults; thus, the initial loading dose necessary to achieve therapeutic levels may be as large as 100 μg/kg.190 In neonates, the initial dose of milrinone on CPB is 25 to 100 μg/kg, followed by a continuous infusion to be started within 90 minutes of the initial dose at a rate of 0.2 μg/kg/min to maintain a therapeutic level. In older infants and children, the rate of continuous infusion is larger, usually 0.5 to 1 μg/kg/min. Dobutamine is an effective, albeit weaker, inotropic agent in children. Although it is reported to have a lesser chronotropic effect than dopamine in neonates, significant tachyarrhythmias may occur. This may be related to structural similarities between dobutamine and isoproterenol.188 In children after cardiac surgery, dobutamine increases cardiac output primarily through increased heart rate. This is consistent with reduction in α-receptors and a higher level of circulating catecholamines in newborns. 

Right Ventricular Dysfunction Primary right ventricular dysfunction is a common finding after CPB in neonates, infants, and children. For example, after repair of TOF, preexisting right ventricular hypertrophy, a right ventriculotomy, and the placement of a transannular patch across the right ventricular outflow tract, resulting in acute pulmonary regurgitation and right ventricular volume overload, are common causes of postoperative right ventricular dysfunction.17 The treatment of right ventricular dysfunction consists of measures directed at lowering PVR and preserving coronary perfusion without distending the RV. In cases of ventricular dysfunction, lowdose epinephrine (0.01-0.03 μg/kg/min) may provide inotropy without vasoconstriction.186 Mechanical ventilation should be adjusted to assist right ventricular function and minimize PVR. In contrast to the LV, the low intracavitary pressure of the normal RV receives two thirds of its coronary filling during ventricular systole. In patients with right ventricular dysfunction, maintaining a normal or slightly elevated systolic arterial pressure maximizes coronary perfusion to the RV and augments contractility. A vasopressin infusion can prove advantageous in such circumstances. If the need for inotropic support persists after the early post-CPB

period, a critical evaluation for other structural and functional abnormalities should be aggressively pursued. Preload should be maintained at a normal to slightly elevated level. Because right ventricular contractility is reduced, it is important to maximize preload to the highest portion of the Starling curve. Overdistention of the RV, however, is not well tolerated, owing to diminished ventricular compliance and diastolic dysfunction. Excessive volume loading may result in significant diastolic dysfunction, tricuspid regurgitation, and worsening forward flow. Generally, CVP much above 12 to 14 mm Hg is poorly tolerated in neonates and infants with right ventricular dysfunction.191 If right ventricular dysfunction is severe, the sternum should be left open.192 This eliminates the impedance imposed by the chest wall and mechanical ventilation, allowing the RV to maximize its end-diastolic volume. An additional strategy in neonates, infants, and children with significant post-CPB right ventricular dysfunction is to allow right-to-left shunting at the atrial level. Typical patients who would benefit from this strategy include neonates undergoing repairs for TOF and truncus arteriosus. Allowing an atrial communication to remain open, with blood shunting in a right-to-left direction, preserves cardiac output and O2 delivery to the systemic circulation. Although these patients have somewhat diminished systemic O2 saturation, their effective cardiac output and tissue O2 delivery are enhanced, systemic perfusion pressure improves and coronary perfusion of the RV is maintained. As right ventricular function improves, right atrial pressure falls, right-to-left shunting decreases, and systemic arterial saturation rises. If right ventricular dysfunction persists to the extent that systemic cardiac output is compromised, consideration should be given to extracorporeal life support (extracorporeal membrane oxygenation [ECMO]). When ECMO is used for circulatory support, venoarterial cannulation is preferred. Venous and arterial access may be achieved through a large central artery and vein, usually the carotid artery and internal jugular vein, or by direct chest cannulation. Recovery from severe ventricular dysfunction is predicated on the concept that the myocardium has sustained a transient injury (i.e., “stunned myocardium”) and is capable of recovery with time.193,194 ECMO is used to decrease ventricular wall tension, increase coronary perfusion pressure, and maintain systemic perfusion with oxygenated blood. ECMO also may be used for left ventricular failure, although success with this condition is less common than that seen with right ventricular dysfunction or pulmonary artery hypertension. Patients placed on ECMO because they fail to separate from CPB demonstrate significantly greater mortality than do those for whom ECMO was instituted later in the postoperative course.195 The children who consistently have the lowest survival rate are those who require ECMO after a Fontan operation.196 The role of ECMO in patients with myocardial injury or pulmonary hypertension is to provide adequate systemic O2 transport and systemic perfusion while allowing the ventricles to rest and recover. ECMO may even provide an effective means of resuscitation for postoperative cardiac patients, particularly if instituted promptly.197 In larger infants and children with predominantly right ventricular dysfunction and satisfactory pulmonary function, a selective right ventricular assist device (VAD) may be preferable to ECMO.198 

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78 • Anesthesia for Pediatric Cardiac Surgery

Pulmonary Artery Hypertension Primary pulmonary hypertension is a devastating disease. The progressive and sustained elevation in PVR eventually leads to right-sided HF and death.199,200 Pulmonary arterial hypertension (PAH) is defined by the presence of mean pulmonary arterial pressure greater than 25 mm Hg at rest or 30 mm Hg during exercise.201 In two studies, the presence of PAH was shown to be a significant predictor of major perioperative cardiovascular complications, including pulmonary hypertensive crises, cardiac arrest, and death in patients undergoing cardiac catheterization or noncardiac surgery under anesthesia.202,203 Suprasystemic pulmonary artery pressure was predictive of major complications. Complications, however, were not associated with age, cause, type of anesthetic, or airway management. Preanesthesia evaluation should gauge disease severity. A history significant for chest pain, syncope, and dizziness, with signs of dyspnea at rest, low cardiac output state, metabolic acidosis, hypoxemia, and signs of right-sided HF warrants caution. Acute increases in PVR resulting in pulmonary hypertensive crises cause an increase in right ventricular afterload, right ventricular dysfunction, and hemodynamic decompensation. Suprasystemic pulmonary artery pressure results in inadequate PBF, inadequate left ventricular preload, low cardiac output, and biventricular failure. The associated hypotension results in coronary ischemia, which worsens this cycle. Perioperative factors thought to precipitate a pulmonary hypertensive crisis include hypoxia, hypercarbia, acidosis, hypothermia, pain, and airway manipulations in patients with pulmonary hypertension. Such patients present for hemodynamic catheterization, drug study, and noncardiac and cardiac surgical procedures. Although each anesthetic has to be tailored to the patient’s pathophysiologic condition and surgical procedure, certain common principles remain. Pulmonary vasodilator therapy and inotropes must be continued in the perioperative period. Investigations include a comprehensive echocardiogram with occasional chest computed tomography angiography to exclude pulmonary thromboembolic disease. After premedication, the patient should be monitored with pulse oximetry to ensure the patient does not hypoventilate or become hypoxic. An intravenous induction with carefully titrated doses of ketamine may be the safest; if no intravenous is present, an inhalational induction with sevoflurane can be performed safely with 100% O2, keeping the end-tidal sevoflurane concentration as low as possible and quickly obtaining intravenous access. Procedures with potential for blood loss, hemodynamic instability, and changes in ventilatory status mandate invasive arterial monitoring. Care should be taken to avoid systemic hypotension while achieving general anesthesia. Ventilation and oxygenation are controlled, and acidosis is treated aggressively. Hypotension in the presence of euvolemia may need to be treated with inotropes and, if necessary, α1-agonists.204,205 Therapy for elevated pulmonary artery pressures is directed at lowering PVR and unloading the RV. Reduction of PVR is accomplished by altering ventilation pattern, inspired O2 concentration, and blood pH. Specifically, manipulating the pulmonary vascular bed in newborns and infants is a matter of regulating partial pressure of CO2 in arterial blood (PaCO2), pH, PaO2, partial pressure of alveolar oxygen, and ventilatory mechanics.206,207 PaCO2

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is a potent mediator of PVR, especially in the newborn and young infant. Reducing PaCO2 to 20 mm Hg and increasing pH to 7.6 produces a consistent and reproducible reduction in PVR in infants with pulmonary artery hypertension. Manipulating serum bicarbonate levels to achieve a pH of 7.5 to 7.6 while maintaining a PaCO2 of 40 mm Hg has equal salutary effects on PVR.208 An increase in the FiO2 and the PaO2 decreases PVR as well. In the circumstance of intracardiac shunts, changes in FiO2 have little effect on PaO2. Thus, by inference, a reduction in PVR induced by increasing the inspired O2 concentration is probably a direct pulmonary vasodilatory effect of PaO2 rather than FiO2. Ventilatory mechanics also play a major role in reducing PVR. Neonates and infants have a closing volume above functional residual capacity. Thus, at the end of a normal breath, some airway closure occurs. This process results in areas of lung that are perfused and yet underventilated. As these lung segments become increasingly hypoxemic, secondary hypoxic vasoconstriction occurs. The net effect is an increase in PVR. Therefore, careful inflation of the lungs to maintain functional residual capacity will selectively reduce PVR. In practice, this is accomplished with relatively large tidal volumes and low respiratory rates, which produce an exaggerated chest excursion. Respiratory rates of 15 to 25 breaths/min are used for neonates and infants. Because PBF occurs predominantly during the expiratory phase of the respiratory cycle, the ventilatory pattern should be adjusted to allow an adequate distribution of gas throughout the lung during inspiration and a more prolonged expiratory phase to promote blood flow through the lungs. End-expiratory pressure must be applied cautiously during the post-CPB period. Low positive end-expiratory pressure (PEEP) (3-5 mm Hg) prevents narrowing of the capillary and precapillary blood vessels, thereby reducing PVR. Higher PEEP or excessive mean airway pressure results in alveolar overdistention and compression of the capillary network in the alveolar wall and interstitium. This condition elevates PVR and reduces PBF.153 The final and perhaps the least well-recognized use of the mechanical ventilator is to assist in unloading the RV. During positive pressure inspiration, intrathoracic pressure increases and creates an increased pressure gradient from the lung to the LA, promoting cardiac output. This ventilatory assist is commonly seen in patients with PAH or right ventricular dysfunction. An augmentation of the arterial pressure trace during inspiration is seen. The use of the ventilator to augment systemic blood flow is very similar to the thoracic pump concept used to explain blood flow during CPR.209 The inspiratory assist must be balanced by the potential negative effects of increased mean airway pressure on PVR and right ventricular afterload. To maximize these cardiopulmonary interactions, high tidal volume with low respiratory rates should be employed. Attempts to manipulate PVR through pharmacologic interventions are also possible. Drugs that have shown promise in decreasing PVR both clinically and experimentally have been the phosphodiesterase inhibitors such as amrinone and milrinone. Both reduce PVR and SVR and increase RV contractility.210 Isoproterenol has mild pulmonary artery–vasodilating properties in the normal pulmonary circulation.211 It reduces PVR in adults after cardiac

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transplantation, but very few data support PVR reduction in infants and young children after cardiac surgery. In immature animals, the myocardium is less responsive to isoproterenol and causes tachycardia and increased myocardial O2 consumption. These latter effects may reduce coronary perfusion and result in relative myocardial ischemia. Both prostaglandin E1 and prostacyclin have a pulmonary vasodilating effect; however, both drugs produce systemic hypotension, which severely limits their use.212,213 There are now ultra–short-acting intravenous vasodilators and inhaled vasodilating agents such as NO. Ultra– short-acting intravenous vasodilators are nonspecific potent vasodilators, with a half-life of seconds. Infusion of these drugs into the right side of the circulation produces a potent short-lived relaxation of the pulmonary artery smooth muscle.214 Once the drug reaches the systemic circulation it is no longer functional. Adenosine and ATPlike compounds have these properties and may have clinical applicability in pulmonary artery hypertension in the future.215 Beginning in the past decade, several potent therapies for pulmonary hypertension have evolved.206,207 A continuous intravenous infusion of prostacyclin improves pulmonary vascular hemodynamics, exercise tolerance, and survival in pulmonary hypertension.216 Sildenafil is a selective phosphodiesterase type 5 inhibitor. Phosphodiesterase type 5 breaks down cyclic guanosine monophosphate. Sildenafil produces acute and relatively selective pulmonary vasodilatation and acts synergistically with NO.217-219 Bosentan is a dual endothelin receptor blocker. Preliminary reports indicate that bosentan improves symptoms, exercise tolerance, and hemodynamics in patients with pulmonary hypertension. The drug is well tolerated and free of side effects apart from a dose-dependent increase in liver enzymes.220 Lung transplantation is the only available surgical therapy for primary pulmonary hypertension; however, the 5-year survival remains less than 50%, and bronchiolitis obliterans remains the single most common cause of death.221,222 Before listing for transplantation, all patients undergo a hemodynamic cardiac catheterization and drug study in which reversibility of pulmonary hypertension with increased inspired O2 concentrations and NO is determined.223 Prostacyclin analogues including inhaled iloprost or intravenous epoprostenol, although used in adult centers, have not become routine in pediatric practice. CPB with associated endothelial injury predisposes to the development of postoperative pulmonary hypertension in patients with CHD. Anatomic factors that impose either obstruction to PBF or residual left-to-right shunting need to be surgically addressed. Elevated LAP resulting from mitral valve disease or left ventricular dysfunction, pulmonary venous obstruction, branch pulmonary artery stenosis, or surgically induced loss of the pulmonary vascular cross-sectional area all raise right ventricular pressure and impose a burden on the right side of the heart. NO, an endothelium-derived vasodilator that is administered as an inhaled gas, represents the most promising development in the therapy for elevated PVR in patients with CHD. Although nonselective, it is rapidly inactivated by hemoglobin and, when inhaled, produces no systemic vasodilation.224 NO reduces pulmonary artery pressure in adult patients with mitral valve stenosis and in selected

pediatric cardiac patients with PAH.225-227 The congenital cardiac patient population in whom NO appears to be effective is patients with acute PVR elevation after open-heart surgery, as well as preoperative pulmonary hypertension accompanying specific anatomic conditions (e.g., total anomalous pulmonary venous return, congenital mitral stenosis).225,227 Because it acts directly on vascular smooth muscle, NO remains effective despite the post-CPB endothelial injury frequently encountered in children.228 Some centers routinely employ low-dose NO (1-5 ppm) after a Fontan operation when the CVP-LAP gradient exceeds 10 mm Hg.229 At our institution, a dose of 20 ppm is the standard dose in both the ICU and the cardiac operating room. Finally, NO can provide diagnostic information that helps distinguish reactive pulmonary vasoconstriction from fixed anatomic obstructive disease either in the postoperative surgical patient or in the patient undergoing pre-transplant evaluation.230,231 In the latter, the distinction between pulmonary vasoconstriction and advanced pulmonary vascular occlusive disease will influence the prediction as to whether a child with pulmonary hypertension in association with either CHD or cardiomyopathy will survive a heart transplant or requires replacement of both heart and lungs. Management strategies for postoperative pulmonary hypertension and treatment of pulmonary hypertensive crises include sedation, moderate hyperventilation (maintaining CO2 partial pressure [PCO2] between 30 and 35 mm Hg), moderate alkalosis (pH > 7.5), increased inspired O2, optimization of PEEP (to maximize functional residual capacity), pulmonary vasodilators (e.g., NO), and the creation or maintenance of an intracardiac right-to-left shunt in an attempt to maintain cardiac output.232,233 NO is also useful in the manipulation of PVR after Fontan-type procedures.234 Care should be exercised in weaning NO in patients, because abrupt withdrawal can precipitate rebound pulmonary hypertension and pulmonary hypertensive crises.234,235 

Anticoagulation, Hemostasis, and Blood Conservation Pediatric anesthesiologists must manage coagulation, hemostasis, and blood conservation in the perioperative period of cardiac surgery. Coagulopathy after CPB remains a significant problem in pediatric cardiac surgery.223 Continuing blood loss after CPB requiring blood component replacement is associated with hemodynamic compromise as well as morbidity. In pediatric patients, restoration of hemostasis has proved difficult; diagnosis of the problem and treatment are marginally effective. Neonates, infants, and children undergoing cardiac surgery with CPB have a higher rate of postoperative bleeding than that seen in older patients.236 First, the ratio of patient body surface area to the nonendothelialized extracorporeal circuit volume is disproportionate; the relatively large inflammatory-type response provoked in response to CPB is inversely related to patient age—the younger the patient, the more pronounced is the response.9 Because complement and platelet activation are linked to the activation of other protein systems in the blood (i.e., fibrinolytic proteins), it is probable that this hemostatic activation, which

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78 • Anesthesia for Pediatric Cardiac Surgery

400

Change from control (%)

results in impaired hemostasis and increased bleeding tendency, plays a major role during pediatric cardiac surgery. Second, the type of operation performed in neonates and infants usually involves more extensive reconstruction and suture lines, creating more opportunities for surgical bleeding than in adult cardiac patients. Operations are also frequently performed using DHCA, which may further impair hemostasis.237 Third, the immature coagulation system in neonates is also likely to contribute to impaired hemostasis.238 Although procoagulant and factor levels may be reduced in young patients with CHD resulting from immature or impaired hepatosynthesis,239 functional bleeding tendencies are usually not present before surgery. Furthermore, compounding the problem of immature coagulation proteins is the massive hemodilution that occurs when initiating CPB in infants and small children. Despite advances in circuit miniaturization, initiation of CPB induces a dilutional thrombocytopenia and reduces levels of factors II, V, VII, VIII, IX, X, ATIII, and fibrinogen.240 Patients with cyanotic heart disease demonstrate an increased bleeding tendency before and after CPB because of a range of factors including thrombocytopenia, low numbers of von Willebrand factor multimers, clotting factor deficiencies, and poor fibrinogen function.241 CPB is a significant stimulant of the coagulant and inflammatory systems, requiring anticoagulation with heparin before its initiation. Heparin is traditionally administered based on patient weight, at an empiric dose of 400 units/kg. Adequacy of heparinization is monitored by the activated clotting time (ACT), a measure of inhibition of the contact activation pathway, with a goal ACT of greater than 480 seconds prior to initiation of CPB. An accurate ACT requires normothermia, normal platelet count and function, and normal levels of other coagulation proteins including antithrombin III. As these derangements are common in children having cardiac surgery, the ACT may not be the ideal monitor of anticoagulation in this population. In neonates, infants, and young children, the ACT does not correlate with plasma heparin concentration,242 and children exhibit evidence of ongoing thrombin generation and coagulation activity despite very high ACT values.243 An alternative to weight-based heparin dosing is use of a blood heparin concentration-based system, which utilizes protamine titration to indicate whole blood heparin concentration at the bedside. Such a setup allows for individual variability in heparin efficacy and metabolism. Although blood heparin concentration devices have shown disappointing results in adults, results in children suggest greater suppression of thrombin generation and hemostatic activity,244 reduced number of blood transfusions, and improvement in clinical outcomes of ventilator hours and ICU stay.245 Blood heparin concentration systems also account for bypass circuit characteristics when deciding heparin dose in the bypass prime. In the absence of such a system, empiric dosing is recommended at 1 to 3 units/mL of priming solution. An important caveat to anticoagulation management in infants is the role of antithrombin III, the body’s most abundant natural anticoagulant and target for heparin efficacy. Neonates have low levels of antithrombin III activity,246,247 and those with CHD have a functional antithrombin III level of approximately 50%.248 Heparin exerts its anticoagulant

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300

200

100

CPB

0 0

I

Postbypass

II

III

ICU

IV

V

Stages PTT Fibrinogen Bleeding time Antithrombin III PT Platelet count Activated clotting time

Fig. 78.13  Plot of blood coagulation profile changes before, during, and after cardiopulmonary bypass (CPB) in 25 children. Clotting times and coagulant factors are shown as percent change from control. Stage I, baseline, before CPB; stage II, post-CPB, before protamine reversal of heparin; stage III, after protamine; stage IV, just before leaving the operating room; stage V, after 3 hours in the intensive care unit (ICU). PT, Prothrombin time; PTT, partial thromboplastin time.

effect by accelerating the reaction between thrombin and antithrombin. Low antithrombin activity is one reason for low heparin sensitivity in the pediatric cardiac population; however, large clinical trials examining antithrombin III replacement have not been conducted. In addition, other heparin cofactors, including α2-macroglobulin, may play an important, though poorly understood, role in anticoagulation in young children.249 Heparin is neutralized with protamine according to the quantity of heparin administered or based on body weight, usually 2 to 4 mg/kg, accounting for heparin administered to the patient only (excluding heparin added to the pump prime). Blood heparin concentration devices may be used to dose protamine according to the amount of circulating heparin in the patient, accounting for metabolism or recent dosing. Delayed hepatic clearance of heparin resulting from organ immaturity and the predominant use of hypothermic circulatory arrest in the young decrease metabolism and excretion of heparin. Younger children require relatively more protamine compared to older children and adults, as reflected by higher circulating heparin levels after CPB.250 Prolonged ACT after adequate protamine dosing may indicate platelet dysfunction, hypofibrinogenemia, or other coagulation abnormalities. This should be assessed before administering additional protamine, which in excess may contribute to postoperative bleeding.251 Bleeding after CPB is not an unusual occurrence. The surgeon should first attempt to identify any obvious source of surgical bleeding at the sites of repair. In general, standard coagulation tests show a prolongation of the partial thromboplastin time, prothrombin time, hypofibrinogenemia, dilution of other procoagulants, and prolonged bleeding time in many pediatric patients, with and without bleeding (Fig. 78.13). The most common reason for persistent

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SECTION V  •  Pediatric Anesthesia

bleeding is platelet dysfunction,252-254 and empiric platelet administration can be warranted. Routine administration of blood products to correct laboratory coagulation abnormalities in the absence of bleeding is never clinically indicated. Under most circumstances, meticulous surgical technique, appropriate administration of protamine, adequate patient temperature, and platelet infusion will correct excessive bleeding. Risk factors for bleeding after bypass include lower body weight,255,256 lower temperatures on bypass,257 resternotomy,257 preoperative congestive HF,257 and presence of cyanotic CHD.256 In these populations, a more aggressive approach is warranted. Although use of transfusion algorithms demonstrate reduced transfusion and even decreased mortality in adults having cardiac surgery,258,259 no large or multicenter trials have been conducted examining transfusion algorithms in children. Complicating the development of algorithms in children is the heterogeneity in congenital defects, the surgical operation performed, and the complexity across congenital heart centers.260 However, several single-center studies show that use of viscoelastic testing (particularly rotational thromboelastography) to guide transfusion after bypass surgery may reduce transfusion requirement256,261,262 and ICU days.262 These studies provide reasonable thresholds for initiating transfusion after bypass as guided by rotational thromboelastometry (ROTEM) parameters, but no large prospective studies have been conducted to validate the targets. Importantly, use of either thromboelastography or ROTEM in children having cardiac surgery must be interpreted against age-appropriate reference values.263,264 Pharmacologic interventions are increasingly used to reduce bleeding after CPB. Antifibrinolytics exert their effects by reversibly binding to lysine analogue sites on plasminogen, a molecule primarily responsible for the breakdown of fibrin. By inhibiting plasminogen, and therefore plasmin, the procoagulant effects of fibrin remain. Lysine analogues epsilon amino-caproic acid and tranexamic acid are efficacious in reducing bleeding and transfusion requirement in pediatric cardiac surgery.265 A large-scale observational study of 22,258 patients found that the serine protease inhibitor aprotinin had effects similar to those of both aminocaproic acid and tranexamic acid in terms of reducing bleeding requiring surgical intervention and mortality.266 Unfortunately, aprotinin was removed from the United States market because of concerns of life-threatening anaphylactic reactions.237,267-271 Dosing schemes for antifibrinolytic therapy are variable, though neonates require reduced loading and infusion doses compared to older children and adults because of decreased clearance.272 After bypass surgery, desmopressin acetate has been administered to improve platelet function with variable success in reducing postoperative blood loss.273,274 Factor concentrates are increasingly used off-label in pediatric cardiac populations to provide needed coagulation factors in small children who may not tolerate the volume of fresh frozen plasma or cryoprecipitate required to satisfactorily raise factor levels.275 Observational evidence suggests that recombinant activated factor VII is efficacious as a rescue agent for protracted after-bypass bleeding, after the transfusion of platelets, fibrinogen, and coagulation factors to provide adequate scaffolding for its

action.275 Fibrinogen concentrate has also been used to replace fibrinogen in pediatric cardiac patients and may be used in place of cryoprecipitate.276 Prothrombin complex concentrates (PCCs) are purified plasma-derived products containing vitamin-K–dependent clotting factors (II, VII, IX, X) in either 3- (3F) or 4- (4F) factor preparations. PCCs are included in many transfusion algorithms in adult cardiac surgical populations but the safety and efficacy in pediatrics remains understudied.277 Both 3- and 4-factor PCC improve thrombin generation in ex vivo studies of neonatal plasma,278,279 but most evidence for clinical use is limited to case reports or small case series. At our institution, we administer 3-factor PCC as part of a transfusion algorithm in severe hemorrhage, after replacement of platelets, fibrinogen, and other coagulation factors. Blood transfusion during the perioperative period must be thoughtful and intentional. Injudicious use of blood products to correct individual coagulation abnormalities separately further exacerbates dilution of existing procoagulants, and carries the risk of multiple donor exposures. Transfusion should be undertaken as specifically indicated by an impairment in tissue oxygenation or documented coagulopathies with clinically significant bleeding. Interestingly, while transfusion algorithms may reduce transfusion, in pediatric populations they may be more likely to alter the pattern of transfusion,262 for example decreasing RBC transfusion while increasing platelet and cryoprecipitate use. Algorithms may improve hemodynamic stability262; research is needed to confirm improved outcomes. Determining the optimal hematocrit is necessary to guide transfusion and is best decided in conjunction with the surgeon based on an individual patient’s lesion, complexities, and planned procedure. RBCs should be administered to maintain a postdilutional hematocrit of at least 20% on CPB280; children with cyanotic CHD require a higher hematocrit. A recent study demonstrated an association between the indication for blood transfusion and postoperative morbidity in a cohort of children having cardiac surgery. Study results indicated that patients who required transfusion to maintain a target postdilutional hematocrit on pump had no increase in morbidity, while those requiring a therapeutic transfusion experienced severe morbidity and mortality.281 An increasingly recognized problem in pediatric cardiac surgical populations is thrombosis. Approximately 11% of children having cardiac surgical procedures experience a thrombotic complication282; risk factors include younger age,282,283 cyanotic disease,282,283 use of DHCA,282 longer duration of in situ central lines,282 and administration of blood products in the absence of intraoperative coagulation testing.284 Alterations in levels of pro- and anti-coagulants in the immature pediatric patient combined with the inflammatory effects of bypass create a hypercoagulable state in many patients postoperatively.285 Decreased antithrombin III levels after cardiac surgery are associated with thrombotic events in adults286 but this has not been evaluated in children. Further, the ability of the infant’s immature antifibrinolytic system to lyse clots composed of adult fibrinogen may be impaired.287 The techniques of thoughtful transfusion and blood conservation must be continued as the patient is transferred

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78 • Anesthesia for Pediatric Cardiac Surgery

to the ICU. Isolated coagulation abnormalities are often present in the postoperative patient with uncomplicated cardiac issues (see Fig. 78.13), but are not associated with excessive bleeding and self-correct during the first postoperative day. Routine correction of these abnormalities with infusion of blood products is not warranted. Administration of blood products should not occur in the absence of clinical evidence of bleeding and the identification of a specific defect requiring targeted component therapy. Routine use of blood products for volume replacement is also to be avoided; lactated Ringer or saline solution can be satisfactorily administered at a reduced cost without the hazards associated with transfusion. 

Postoperative Management Immediate postoperative care of the pediatric patient who has undergone cardiothoracic surgery is an important period in the overall sequence of anesthetic and surgical management. Although the primary influence on outcome is determined by the conduct of the operation, postoperative care is an important factor. As a member of the operative team, it is necessary that the anesthesiologist understand and become involved during the immediate postoperative period. Detailed principles of postoperative management of pediatric cardiac surgical patients are beyond the scope of this chapter. However, a few general guiding principles and approaches are given to provide fundamental knowledge for the anesthesiologist. The postoperative period can be characterized by a series of physiologic and pharmacologic changes as the body convalesces from the abnormal biologic conditions of CPB and cardiac surgery. During this period, the effects of the cardiac operation, any underlying disorders, the effects of hypothermic CPB, and special techniques such as DHCA may create special problems. In the immediate postoperative setting, abnormal convalescence and specialized problems must be recognized and managed appropriately. Fortunately, most patients are able to balance the cost imposed by the physiologic trespass created by the surgical repair and the effects of CPB against the benefit of reduced pathophysiologic loading conditions, resulting in low morbidity and mortality. Therefore, the guiding principle in the management of the postoperative patient is an understanding of both normal and abnormal convalescence after anesthesia and cardiac surgery. The immediate postoperative period, even that of normal convalescence, is one of continuous physiologic change because of the pharmacologic effects of residual anesthetic agents and the ongoing physiologic changes secondary to abrupt alteration in hemodynamic loading conditions, surgical trauma, and extracorporeal circulation. Anesthesia and surgery affect not only the patient’s conscious state but also cardiovascular, respiratory, renal, and hepatic function; fluid and electrolyte balance; and immunologic defense mechanisms. Despite these changes, postoperative care should be predictable and standardized for most patients undergoing cardiac procedures. In general, the four temporal phases of postoperative management in the cardiac patient are (1) transport to the

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ICU, (2) stabilization in the ICU, (3) weaning from inotropic and ventilatory support, and (4) mobilization of fluids. Patients proceed through these phases at variable rates based on such factors as the underlying disease process, preoperative medical condition, sequelae of the surgical procedure, duration of CPB, and presence or absence of intraoperative complications. One of the most important functions of the ICU team is to identify postoperative complications in the patient who convalesces abnormally and to provide interventional therapy. Because physiologic change after cardiac surgery is dramatic but self-limiting during normal convalescence, recognition of abnormal processes can be difficult. Under such circumstances a uniform, multidisciplinary approach with experienced clinicians and nurses facilitates the identification of any abnormalities in convalescence. These abnormalities often are indications for closer observation, more invasive monitoring, pharmacologic intervention, and increased cardiopulmonary technical support. Complications include hypovolemia, residual structural heart defect, right and left ventricular failure, hyperdynamic circulation, pulmonary artery hypertension, cardiac tamponade, arrhythmias, cardiac arrest, pulmonary insufficiency, oliguria, seizures, hypercoagulable state, thrombosis, and brain dysfunction. It is critical to detect these departures from the normal convalescent course and to treat them aggressively. One important area in which the anesthesiologist can aid the recovery of the cardiac patient is pain control. Pain and sedation are among the most common problems requiring ICU intervention. Many factors influence the onset, incidence, and severity of postoperative pain. The attenuation of the stress response in the immediate postoperative period using infusions of potent opioids in the critically ill infant reduces morbidity.95 Attenuation of postoperative pain can be attempted with a preoperative medication and an intraoperative anesthetic management technique that includes the use of potent opioids. Patients who receive no opioids preoperatively or during the operative procedure will require analgesics in the immediate postoperative period once the inhalation anesthetic is eliminated. Most cases of postoperative pain can be managed by the administration of small intravenous doses of opioids, usually morphine or hydromorphone. This is important in a patient being weaned from the ventilator during the early postoperative period. Patients who are intubated and ventilated overnight should receive adequate sedation and pain control until ventilatory weaning is begun. This is usually accomplished by a continuous infusion of a benzodiazepine and an opioid. Continuous infusion of sedatives and analgesics results in a more consistent and reliable control of postoperative pain. When separated from mechanical ventilation, the patient is concurrently weaned from the sedatives and analgesics. In patients with reactive pulmonary artery hypertension, opioids have been shown to prevent hypertensive crisis.92 Regional anesthesia may be used for postoperative pain control in infants and children after thoracotomy. This method avoids opioid-induced respiratory depression from intravenous doses of these drugs. The administration of opioids in the epidural space is a very effective approach to pain management. This technique is used in children for postoperative pain control via the caudal route as a “single

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SECTION V  •  Pediatric Anesthesia

shot” or by a small caudal catheter. Morphine or hydromorphone provides effective analgesia with a duration of 6 to 12 hours, with no significant respiratory depression. Caudal morphine 0.05 to 0.075 mg/kg delivered in a total volume of 1.25 mL/kg of sterile saline has been used with good success in our practice. The use of regional anesthesia for postoperative pain appears to be best suited for the child extubated in the early postoperative period. Relative contraindications of this technique include hemodynamic instability and patients with abnormal clotting profiles and/ or continued active bleeding. Using regional analgesia can result in better arterial oxygenation, a more rapid ventilator weaning, and decreased postoperative respiratory complications. However, urinary retention occurs frequently in patients without a bladder catheter. Children requiring large thoracotomies or a bilateral thoracosternotomy (i.e., “clamshell”) incision merit consideration for thoracic epidural analgesia. This technique significantly reduces the respiratory depression and pulmonary mechanics abnormalities that accompany the quantity of systemic opioids that would be necessary to provide adequate analgesia for these excruciatingly painful incisions. If the procedure requires systemic heparinization, we will typically defer placement of these catheters until the heparin effect is neutralized. For the patient undergoing coarctation repair via a left thoracotomy there is some concern for paraplegia following the operation. However, as the incidence of paraplegia in children is exceedingly low, we usually choose to place the caudal or epidural catheter before surgical incision to maximize the benefit intraoperatively; however some centers choose to place it at the end of surgery after it is clear there is no neurologic impairment. For patients undergoing heart, lung, or dual transplantations, a thoracic epidural catheter is placed at a time in the postoperative period when the patient can be weaned from intravenous medications that would adversely affect the patient’s ability to breathe in close proximity to the planned extubation. It is helpful for these patients to have a functioning thoracic epidural catheter for several days.

POSTOPERATIVE NEUROPSYCHOLOGIC MORBIDITY Neurologic morbidity has been identified to be increasingly problematic in neonates and infants with CHD as surgical mortality rates have improved. Although early postoperative CNS sequelae such as stroke and seizures occur in a small percentage of neonates with CHD, the importance of more subtle neurologic abnormalities at long-term followup is being increasingly recognized.222,231,288 These findings may include fine and gross motor impairments, speech and language delays, disturbances in visual-motor and visual-spatial abilities, attention-deficit disorders, learning disorders, and impaired executive functioning. The presence of congenital brain disease in patients with CHD represents a challenge in improving long-term neurologic outcomes. Many neonates with CHD have congenital structural brain abnormalities, chromosomal abnormalities, or both, as well as physiologic abnormalities that may impair brain development. Brain abnormalities on head ultrasonography have been noted in one fifth

of full-term infants undergoing heart surgery, with half of them being present preoperatively.288 Postoperatively, secondary neurologic injury may be related to post-CPB alterations in cerebral autoregulation and additional hypoxic-ischemic insult, seizures, or other issues associated with prolonged ICU stay. In addition to prenatal and modifiable perioperative factors, genetic and environmental factors are known to be important. Unfortunately, modifiable perioperative factors may explain less of the variability in long-term outcomes than do patientspecific factors. New, postoperative neurologic injury may be detected clinically in over 10% of infants,288a increasing to over 50% using more sensitive brain imaging techniques such as MRI.289,290 Given that new neurologic injury can occur at various time points during the neonate’s hospitalization, perioperative attention to reducing known risk factors is critical. Mechanisms of CNS injury in infants undergoing cardiac surgery include hypoxia-ischemia, emboli, reactive O2 species, and inflammatory microvasculopathy. Preoperatively, the primary focus is on preventing hypoxic-ischemic injury and thromboembolic insults. Modifiable intraoperative factors associated with CNS injury include, but are not limited to, pH management, hematocrit during CPB, regional cerebral perfusion, and the use of DHCA. The adverse effects of CPB may be greater in infants than larger children or adults given the immaturity of their organ function and tissues, and the size of the CPB circuit relative to their body size.291 However, a significant amount of research has been conducted in the area of intraoperative prevention of neurologic injury. With ongoing changes in technology and new therapies, the conduct of CPB and other support techniques have been actively under investigation. The developmental consequences of exposure to general anesthetics are not well understood and are difficult to elaborate on in the absence of prospective randomized controlled trials, because of multiple factors that affect neurologic outcome in this population. Current literature suggests that multiple exposures, cumulative doses of exposure, and exposure in infancy might increase the risk for neurodevelopmental delay.292-298 Thus, pediatric cardiac anesthesia is associated with all three risk factors, so attempting to minimize time of exposure, bundling of necessary procedures only if it will shorten the overall exposure to anesthesia, and delaying nonessential procedures to an age associated with less neurologic risk might be appropriate. Careful choice of anesthetic agents that do not act on different neuroreceptors at key time points in development might be critical. Our current practice has evolved to minimize neurotoxicity with time under anesthesia minimized by getting help early if there is difficulty with intravenous access and having the surgeon in the room and ready to start immediately postinduction. NIRS monitors are used in all cases to optimize cardiac output and help define the need for blood transfusions. Multiple anesthetics are combined and administered in lower individual doses with the thinking that this is less toxic than a single anesthetic at a higher concentration. In all cases, a dexmedetomidine infusion is administered to decrease the dose of the other hypnotics and, when possible, regional techniques are used to reduce the total anesthesia dose. 

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78 • Anesthesia for Pediatric Cardiac Surgery

MECHANICAL ASSIST DEVICES Survival in children with congenital cardiac as well as pulmonary defects has improved over recent decades as a result of improved preoperative management, surgical techniques, anesthesia management, drug therapies, and postoperative management. Despite these advances, patients may still require therapies for both acute and chronic HF that are refractory to medical therapy. Mechanical support in the form of ECMO or VADs may then need to be instituted. Examples of conditions that may require support include failure to wean from CPB, acute cardiac arrest, malignant arrhythmia, and worsening myocardial function secondary to the underlying congenital defect or related to acquired cardiomyopathy. Fortunately, however, the incidence is small, with less than 2% of post-CPB patients requiring this intervention.299 Mechanical support can thus be used as a treatment option to allow for recovery of ventricular function, as a bridge to transplant, or to support the heart in those with marginal functional reserve requiring invasive diagnostics or treatments (e.g., Williams syndrome with severe supravalvular pulmonary or aortic stenosis). As with any therapy, contraindications must be excluded before embarking on the use of a mechanical assist device. These may include extreme prematurity, severe and irreversible multiorgan failure, incurable malignancy, and preexisting neurologic devastation.299 Anesthetic management in the use of ECMO is supportive, with management limited to assistance in the resuscitative efforts and hemorrhage associated with the cardiac surgery that was ongoing at the time of conversion to ECMO. Once the patient is on full ECMO support, ventilation is continued but at a slower rate of ventilation on the order of 10 breaths/min, with a peak pressure of 20 cm H2O, PEEP set at 5 to 10 cm H2O, and FiO2 decreased to about 40%. These settings aid in the prevention of atelectasis with management of CO2 and O2 related to flow across the circuit membrane. This is very different from the patient into whom a VAD is placed. Here the anesthesiologist continues to manage the patient as for routine CPB weaning. If a systemic VAD is placed, careful attention must be given to the ventricle pumping blood into the pulmonary bed because failure of this ventricle will have disastrous consequences. Thus, management tailored to unload this pulmonary ventricle is vitally important and will include inodilators in the form of phosphodiesterase inhibitors, inotropic support, and possibly even inhaled NO to decrease PVR and promote forward flow. In association with the perfusionist, intravascular volume loading is assessed and maintained for effective functioning of the VAD and thus adequate offloading of the assisted ventricle. Careful attention to pulmonary function is also vital. Adequate pulmonary toilet, recruitment maneuvers, and appropriate ventilatory parameters must be used. Bleeding is a potential complication in the implantation of the VAD and thus a clear strategy must be planned for in the form of antifibrinolytics, adequate volumes of blood and blood products, and even possibly the use of activated clotting factors (e.g., factor VII, PCCs).300 As can be seen in Table 78.10 differences can be appreciated between assist devices. The potential for bleeding exists at the time of insertion of both of these modalities; however, it would seem from clinical experience that because of the

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TABLE 78.10  Comparison of Extracorporeal Membrane Oxygenation Versus Ventricular Assist Device Comparison Factors

ECMO

VAD

Bleeding at insertion

++

++

Sternotomy

Not required

Required

Left atrial venting

±

−

Blood product use

+++

+

Number of cannulae for biventricular support

2

4

Pulmonary support

+

−

Intravenous anticoagulation

+

±

Duration of support

Weeks

Months

Emergent support

Yes

No

Patient mobility

−

+

ECMO, Extracorporeal membrane oxygenation; VAD, ventricular assist device.

extensive dissection and need for sizeable ventriculotomy, implantation of a VAD (and especially bi-VAD) is more problematic. The requirements of anticoagulation to keep the ACT in the range of 180 to 200 for ECMO also may lead to ongoing and significant bleeding, especially if placed into a patient who requires support in the immediate perioperative phase. The use of an ECMO circuit with a membrane oxygenator requires ongoing intravenous anticoagulation with maintenance of the ACT in the aforementioned range. Apart from the immediate postoperative phase, patients with VAD systems can be transitioned to oral agents. A twopart therapy is recommended. Antiplatelet therapy includes aspirin or clopidogrel. The second part of the therapy will entail the use of anticoagulation with either warfarin (Coumadin) or subcutaneous low-molecular-weight heparin.299 Three potential disadvantages exist in the use of the VAD system. The lack of pulmonary support when using the VAD limits its use to patients whose lung function is adequate. Second, Table 78.10 illustrates that biventricular support requires two separate VAD devices, necessitating the placement of four cannulas, which may be technically difficult in a very young child. The third disadvantage is that VAD placement cannot be performed in a code situation or at the bedside as with ECMO. Important advantages of the VAD system are the ability of patients to ambulate while on support and that VAD support can be maintained for months in contrast to the weeks only of ECMO support. Another important advantage over ECMO is that these patients will not require further venting of the LA. In patients on ECMO this is achieved by the placement of a left atrial vent at the time of sternotomy or a balloon atrial septostomy, which may require transfer to the catheterization laboratory with the possible complications associated with transport of a patient on an ECMO circuit. Despite successful resuscitation and placement onto mechanical assist devices, morbidity and mortality remain high, with ECMO appearing to have worse outcomes. The mortality rate for ECMO in the 1990s was on the order of 47%, with survival in series published in the early 2000s not showing much improvement.301-304 In contrast, the survival for those into whom a VAD is placed appears to

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be superior within the quoted series, with up to 80% of patients surviving to transplantation or being successfully weaned from support.303,305 In the study by Blume and co-workers,302 however, it was noted that associated CHD, and patients who are younger and smaller, have a higher mortality than those with fulminant myocarditis and cardiomyopathy.302 Alongside survival data, the next most important marker is neurologic outcome, and it appears that this is also better in the VAD group.306,307 Risk factors for poor neurologic outcome were once again of low weight and duration of DHCA, both of which place patients on ECMO at a survival disadvantage because patients on ECMO will be smaller and some of those who undergo DHCA for repair of congenital anomalies will require emergent ECMO support to wean from CPB or in the immediate postoperative phase.308 Survival predictors are important in our management of these patients. One common variable that can predict survival is the return of ventricular function between 3 and 5 days after the initiation of support.304,308 Both of these modalities have been used successfully as a bridge to transplantation, with patients with a VAD having a greater than 80% survival to transplantation and patients on ECMO showing a less than 60% survival. Yet ECMO is used often in the infant population and in those with complex CHD, both of which are factors known to increase mortality among VAD patients.308 The important causes of morbidity and mortality in patients on both of these modalities include cerebrovascular events secondary to either hemorrhagic or embolic phenomena, circuit-related issues (e.g., circuit thrombosis), renal failure requiring hemofiltration, sepsis, ongoing hemorrhage, and multiple-organ failure. Although these modalities are often compared to each other, they both have unique places in the care of children with cardiac disability. ECMO has a great advantage in that it can be employed rapidly in a code situation for a patient of any age or size. In the past, size has been the limiting factor for implantation of VAD systems into pediatric patients. The Berlin Heart VAD (Berlin Heart AG, Berlin, Germany) is a pulsatile-flow device and available for use even in neonates. The system has been employed in Europe for over 20 years and has pump sizes from 10 to 80 mL. Although this is currently the only FDA-approved VAD for children, a high incidence of adverse events such as embolic stroke, bleeding, and infections are noted.309 This has led to the increased use of adult continuous-flow devices including the HeartMate II (Thoratec Corp., Pleasanton, CA) and HeartWare HVAD (HeartWare Inc., Framingham, MA) in children who may need it for longer periods of time, or who will potentially discharge home on the device. The Infant Jarvik VAD, a pediatric-specific continuous-flow device is currently undergoing pre-clinical testing. There are a number of other short-term VAD options that can provide additional organ support including oxygenation, hemodialysis, and plasma exchange if needed. The CentriMag/PediMag (Thoratec Corp., Pleasanton, CA) and the Jostra Rotaflow (MAQUET Cardiovascula, Wayne, NJ) are both rotary or centrifugal pumps used for short-term VAD support in multiorgan failure patients. Finally, there are percutaneous VADs now small enough to place in children. The Impella 2.5 (Abiomed Inc., Danvers, MA) is an axial VAD catheter that has been used in children as small

as 22 kg. One can appreciate how these modalities complement each other, with ECMO being used acutely, and then once the patient is physiologically stable, but still requiring support, a VAD can be implanted for intermediate or longterm support. Recent data from the Organ Procurement and Transplant Network supports a survival to transplant advantage for patients with VAD (in particular, CentriMag) compared to ECMO.310 A newer mechanical assist device for use in children is the temporary Total Artificial Heart (TAH) system. The TAH system is indicated for use as a bridge to transplant for patients at imminent risk for death from biventricular failure. The implantation and use of this device is unique in that it requires the complete removal of the native myocardium, such that recovery without transplantation is not possible. Once the myocardium is removed, inflow and outflow pumping chambers are sown into the right and left heart vessels. Sizing requirements include patient body surface area of 1.7 m2 or greater, echocardiographic left ventricular end-diastolic diameter of 70 mm or greater, a CT scan with an anterior-to-posterior dimension at the 10th thoracic vertebrae of 10 cm or greater, and a chest radiograph with a cardiothoracic ratio of 0.5 or greater. Smaller TAH devices may be available soon, which would allow implantation in smaller patients. This device has been used successfully as a bridge to transplant in a patient with failing Fontan physiology who later went on to receive a heart transplant. 

Anesthesia for Heart and Lung Transplantation Although perioperative management for thoracic organ transplantation is considered elsewhere in this text, the application of these procedures to children requires some specific modification. Differences include the characteristics of the candidates, preparation of these children, anesthetic management, surgical considerations, post-CPB management, and outcome. Even though some of the earliest heart transplant procedures were performed for congenital heart malformations, this indication became rare by the early 1980s. In 1984, over 60% of the few pediatric heart transplant procedures were performed in patients with cardiomyopathy, usually adolescents. In the next decade, a dramatic rise in the number of infants and young children with congenital heart malformations treated with heart transplantation resulted in a marked shift in the demographics (Fig. 78.14).311 By 1995, over 70% of the children receiving heart transplants were younger than 5 years of age, with half of those younger than 1 year. The overwhelming majority of these infants received transplants for congenital heart malformations for which reconstructive options either had failed or were not believed to exist (Fig. 78.15).311 The implications of this shift reach into every element of perioperative management. Children considered for heart transplantation are more likely to have pulmonary hypertension than adults. Most adult transplant programs will not offer heart transplant therapy to patients with PVR over 6 Wood units/m2.312The exclusion threshold in infants and children remains controversial. Some programs accept patients with PVR as high

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78 • Anesthesia for Pediatric Cardiac Surgery

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Number of transplant procedures

400 6-15 1-5 1

350 300 250 200 150 100 50 0

1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997

Fig. 78.14  Demographic data for pediatric heart transplantation by age.  Stacked bar graph illustrates the total number and age distribution for heart transplantation in patients younger than 16 years of age. Note the rapid rise in transplant procedures performed during the late 1980s, with particular growth in the population of children 5 years of age and younger. Having peaked in the mid-1990s, the total number of transplant procedures (both adult and pediatric) has declined slightly, but the relative age proportions within the pediatric population remain relatively constant. (Data from the Registry of the International Society for Heart and Lung Transplantation, Addison, TX.)

100

80

60

40

20

0

1

1-5

6-15

0-15

Age (yr) Retransplant Myopathy Congenital

Fig. 78.15  Indication for heart transplantation in children. Over the past 2 decades, the major indications for pediatric heart transplantation were nearly equally divided between congenital malformation and cardiomyopathy. In later years, pediatric recipients with congenital malformations assumed a slight plurality as a result of shifting age demographics. As illustrated, younger children are more likely to undergo heart transplantation because of congenital malformation. (Data from the Registry of the International Society for Heart and Lung Transplantation, Addison, TX.)

as 12 Wood units/m2, particularly if the pulmonary vasculature responds to vasodilators such as O2, NO, calcium channel blockers, or prostacyclin.313 Neonates are generally assumed to have elevated PVR, but outcome data from some programs suggest that the importance of this factor for postoperative outcome is substantially less in the first year of life, perhaps because the infant donor hearts, having recently undergone transitional circulation, are better prepared to cope with the right ventricular pressure load that elevated PVR imposes.314 The anesthetic plan for pediatric heart transplantation must accommodate a wide spectrum of pathophysiology. Recipients with congenital heart malformations benefit from the analysis of loading conditions and optimizing hemodynamics discussed previously. Although a few

of these patients undergo heart transplantation because the natural history of reconstructive heart surgery poses greater risk despite reasonable ventricular function, most candidates exhibit some manifestations of impaired ventricular performance. Accordingly, they require careful titration of anesthetic agents with minimal myocardial depressant characteristics to avoid cardiovascular collapse. In this fragile population, even modest doses of opioids can be associated with marked deterioration in systemic hemodynamics, presumably by reducing endogenous catecholamine release. As with most congenital heart patients, skilled management of the airway and ventilation represents crucial elements in a satisfactory induction, particularly in the presence of elevated PVR. No matter how elegant the anesthetic plan in conception and implementation, a certain proportion of these children will decompensate on induction, necessitating resuscitative therapy. A particularly critical time is that of central line placement, when transplant patients may not tolerate the Trendelenburg position; a level table and the use of ultrasound is sufficient to place a central line. Although orthotopic heart transplantation poses technical challenges in neonates and young infants, the replacement of an anatomically normal heart is less complex than several reconstructive heart procedures commonly performed in patients at this age. However, the need to adapt this procedure to incorporate repair of major concurrent cardiovascular malformations requires the consummate skill and creativity that remain the province of a few exemplary heart surgeons in congenital disease.315,316 Having withstood extended ischemic periods, heart grafts are extraordinarily intolerant of superimposed residual hemodynamic loads that may accompany imperfect vascular reconstruction. The extensive vascular repair and, particularly in older children with long-standing hypoxemia, the propensity to coagulopathy together elevate hemorrhage to a major cause of morbidity and even mortality in pediatric heart transplantation. Nevertheless, once successfully implanted, these grafts will respond to physiologic factors that stimulate growth and adaptation in the developing infant and child.317 Management considerations during separation from CPB and the early postoperative period are primarily focused on three pathophysiologic conditions: myocardial preservation, denervation, and PVR. Even expeditious transplant

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SECTION V  •  Pediatric Anesthesia

procedures usually force the heart to endure ischemic periods that exceed those encountered during reconstructive surgery. Although some researchers believe the infant heart is more tolerant of extended ischemia, these hearts will demonstrate a period of reperfusion injury, and virtually all require pharmacologic and, in some cases, mechanical support.314 In addition, endogenous adaptive responses and exogenous pharmacologic agents that act by myocardial sympathetic activation are ineffective in the denervated graft. Because the majority of children presenting for heart transplantation exhibit some element of elevated PVR, even with isolated end-stage cardiomyopathy, the RV of a newly implanted heart is particularly vulnerable to failure. Ventilatory and pharmacologic interventions are usually configured to exert a favorable impact on PVR and provide inotropic and chronotropic support. Once the lungs are fully expanded, we ventilate to PaCO2 values in the low 30 mm Hg range using an FiO2 of 1. Virtually all recipients receive low-dose inotropic support such as epinephrine, milrinone, dopamine, and/or isoproterenol to promote inotropy, chronotropy, and lower PVR. As mentioned previously, a major concern is RV dysfunction, hence we will generally start iNO for the immediate post-CPB period. Most transplant centers have a specific regimen for immunosuppression to be initiated in the perioperative period. As with adults, pediatric transplant programs typically employ triple-drug immunosuppression with a calcineurin inhibitor (e.g., cyclosporine, tacrolimus), antimetabolite (e.g., azathioprine), and steroid. After an interval without rejection, some pediatric programs will taper and discontinue one or even two of these agents, particularly in neonates, in whom some element of tolerance develops.318,319 Survival after pediatric heart transplant is improving. The principal risk factors are age younger than 1 year and congenital heart defects. Because these factors are closely related (i.e., the vast majority of infants younger than 1 year of age undergo transplantation for a congenital heart defect), it is difficult to determine the independent effect of age. Concurrent repair of structural cardiovascular anomalies substantially increases perioperative risks for hemorrhage, residual hemodynamic loading conditions, and right-sided HF from elevated PVR. The greatest risk of mortality is found in the first year after transplant; however, infants who survive the first postoperative year have better long-term survival than other age groups.320. Average survival for infants is 18 years of age, which is the time at which 50% of patients are alive after transplant.321 Average survival is 15 years for those transplanted at ages 1 to 10 years of age, and 11 years survival for those transplanted as teenagers. The sequelae of rejection and the consequences of the immunosuppression result in significant ongoing morbidity and mortality; despite advances in pharmacologic therapy, rates of acute rejection in the first year have not changed appreciably.321 A unique quality of neonates is that their immune system remains immature, unable to produce antibodies effectively against foreign blood cells, until approximately 12 to 24 months of age. Infants also have a poorly developed complement system. These developmental characteristics allow for transplantation of an ABO-mismatched organ into an infant, which has expanded the pool of available organs for that population. Anesthetic implications for infants who are candidates for ABO-incompatible transplant surround

transfusion management—these patients should receive only ABO compatible blood products before transplant, and should not receive whole blood.321 Lung and heart-lung transplantation have achieved respectable operative survival rates in children.322 They remain the only viable surgical therapy for infants and children with severe pulmonary vascular disease and selected progressive pulmonary diseases. These remain uncommon procedures in pediatrics. Lung transplantation carries the additional morbidity of obliterative bronchiolitis, a debilitating small airway disease that results in gradual deterioration in flow-related pulmonary functions over time. Despite a low operative mortality rate, 5-year survival is only 53%.322 Patients with transplanted hearts also present for surveillance cardiac catheterizations, biopsies, and other procedures.299,323-325 The anesthesia plan in these patients should take into account the physiologic and pharmacologic problems of allograft denervation, the side effects of immunosuppression, the risk for infection, and the potential for rejection.323-325 Cardiac allograft vasculopathy is the leading cause of morbidity and mortality after transplantation, leading to progressive graft dysfunction with HF, an increased risk for dysrhythmia, and the possibility of arrhythmogenic sudden death. Conventional revascularization procedures are ineffective because cardiac allograft vasculopathy is caused by intimal proliferation leaving retransplantation as the only therapeutic option. Hyperlipidemia after heart transplantation is a common occurrence in both adults and children and is aggravated by chronic steroid therapy and other immunosuppressive agents. Statins are used with good results in controlling hyperlipidemia after transplantation and are likely to manifest inherent immunosuppressive effects. Risk factors for posttransplant renal dysfunction are the use of calcineurin inhibitors, mechanical circulatory support, prolonged inotropic support, and preexisting renal dysfunction. Newer, more potent immunosuppressive agents (e.g., tacrolimus) have led to steroid-sparing regimens late after transplantation, eliminating the detrimental effects of long-term steroid administration. Agents such as sirolimus may now be used in combination with lower levels of calcineurin inhibitors, thus minimizing long-term nephrotoxicity. Posttransplant lymphoproliferative disorders represent a pathologic spectrum of abnormal lymphoid proliferation ranging from localized early lesions to polymorphic disease or, in some cases, monomorphic lymphomatous disease. From a clinical perspective, the most common sites of disease and presenting symptoms included the gastrointestinal tract and pulmonary systems. Patients with polymorphic disease are treated primarily by a reduction or temporary cessation of immunosuppression, along with adjunctive surgical therapy for tissue diagnosis or obstructive lesions. Most centers reserve traditional chemotherapeutic regimens for patients with nonresponsive polymorphic disease and monomorphic disease. As a result of cardiac denervation, autonomic regulatory mechanisms are not available to prevent the wide swings in a patient’s hemodynamic state and the stress response is slower than usual. Cardiac parameters are significantly altered, and patients may experience a decrease in systemic blood pressure and cardiac filling pressures. Compensatory mechanisms are delayed, and reductions in cardiac output lead to decreased coronary

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78 • Anesthesia for Pediatric Cardiac Surgery

and cerebral perfusion, especially on the background of hypertension. Drugs with direct myocardial and vascular effects are the mainstay of therapy. Most immunosuppressive agents affect hepatic and renal functions and interact with anesthetic drugs. 

Anesthesia for Closed-Heart Operations Early corrective repair in infancy has significantly reduced the number of non-corrective, palliative closed-heart operations. Corrective closed-heart procedures include PDA ligation and repair of coarctation of the aorta. Non-corrective closed-heart operations include pulmonary artery banding and extracardiac shunts such as the Blalock-Taussig shunt. These procedures are performed without CPB. Therefore, venous access and intraarterial monitoring are important in evaluating and supporting these patients. A pulse oximeter and NIRS monitors (cerebral and somatic) are invaluable devices during intraoperative management. Ligation of a PDA is typically performed through a left thoracotomy, although video-assisted thoracoscopic techniques are increasingly common.326,327 Physiologic management is that of a left-to-right shunt producing volume overload. Patients with a large PDA and low PVR generally present with excessive PBF and CHF. Neonates and premature infants also run the risk for having substantial diastolic runoff to the pulmonary artery, potentially impairing coronary perfusion. Thus, patients range from an asymptomatic healthy young child to the sick ventilator-dependent premature infant on inotropic support. The health of the former patient allows a wide variety of anesthetic techniques culminating in extubation in the operating room. The latter patient requires a carefully controlled anesthetic and fluid management plan. Generally, a trial of medical management with indomethacin and fluid restriction is attempted in the premature infant before surgical correction. Transport of the premature infant to the operating room can be especially difficult and potentially hazardous, requiring great vigilance to avoid extubation, excessive patient cooling, and venous access disruption. For these reasons, many centers are now performing ligation in the neonatal ICU. A subset of premature infants with PDAs is located at institutions without cardiac surgical teams. Ligation of the PDA in these patients requires either transfer of these high-risk neonates to a center that has a team who routinely perform the procedure or the availability of a team capable of performing the procedure who is willing to travel to perform the procedure in the neonate’s home neonatal ICU (NICU). Gould and associates328 reviewed the experience with onsite and off-site ligations of a team composed of a pediatric cardiac attending anesthesiologist, a certified registered nurse anesthetist, an attending pediatric cardiothoracic surgeon and fellow, and cardiac operating room nurses. There were no anesthetic-related complications in their group. No differences were found in the incidence of perioperative complications in the procedures in the two sites. This study showed PDA ligations can be performed safely in the NICUs of hospitals lacking onsite pediatric cardiac surgical units, without incurring the risk inherent in transport of critically ill infants. In addition, patient care is

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continued by the neonatology team most familiar with the child’s medical and social history and the patient’s family is minimally inconvenienced. Complications of PDA ligation include inadvertent ligation of the left pulmonary artery or descending aorta, recurrent laryngeal nerve damage, and excessive bleeding as a result of inadvertent PDA disruption. Placement of a pulse oximeter on the lower extremity should alert the anesthesiologist and surgeon in the case of inadvertent aortic ligation. After ductal ligation in premature infants, worsening pulmonary compliance can precipitate a need for increased ventilatory support, and manifestations of an acute increase in left ventricular afterload should be anticipated, especially if left ventricular dysfunction has developed preoperatively. PDA ligation has been performed in infants and children using thoracoscopic surgical techniques. This approach has the advantage of limited incisions at thoracoscopic sites, promoting less postoperative pain and discharge from the hospital the same day of surgery. Coarctation of the aorta is a narrowing of the descending aorta near the insertion of the ductus arteriosus. Obstruction to aortic flow results and may range from severe obstruction with compromised distal systemic perfusion to mild upper extremity hypertension as the only manifestation. Associated anomalies of both the mitral and aortic valves can occur. In the neonate with severe coarctation, systemic perfusion depends on right-to-left shunting across the PDA. In these circumstances, left ventricular dysfunction is very common and prostaglandin E1 is necessary to preserve sufficient systemic perfusion. Generally, a peripheral intravenous line and an indwelling arterial catheter, in the right upper extremity, are recommended for intraoperative and postoperative management. In patients with left ventricular dysfunction, a central venous catheter may be desirable for pressure monitoring and inotropic support. The surgical approach is through a left thoracotomy, whereby the aorta is cross-clamped and the coarctation repaired with an end-to-end anastomosis, patch aortoplasty, or subclavian patch. During cross-clamping, we usually allow significant proximal hypertension (20%-25% increase over baseline), based on evidence that vasodilator therapy may jeopardize distal perfusion and promote spinal cord ischemia. Intravascular crystalloid administration of 10 to 20 mL/kg is given just before removal of the clamp. The anesthetic concentration is decreased, and additional blood volume support is given until the blood pressure rises. Postrepair rebound hypertension as a result of heightened baroreceptor reactivity is common and often requires medical therapy. After cross-clamping, aortic wall stress resulting from systemic hypertension is most effectively lowered by institution of β-blockade with esmolol or α/β-blockade with labetalol.329 Recent work indicates that patients younger than 6 years of age should receive an initial dose of esmolol 250 to 500 μg/kg, followed by an infusion of 250 to 750 μg/kg/min, depending on the blood pressure. Despite an esmolol infusion, 25% to 50% of patients have a blood pressure that is above the targeted range, requiring a second drug. Sodium nitroprusside or nicardipine is usually chosen as the second drug. Propranolol is useful in older patients but can cause severe bradycardia in infants and young children. Although it actually increases calculated aortic wall stress in the absence of β-blockade by accelerating dP/

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SECTION V  •  Pediatric Anesthesia

dT (contractile force), the addition of sodium nitroprusside may be necessary to control refractory hypertension. Captopril or an alternative antihypertensive regimen is begun in the convalescent stage of recovery in patients with persistent hypertension. The management of infants undergoing placement of extracardiac shunts without CPB centers on goals similar to those of other shunt lesions—balancing pulmonary and systemic blood flow by altering PaCO2, PaO2, and ventilatory dynamics. Central shunts are usually performed through a median sternotomy, whereas Blalock-Taussig shunts may be performed through a thoracotomy or sternotomy. In patients in whom PBF is critically low, partial cross-clamping of the pulmonary artery required for the distal anastomosis causes further reduction of PBF and desaturation, necessitating meticulous monitoring of pulse oximetry. Careful application of the cross-clamp to avoid pulmonary artery distortion will help maintain PBF. Under circumstances in which severe desaturation and bradycardia occur with cross-clamping, CPB will be required for the procedure. Intraoperative complications include bleeding and severe systemic O2 desaturation during chest closure, usually indicating a change in the relationship of the intrathoracic contents that results in distortion of the pulmonary arteries or kink in the shunt. Pulmonary edema may develop in the early postoperative period in response to the acute volume overload that accompanies the creation of a large surgical shunt. Measures directed at increasing PVR, such as lowering inspired O2 to room air, allowing the PaCO2 to rise, and adding PEEP are helpful maneuvers to decrease PBF until the pulmonary circulation can adjust. Decongestive therapy such as diuretics and digoxin may alleviate the manifestations of CHF. Under such circumstances, early extubation is inadvisable. Pulmonary artery banding is used to restrict PBF in infants whose defects are deemed uncorrectable for either anatomic or physiologic reasons. These patients are generally in CHF with reduced systemic perfusion and excessive PBF. The surgeon places a restrictive band around the main pulmonary artery to reduce PBF. Band placement is very imprecise and requires careful assistance from the anesthesia team to accomplish successfully. Many approaches have been suggested. We place the patient on 21% inspired O2 concentration and maintain the PaCO2 at 40 mm Hg to simulate the postoperative state. Depending on the malformation, a pulmonary artery band is tightened to achieve hemodynamic (e.g., distal pulmonary artery pressure ˙ Qs ˙ 50%-25% systemic pressure) or physiologic (e.g., Qp/ approaching 1) goals. Should the attainment of these objectives produce unacceptable hypoxemia, the band is loosened. 

Anesthesia for Interventional or Diagnostic Cardiac Procedures Advances in interventional and diagnostic cardiac catheterization techniques are significantly changing the operative and nonoperative approach to the patient with a congenital heart defect. Common interventions in the cardiac

TABLE 78.11  Common Interventions in the Cardiac Catheterization Laboratory Device Closures

Coil Embolization

SIMPLE INTERVENTIONS Atrial septal defect (ASD)

Decompressing veins

Ventricular septal defect (VSD)

Aortopulmonary (AP) collaterals

Patent ductus arteriosus (PDA)

Surgical shunts

Patent foramen ovale (PFO)

Coronary/atrioventricular fistulas

Balloon valvuloplasty

Balloon angioplasty

Aortic stenosis (AS)

Branch pulmonary artery stenosis

Pulmonary stenosis (PS)

Coarctation of the aorta

COMPLEX INTERVENTIONS Hypoplastic Left Heart Syndrome (HLHS) After Norwood Pulmonary artery stenosis Angioplasty Shunt thrombosis

Dilation/thrombectomy

Restrictive ASD

Balloon septostomy

Aortic arch obstruction

Angioplasty

AP collaterals

Coil embolization

Post Glenn/Fontan Decompressing veins

Coil embolization

Baffle leaks

Device/coil embolization

Systemic vein stenosis/ thrombosis

Angioplasty/thrombectomy

Right ventricular failure

Creation of fenestration

Exercise intolerance

Closure of fenestration

AP collaterals

Coil embolization

Obstructive Fontan pathway

PA angioplasty, balloon septostomy

Transposition of Great Arteries

Balloon atrial septostomy

Tetralogy of Fallot (TOF) Shunt thrombosis

Thrombectomy

Pulmonary artery stenosis

Angioplasty

AP collaterals

Coil occlusion

MISCELLANEOUS INTERVENTIONS Severe pulmonary hypertension Atrial septostomy ECMO left heart decompression

Atrial septostomy

Stenosis of pulmonary veins

Balloon angioplasty stent

Stenosis/thrombosis of systemic Balloon angioplasty/thrombectomy veins ECMO, Extracorporeal membrane oxygenation.

catheterization laboratory are shown in Table 78.11. Nonoperative interventional techniques are being used instead of procedures requiring surgery and CPB for safe closure of secundum ASDs, VSDs, and PDAs. Stenotic aortic and pulmonic valves, recurrent aortic coarctations, and branch pulmonary artery stenoses can be dilated in the catheterization laboratory, avoiding surgical intervention.330,331

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78 • Anesthesia for Pediatric Cardiac Surgery

These techniques shorten the hospital stay and are particularly beneficial to patients with recurrent coarctation and muscular or apical VSDs, who are at a higher risk for operative intervention. Many patients with complex cardiac defects are poor operative candidates. Innovative interventional procedures improve vascular anatomy, reduce pressure loads on ventricles, and decrease the operative risk for these patients. For example, in TOF with hypoplastic pulmonary arteries, balloon angioplasty and vascular stenting procedures create favorable pulmonary artery anatomy and reduce pulmonary artery pressure and right ventricular end-diastolic pressure. Complications are more common during interventional catheterization and include arterial thrombosis, arrhythmias (especially heart block), hemodynamic instability, embolization of devices or coils, bleeding, perforation of the major vessels or heart, and lung reperfusion injuries.332 Complications are more common in smaller infants, particularly those younger than 6 months of age. Constant vigilance, correction of electrolyte imbalance, maintenance of acid-base status, and appropriate heparinization will mitigate some of the morbidity. Appropriate and early transfusion with deployment of rapid-response ECMO in the resuscitation of an infant in cardiac arrest improves outcome. High-risk patients undergoing diagnostic evaluation of pulmonary artery hypertension in anticipation of heart-lung transplantation also require anesthetic management. Despite the attendant high risks for the procedure in patients with suprasystemic right ventricular pressure, these patients are best managed with general anesthesia and controlled ventilation. Anesthetic management of interventional or diagnostic procedures in the catheterization laboratory must include the same level of preparation that applies in caring for these patients in the operating room. These patients have the same complex cardiac physiology and, in some cases, greater physiologic complexity and less cardiovascular reserve. Interventional catheterization procedures can impose acute pressure load on the heart during balloon inflation. Large catheters placed across mitral or tricuspid valves create acute valvular regurgitation or, in the case of a small valve orifice, transient valvular stenosis. When catheters are placed across shunts, severe reductions in PBF and marked hypoxemia may occur. The anesthetic plan must consider the specific cardiology objectives of the procedure and the impact of anesthetic management in facilitating or hindering the interventional procedure. In general, the three distinct periods involved in an interventional catheterization are the data acquisition period, the interventional period, and the postprocedural evaluation period. During the data acquisition period, the cardiologist performs a hemodynamic catheterization to evaluate the need for and extent of the planned intervention. Catheterization data are obtained under normal physiologic conditions— that is, room air and physiologic PaCO2. Increased FiO2 or changes in PaCO2 may obscure physiologic data. Although some patients may require O2 administration if the PBF is such that the administration of room air may lead to lifethreatening hypoxia, a discussion with the interventional cardiologist is essential in the care of these children. Ideally a patient would be kept spontaneously ventilating, but this

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is impractical. A secured airway allows the anesthesiologist to concentrate on hemodynamic issues. Positive-pressure ventilation also reduces the risk for air embolism; the cardiologist can measure pressures during expiration to obtain the most accurate data. During spontaneous ventilation, a large reduction in intrathoracic pressure can entrain air into vascular sheaths and result in moderate-to-large pulmonary or systemic air emboli. Precise device placement is also facilitated with muscle relaxants that eliminate patient movements and controlled ventilation, thereby reducing the respiratory shifting of cardiac structures. Substantial blood loss and changes in ventricular function occur commonly during the intervention. In the postprocedural period, the success and physiologic impact of the intervention are evaluated. Blood pressure, mixed venous O2 saturation, ventricular end-diastolic pressure, and cardiac output, when available, are used to assess the impact of the intervention. Persistent severe hemodynamic derangement indicates the need for ICU monitoring and respiratory or cardiovascular support. A brief description of some of the interventional procedures and the associated anesthetic implications follows. The success of these interventions will undoubtedly result in widespread availability and use over the next few years.

TRANSCATHETER TECHNIQUE FOR ATRIAL SEPTAL DEFECT CLOSURES In the transcatheter technique for ASD closures, a collapsed double-umbrella clamshell device is loaded into a large introducer sheath placed through the femoral vein, advanced to the RA, and placed across the ASD into the left atrial chamber. Each side of the device consists of a Dacron mesh patch suspended in six spring-loaded arms that open like an automatic umbrella. Using biplane fluoroscopy and TEE, the catheter is positioned in the LA away from the mitral valve.333 The sheath is pulled back to open the six distal arms and its Dacron mesh cover into the LA. The sheath and device are then pulled back so the distal arms contact the left atrial septum. Fluoroscopy and TEE or intracardiac echocardiography are used to confirm that the arms are on the left atrial side and do not interfere with mitral valve motion. Once adequately seated, the sheath is pulled farther back to expose the proximal side of the device and the proximal arms, which spring open to engage the right side of the atrial septum. When proper positioning is certain, the device is released.333 Device closure of secundum ASD is the preferred therapeutic approach. Data continue to support closure of defects of small-to-moderate size ( 5, moderate is PaO2/FiO2 = 100 to 200 with PEEP > 5, and severe is PaO2/FiO2 < 100 with PEEP > 10. □ Traumatic brain injury (TBI) is composed of two components—an initial primary injury owing to direct mechanical deformation of brain parenchyma and a subsequent secondary injury that can develop over hours to days. Secondary injury may be the result of multiple mechanisms including ischemia, excitotoxicity, metabolic failure and eventual apoptosis, cerebral swelling, axonal injury, and inflammation and regeneration. □ A vascular occlusive crisis in the lungs leads to acute chest syndrome (ACS). Acute chest syndrome is the leading cause of death and the second most common complication in sickle cell disease. □ Tumor lysis syndrome is a metabolic crisis precipitated by acute lysis of a large number of tumor cells. Serum uric acid, potassium, and phosphate concentrations are elevated. The elevated phosphate concentrations cause hypocalcemia. □ The role of family in the pediatric intensive care unit (PICU) has evolved over time, and the inclusion of family in the care of their child is now recognized as an important part of critical care. □ Accidents and trauma are the leading causes of death in children 1 to 14 years of age.

Relationship Between the Intensive Care Unit and the Operating Room The field of pediatric intensive care may have originated from anesthesia, but these areas have grown apart over time. Due to the extensive training, there are few individuals who cover both disciplines. With more complex patients, it is likely that care will occur both in the operating room and the intensive care unit (ICU). There needs to be excellent communication between the ICU and operating room clinicians to ensure a seamless transition of care. Many institutions require an attending to attending handoff between the ICU and anesthesia for each case. It

is important that this occurs in the preanesthetic as well as the postanesthetic setting. Information regarding current ICU therapy response can simplify a potentially difficult anesthetic. Similarly, understanding the operative and anesthetic course will guide the next several days of management. A complete anesthesia sign-out includes pertinent past medical history, allergies, ease of mask ventilation, induction agents, ease of intubation, decisions regarding extubation, venous and arterial access, blood products, fluid totals, inotropic agents, medications delivered including timing of antibiotics, complications, laboratory values, and most recent blood gas. This information may be available in the anesthetic record; however, a short verbal summary by the anesthesiologist provides a greater amount of practical detail.  2513

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SECTION V  •  Pediatric Anesthesia

Family Partnered Care in the Pediatric Intensive Care Unit The family is an important part of the critical care team and needs to be included in shared decision making. In pediatric hospitals, families participate in multidisciplinary rounds with their nurses, respiratory therapists, pharmacists, and physician caring for their child. This does not require more time than traditional rounds and it does not compromise teaching.1 There has been a significant push to increase family participation in both pediatric and adult ICUs. Family engagement is part of the ICU Liberation ABCDEF Bundle that is directed and supported by the Society of Critical Care Medicine. A great amount of information is available at www.iculiberation.org. An international multidisciplinary team of experts in neonatal, pediatric and adult critical care recently published Guidelines for Family Centered Care.2 The guidelines address the need for family presence in the ICU, the need for family support beyond the ICU; goals for communication, use of consult services such as Palliative Care and Ethics, and a means to address the operational and environmental issues in ICUs that prevent family engagement. We see significant family satisfaction with participation in rounds and we believe it likely benefits the team and patient as well.3-5 We anticipate a point in the future where we do not need to prove to anyone the need to have family involvement. Giving the family a greater presence in the ICU with more responsibility and autonomy in decision making can increase their anxiety and distress. In addition to the potential development of posttraumatic stress disorder (PTSD) in our patients,6-8 parents of children admitted to an ICU can incur severe emotional distress.9 A recent review places the incidence of PTSD in parents of children in the PICU between 10% and 21%, with symptoms of PTSD occurring in up to 84% of families.10 PTSD can occur no matter how routine the caregivers may view the process. The ICU is a unique and often terrifying experience for families and children. The process of ICU care involves multiple caregivers, changing shifts, and endless physicians. For families in the ICU, there can be a loss of control, significant financial worries, and other factors that affect coping. Helping parents cope with their child’s critical illness and these stressors is a central part of intensive care. Parents may display behaviors that out of context may seem abnormal, such as excessive clinginess, intellectualizing the process, blaming others (including their spouses), minimizing, and seeking opinions everywhere (the internet, environmental care, etc.). We must attempt to understand what drives these behaviors to provide optimal care. We must help the parents be parents and educate them about their child’s illness. This emphasizes that social workers, psychologists, and child and family therapists are all part of the critical care team. With the move to family-centered care, we must address the issue of parental presence during invasive procedures and cardiopulmonary resuscitation (CPR) efforts. There is increasing literature that families would like to have the choice to stay during CPR events or invasive procedures and the parents do find benefit to being present.11-14 We believe that allowing parents to stay during procedures or resuscitation is helpful for the parents coping with the trauma of

a critically ill child. As each PICU addresses this issue there are several things to consider. Caregiver attitudes toward parental presence will need to be addressed, as the likelihood of this event increases over time. The decision to allow parental presence cannot be forced on providers. However, we have seen that resistance to family presence among providers is decreasing over time. A means for declining on the part of the clinician as well as the parent must be available. There must be someone identified who will stay with the family and support them. In our ICUs, this role been filled by social workers or members of the clergy. For those who are looking for assistance in making the transition to parental presence during CPR, there have been guidelines published from a national consensus conference.15 Parental presence during invasive procedures may pose a different challenge as these events occur more frequently compared with CPR. In the same manner, someone other than the person performing the procedure should be looking after the family, even for what we believe to be routine procedures. We also must give younger trainees the opportunity to opt out of family presence during procedures. A final topic that needs to be addressed is the use of palliative care services for our critically ill patients. There is a role for early consultation of palliative care, as we do not believe in restricting its use or support to just those patients who are near to death. We feel that there is a significant benefit to early engagement for children who are at high risk for mortality during their hospitalization, for children with complex diseases, or those where they cognitive and physical abilities following ICU discharge will be significantly different than previously. There are great benefits to palliative care intervention to provide families ongoing support and opportunities to develop coping mechanisms. Many different PICUs have developed automatic triggers for palliative care consultation, so as not to miss opportunities to improve family support. Examples of triggers can be PICU duration, episodes of CPR, prolonged mechanical ventilation, and specific types of surgeries. A review by the IPALICU (Improving Palliative Care in the ICU) Advisory Board in 201416 addresses the needs and goals of palliative care integration in the PICU.1 

Disclosure of Medical Errors We believe it is ethically correct to disclosure medical errors to families. However, some clinicians may continue to resist due to concerns regarding litigation. In a survey of 1018 Illinois residents, 27% indicated they would sue, but 38% stated they would recommend the hospital if appropriate disclosure and remediation occurred.17 The conclusion drawn by the author of the study was that “[p]atients who are confident in their providers’ commitment to disclose medical errors are not more litigious and far more forgiving than patients who have no faith in their providers’ commitment to disclose.” Explanations of medical errors should come from the senior member of the team to the family. This is usually the current ICU attending, but can be the medical director of the ICU, based on the complexity of the incident and outcome. The discussion should include an explanation of what happened in layman’s terms, how it occurred, the repercussions and change of care planned for

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79 • Pediatric and Neonatal Critical Care

the child, and what will be done to prevent a similar error in the future. We find it helpful to have the ICU social worker present to help validate concerns and provide support. The attending remains present until all questions are answered or additional time is scheduled if necessary. Most hospitals will track errors or negative outcomes through a quality assurance program. Depending on the incident, a “root cause analysis” should be performed. Medical errors will occur, but they should also be an opportunity to improve practice quality and prevent future events. In an ICU setting, there unfortunately will also be a need to cope with death and dying.18 Palliative care plays an important role when nothing medically can be done for the child. We also find their services exceedingly helpful for children with chronic medical conditions who are anticipated to die during a future admission. With a team approach, we try to minimize pain and suffering for the child and family at the end of life. Caregivers in and ICU must understand when to allow the families choices and support them over what may be their own beliefs and practices—as long as the goal remains to prevent further pain and suffering.19 The awareness of medical futility is increasing over time. However, with this concept there is a significant interplay with financial, societal, ethical, personal, and religious opinions and feelings. It may be difficult to define futility, but when the pain and suffering of continuing life are more severe than the inevitability of death, care may become futile. However, pain relief and caring support for the child and family can never be classified as futile care. 

Organization of the Pediatric Intensive Care Unit Medical and nursing directors, hospital administrators, and representatives from pediatric medicine, anesthesia, surgery, and the pediatric subspecialties should be responsible for policy and procedures pertaining to the PICU and should make recommendations regarding personnel staffing, equipment purchases, and structural and design changes within the unit. The medical director oversees the quality of patient care, patient triage, implementation of policy and procedures, in-service education, and coordination of consultants. Physician coverage should be full-time geographic at the resident, fellow, and attending staff level, and should include in-house, full-time coverage at night. The nursing director should have special skills in pediatric intensive care, education, and personnel management. The nursing staff must be trained in all aspects of pediatric critical care and resuscitation. Staffing should be flexible enough to provide one-on-one patient care when necessary. A multidisciplinary in-service program is essential for continuing education and orientation. Other team members include respiratory therapists, physical therapists, nutritionists, social workers, laboratory technologists, pharmacists, and psychiatrists and psychologists for the patients and staff. All medical and support personnel should be encouraged to participate in rounds, educational endeavors, and team meetings whenever possible. There must be adequate workspace around each bed and enough storage space to keep life support equipment within reach. Space for reading, meeting, sleeping, and showering should be available

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for the staff. Space should be provided for parents to remain with their children during the day and for parents to sleep overnight. Parents should be encouraged to participate as much as possible in the care of their child. Each bed space should be standardized so that it can be used to provide any level of care. Private rooms are ideal, but if shared rooms are necessary, the distance between beds must be adequate to ensure privacy and minimize nosocomial infection. Isolation rooms should be available within the confines of the unit. Devices for diversion and entertainment should be available for conscious children. Television and computer games are often better than heavy sedation.20,21 Adequate nurses and nursing involvement at the bedside will prevent potentially life-threatening events. Because sick children require close personal observation, centrally monitored nursing stations have little place in the PICU. 

Cardiovascular System STRUCTURAL AND FUNCTIONAL DEVELOPMENT The shape of the heart is complete by 6 weeks’ gestation, but myofibrillar density and maturation increase through the first year of postnatal life. During this time, myocytes engage in rapid protein synthesis and rapid cell growth, which requires a high intracellular concentration of nuclei, mitochondria, and endoplasmic reticulum. The greater number of nonelastic and noncontractile elements makes the neonatal myocardium less compliant, and it contracts less efficiently than the adult myocardium. In the fetus and newborn, the decreased ventricular compliance causes small changes in end-diastolic volume to induce large changes in end-diastolic pressure. In addition, augmentation of stroke volume by the Frank-Starling mechanism is less effective in young children. The newborn is more dependent on heart rate (HR) for maintenance of cardiac output.22,23 Cardiac output increases only about 15% with volume loading; it increases much more by increasing the HR.24 This is an important consideration when taking care of the critically ill infant. 

DEVELOPMENT OF THE CIRCULATION The adult and fetal circulation differs in many ways. The fetal circulation is distinguished by (1) the placenta as the organ of respiration, (2) high pulmonary vascular resistance (PVR), (3) low systemic vascular resistance (SVR), and (4) fetal ventricles that pump in parallel with right ventricular dominance. While the fetus lives in a low oxygen environment, the oxygen content of the blood of the fetus is similar to that of adults (20 mL of oxygen/100 mL of blood) because of a higher concentration of hemoglobin that has high affinity for oxygen. The neonatal circulation has several shunts—the ductus arteriosus, ductus venosus, and foramen ovale—that direct more oxygenated blood to the brain and heart and bypass the lungs. Changes then occur that allow the parallel circulation of the fetus to convert to the series circulation of the adult:   

1. With the first breath, expansion of the lung, increased alveolar oxygen, an increase in pH, and neurohumoral

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SECTION V  •  Pediatric Anesthesia

mediators and nitric oxide (NO) relax the pulmonary vasoconstriction.25 2. When the placenta separates from the uterine wall, the placental blood vessels constrict, and SVR and left ventricular afterload increase. The decrease in PVR plus increase in SVR raises left atrial pressure above right atrial pressure (RAP) and functionally closes the “flap valve” of the foramen ovale. The foramen ovale may not close anatomically for months to years, if ever. It is patent in at least 15% of adults.26,27 3. The decrease in PVR causes flow through the ductus arteriosus to reverse. This exposes the ductus to oxygenated systemic arterial blood, which along with the rapid decrease in prostaglandin E2 after birth closes the ductus. Anatomic closure of the ductus requires several weeks. 4. The ductus venosus closes passively with removal of the placental circulation and readjustment of portal pressure relative to inferior vena cava pressure. 5. There is a further gradual decline in PVR secondary to structural remodeling of the muscular layer of the pulmonary blood vessels. During fetal life, the central pulmonary vascular bed has a relatively thick muscle layer. After birth, the muscle coat thins and extends to the periphery of the lung—a process that takes months to years to complete. 

DEVELOPMENT OF AUTONOMIC CONTROL OF THE CIRCULATION The functional integrity of autonomic circulatory control during fetal and perinatal development is still a matter of considerable speculation. The fetal heart has reduced catecholamine stores and increased sensitivity to exogenously administered norepinephrine (NE). Adrenergic innervation of the human myocardium is complete between 18 and 28 weeks’ gestation. Human newborns have low cardiac stores of NE and decreased numbers of sympathetic nerves after birth. Adrenergic responses are apparently present but diminished in newborn humans. In human neonates, the cholinergic system is completely developed at birth, and the heart is sensitive to vagal stimulation. Bradycardia is the probable response to an increase in autonomic tone. The baroreceptor reflex is present but incompletely developed at term in humans. In preterm infants, postural changes elicit no change in HR, suggesting an incomplete or attenuated baroreceptor response.26 The chemoreceptor response is well developed in utero. The fetal bradycardia that occurs in response to hypoxia is thought to be mediated through chemoreceptors and may be similar to the oxygen-conserving mechanisms of diving animals.27 

MYOCARDIAL METABOLISM Fetal myocardial metabolism differs from that of adults. Relative “hypoxia” is normal in utero, and infant hearts tolerate hypoxia better than the hearts of adults do. This difference may be due in part to high concentrations of glycogen in fetal myocardial tissue and to the ability to more effectively use anaerobic metabolism. Because of the high glycogen stores and the ability to use anaerobic metabolism

efficiently, the fetal/newborn heart is relatively resistant to hypoxia and can be resuscitated more easily if oxygenation and perfusion are reestablished reasonably quickly. Oxygen consumption increases precipitously after birth, presumably because neonates are required to maintain their own temperature. A full-term infant’s oxygen consumption in a neutral thermal environment is approximately 6 mL/ kg/min; it increases to 7 and 8 mL/kg/min at 10 days and 4 weeks, respectively. 

Common Cardiovascular Disease States CONGENITAL HEART DISEASE Congenital heart disease causes significant alterations in oxygenation, perfusion, and myocardial function after birth (Box 79.1). These abnormalities can be divided into hypoxic and normoxic lesions. The latter include obstructive lesions of the left side of the heart (mitral valve stenosis, aortic valve stenosis, aortic stenosis, anomalous pulmonary venous return, ventricular septal defect, or patient ductus arteriosus with a right-to-left shunt), whereas hypoxic lesions include tricuspid valve stenosis, pulmonary valve stenosis, pulmonary artery stenosis or aplasia, and the tetralogy of Fallot. Right-sided lesions cause hypoxia if the left-to-right shunting of blood is sufficient to cause congestive heart failure (CHF) and pulmonary edema. Newborns with significant congenital heart disease commonly have either cyanosis or CHF. The degree of dysfunction usually changes during the first few months of life as PVR decreases to adult levels. As PVR decreases, left-to-right shunting of blood usually increases, and the symptoms of CHF become more apparent. Many neonates with a significant ventricular septal defect, which may or may not be observed during the preoperative workup, have no left-to-right shunting for several weeks after birth; however, induction of alkalosis during surgery can increase shunting. In the newborn, the usual signs and symptoms of CHF include poor feeding, irritability, sweating, tachycardia, tachypnea, decreased peripheral pulses, poor cutaneous perfusion, and hepatomegaly. Many patients with pulmonary edema exhibit tachypnea without retractions. Cyanosis occurs with structural cardiac disease,

BOX 79.1  Common Congenital Heart Malformations in the Newborn 1. Cyanotic congenital heart lesions □ Tetralogy of Fallot □ Transposition of the great arteries □ Hypoplastic left heart syndrome □ Pulmonary atresia with an intact ventricular septum □ Single ventricle □ Total anomalous pulmonary venous return □ Tricuspid atresia 2. Congenital heart lesions manifested as congestive heart failure □ Ventricular septal defect □ Patent ductus arteriosus □ Critical aortic stenosis □ Coarctation of the aorta

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79 • Pediatric and Neonatal Critical Care

but other causes such as respiratory disease, increased PVR (persistent pulmonary hypertension), and methemoglobinemia must also be considered. Congenital heart disease is diagnosed by physical examination, electrocardiogram (ECG), chest radiograph, and echocardiogram, postnatally and via fetal echocardiography. Cardiac catheterization is occasionally performed as interventional therapy or as a diagnostic tool. Magnetic resonance imaging (MRI) is used to define the anatomy of congenital heart lesions before cardiac surgery. Initial treatment of congenital heart disease is aimed at relieving CHF, improving systemic perfusion, and improving or maintaining pulmonary blood flow. The ductus arteriosus must be maintained open in instances of hypoplastic left heart syndrome, aortic stenosis or atresia, interrupted aortic arch, and symptomatic neonatal coarctation of the aorta. In many cases, infusion of PGE1 sustains life until definitive surgical correction can be performed.28 

ACUTE CIRCULATORY FAILURE IN CHILDREN (SHOCK AND SEPSIS) Shock Shock is the inability to provide adequate oxygen to the tissues that require it. The condition of shock depends on the balance of supply and demand of oxygen. Typically the body delivers excess oxygen to the tissues. Under periods of stress or illness there can be a decrease in supply caused by diminished blood flow or as decreased oxygen in blood. There can also be increased demand or oxygen extraction from the tissues. The content of oxygen is the blood is dependent on the amount bound to hemoglobin and the amount dissolved in plasma. Oxygen content (CaO2) (mL/ dL) = (1.34g/dL) (SaO2) (Hb) + (PaO2) (0.003). The normal oxygen content is approximately 20 mL/dL. Delivery of oxygen to the tissues depends on oxygen content and cardiac ˙ 2) (mL/min) = oxygen content output. Oxygen delivery ( DO (CaO2) × cardiac output (CO) × 0.01. Oxygen consumption ˙ 2) is the demand portion of the equation. Oxygen con(VO ˙ 2) is independent of oxygen delivery (VO ˙ 2) sumption (VO above a critical threshold and over a wide range. Below this ˙ 2 is dependent on DO ˙ 2. For infants and critical threshold VO 2 ˙ VO young children, 2 is estimated at 175 mL/min/m . Oxygen consumption is equal to oxygen delivery multiplied by ˙ 2 × O2 EX . ˙ 2 = DO oxygen extraction (O2EX) by the body: VO Oxygen extraction O2EX is equal to (CaO2 – CvO2)/CaO2. CaO2 is the oxygen content of arterial blood and CvO2 the oxygen content of venous blood. The difference between oxygen content of arterial and venous blood is predictably 4 to 6 mL/100 mL blood. Initially, as oxygen delivery decreases, the oxygen consumption can remain constant via increased extraction. Below a critical threshold in oxygen delivery, oxygen consumption becomes dependent on delivery. When oxygen to meet metabolic needs of the body cannot be met, nonessential metabolism is decreased or eliminated. Such metabolism includes growth, neurotransmitter synthesis, thermoregulation, and so forth. In this way the remaining oxygen can continue to be substrate for mitochondria. There are organs in the body, such as the kidney, skin, intestines, and skeletal muscle, that receive a high supply of blood relative to their metabolic needs. These organs also have a high proportion of sympathetic nerve innervations that allow for redistribution of blood flow to

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organs that with limited oxygen reserves such as the brain and heart. 

Classification of Shock There are several schemas which clinicians use to classify shock. Further within these classification schemas, disease states can fall into more than one category. One classification schema separates shock into the categories of hypovolemic, cardiogenic, distributive or vasogenic, and extracardiac obstructive. Hypovolemic shock can be due to hemorrhage from trauma or gastrointestinal (GI) losses from internal bleeding. Nonhemorrhagic hypovolemic shock can be due to external losses of fluid from vomiting, diarrhea, polyuria, and poor fluid intake. Fluid redistribution in cases of burns, trauma, and anaphylaxis can also be a cause. Cardiogenic shock may be myopathic due to decreased heart function. For adults this may commonly follow myocardial infarction. For children, myocarditis or cardiomyopathy are more common. Other causes of cardiogenic shock include mechanical failure such as valvular regurgitation or obstruction. Significant arrhythmias may result in cardiogenic shock when contractions are so asynchronous they decrease cardiac output. Extracardiac obstructive shock results from a physical obstruction that prevents adequate forward circulatory flow. Causes include inadequate preload secondary to mediastinal masses, increased intrathoracic pressure from tension pneumothorax, constrictive pericarditis, and cardiac tamponade from pericardial effusions. Pulmonary hypertension, pulmonary embolus, and aortic dissection can cause obstruction to systolic contraction. Distributive shock is caused by a decrease in SVR and the maldistribution of end-organ blood flow. Cardiac output may be increased in distributive shock, however, blood pressure may remain low due to a very low SVR. Septic causes of distributive shock can be related to bacterial, fungal, viral or rickettsial infections or toxins produced from these infections. Toxic shock syndrome would be an example of toxinmediated hypotension. Anaphylactic or anaphylactoid reactions are a type of distributive shock. Systemic inflammatory response syndrome (SIRS) may present with distributive shock. Spinal shock can result in distributive shock on a neurogenic basis. Adrenal insufficiency with low circulating hormones results in distributive shock decreased SVR.  Diagnosis of Shock Maintaining a high index of suspicion is important to rapidly identify shock in pediatric patients. Volume losses may be readily apparent from the history of present illness. Fever, rash and irritability may point to infection. However, cardiogenic shock may present with vague reports of decreased activity and level of alertness. In addition, if the patient’s shock is currently compensated, changes in physical findings may be limited. A child in shock may present initially with tachycardia, cold extremities, and poor capillary refill. Further, in distributive shock, the child may be warm with just an isolated tachycardia. A brief pertinent physical exam should evaluate level of alertness, peripheral perfusion, mucous membranes, pulse rate and quality, respiratory effort, urine output, and blood pressure. In children, blood pressure may be preserved until the degree

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SECTION V  •  Pediatric Anesthesia

of shock has progressed. Hypotension is a sign of late and decompensated shock in children. Metabolic acidosis may not be present on the initial laboratory tests. 

Compensatory Mechanisms The body applies compensatory mechanisms with the onset of shock to maintain adequate tissue perfusion for as long as possible. There is redistribution of fluid from the intracellular and interstitium to the vascular space. There is a decrease in glomerular filtration to limit renal fluid losses. Renal fluid losses are also limited by the release of aldosterone and vasopressin. There is an increase in sympathetic activity and release of epinephrine. This results in decreased venous capacitance and some preservation of blood pressure. HR is increased as the body tries to maintain cardiac output. There is an increase in cardiac contractility through circulating catecholamines and adrenal stimulation. Increase in sympathetic nerve stimulation shunts blood away from nonvital organs. At the tissue level, transfer of oxygen from hemoglobin is increased by increased red blood cell (RBC) 2, 3-diphosphoglycerate, fever, and tissue acidosis.  Therapy and Outcomes Aggressive therapy to treat pediatric septic shock appears to have resulted in improved outcomes. Therefore therapy for septic shock appears to be a good model for the treatment of shock in general. The overall goal of therapy in shock is to treat the underlying cause, return adequate oxygen delivery to the tissues, and remove metabolic products that developed during anaerobic metabolism. It appears the faster the body returns to adequate perfusion, the better the overall outcome. Many hospitals have developed sepsis pathways based on the data presented as follows that act as guidelines for resuscitation and are readily available to all care providers (Fig. 79.1). In 1991 Carcillo et  al.29 described a population of 34 children that presented with septic shock to an emergency department. Shock was diagnosed based on hypotension for age, with decreased perfusion, poor peripheral pulses, cool extremities, and tachycardia. Sepsis was defined as a positive blood or tissue culture. Remarkably, within 6 hours of presentation, all the patients had a pulmonary artery catheter placed. The overall mortality for the group was 47%. However, in the nine patients who received more than 40 mL/kg of fluids in the first hour, there was only one death (mortality 11%). The authors point out this patient died with a second episode of sepsis 2 weeks later. In this study, the rapid fluid administration was not associated with an increase in cardiogenic pulmonary edema or ARDS. In 2001 Rivers et al.30 published a study in adult patients with septic shock showing early, aggressive, goal directed therapy in the first 6 hours of care improved mortality. There were 263 adults were enrolled; 133 received standard therapy based on clinician discretion. The 130 patients randomized to early goal-directed therapy followed protocols treating hypovolemia and supporting blood pressure with vasoactive agents if necessary. The baseline characteristics of the two groups were similar. The in-hospital mortality was 46.5% in the standard therapy group and 30.5% in early goal-directed therapy group (P < .01). Although in adults, this demonstrated the need for early aggressive intervention.

Following the Rivers publication, a task force was formed by members of the Society of Critical Care Medicine to address shock in children. Their work was published in 2002 as “Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Patients in Septic Shock.”31 Their guidelines were incorporated into the American Heart Association’s (AHA) Pediatric Advanced Life Support (PALS) Provider Manual. Their guidelines were translated into Spanish and Portuguese and disseminated widely. The effectiveness of these interventions as well as an 2007 update was published by the same group in 2009.32 They highlighted significant improvements in mortality in dengue shock syndrome, malaria, and septic shock treated by community physicians using early goal directed therapy.33-35 The guidelines include rapid recognition of shock and early antibiotic administration and early administration of intravenous (IV) crystalloid. The initial resuscitation should include 20 mL/kg of isotonic saline or colloid pushed as a bolus to over 60 mL/kg until there is an improvement in the patient’s perfusion or rales or hepatomegaly develops. The goal is for the initial fluid resuscitation to occur in the first 15 minutes of therapy, and therapy should be initiated even if peripheral IV cannulation attempts fail, by placing and intraosseous (IO) device (Fig. 79.2). The guidelines target therapeutic end points of normal pulses with no difference between peripheral and central; capillary refill ≤ 2 seconds; warm extremities, normalization of blood pressure for age, mental status, glucose concentration, ionized calcium concentration; and urine output greater than 1 mL/kg/h. If central venous access is not readily obtained, consideration should be given for placement of an IO line. Cold shock (cold mottled extremities with prolonged capillary refill) should be treated with dopamine up to 10 μg/kg/ min and then epinephrine 0.05 to 0.3 μg/kg/min if there is no improvement. Warm shock (brisk capillary refill) should be treated with NE. Arrangements should be made early to admit the child to an ICU. If shock is not reversed with the inotropic support, hydrocortisone should be considered for catecholamine resistant shock. Recommendations for stabilization in the ICU following the first hour of therapy include monitoring central venous pressure, central venous saturation, and cardiac output. Persistent shock that is resistant to catecholamines should prompt the clinician to rule out pericardial tamponade, pneumothorax, or significantly elevated intra-abdominal pressure that may be compromising circulation. In the absence of a correctible condition, extracorporeal membrane oxygenation (ECMO) should be considered. There were several new recommendations in the 2007 guidelines that addressed changes in the literature between 2002 and 2007. It was identified that the availability of skilled practitioners to place central venous access could delay the initiation of inotropic support. Therefore, the 2007 guidelines recommended the use of a peripheral IV dopamine or epinephrine if there was delay in obtaining central venous access. Ongoing monitoring of the access site should be performed. It was not recommended to use NE in a peripheral IV, due to risk of extravasation. In the 2002–2007 interval there were several pediatric and adult studies indicating adrenal suppression and increased severity of illness adjusted mortality with the use of etomidate.36,37 The 2007 guidelines do not

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ICU pathway for the evaluation/treatment of infants > 28 days and children with severe sepsis/septic shock Goals and metrics

Children with severe sepsis/septic shock

Antibiotic recommendations

Recommended laboratory studies

MD/CRNP/RN rapid assessment Begin supplemental O2 regardless of SpO2 Immediate IV access, IV escalation plan NS 20 mL/kg boluses Order antibiotics and labs, obtain cultures Ensure 1st antibiotic within 1st hour Correct hypoglycemia, hypocalcemia PICU sepsis order set

20 min

Monitor response – VS targets and clinical goals

45–60 min

Infection source control

Fluid choice and blood products Respiratory support

Repeat 20 mL/kg boluses

Intubation and sedation medications

If > 40 mL/kg, order dopamine to bedside Fluid refractory shock Consider CVL, arterial line, foley

Warm shock Titrate dopamine, norepinephrine Consider epinephrine, vasopressin PRBC if Hgb < 10 g/dL Consider ETT

Cold shock - low BP Titrate dopamine, epinephrine Consider norepinephrine, dobutamine PRBC if Hgb < 10 g/dL Consider BNP, ECHO, ETT

Cold shock - normal BP Titrate dopamine, epinephrine Consider milrinone or dobutamine if (ScvO2 < 70% or lactate elevated) PRBC if Hgb < 10 g/dL Consider BNP, ECHO, ETT

1–6 hours Catecholamine resistant shock

Adjuvant therapies IVIG, Plasma Exchange, Diuresis, RRT Immunocompromised patients Nutrition 1st 24 hrs, > 24 hrs PICU discharge

Give stress-dose hydrocortisone Evaluate for: Pericardial Effusion Pneumothorax Intra Abdominal Hypertension Primary cardiac dysfunction

ECMO

Continue to monitor clinical goals following resolution of shock Wean FiO2 to keep SpO2 92-98% Continue lung protective strategies Consider diuretics or dialysis if fluid overload > 10-15% PRBCs if Hgb < 7 g/dL Wean hydrocortisone when vasoactive infustions no longer required Monitor culture results and reassess antibiotic coverage Consult ID if culture negative sepsis to determine antibiotic duration PT/OT consult, consider PM&R consult

Fig. 79.1  Sepsis resuscitation pathway.  ECMO, Extracorporeal membrane oxygenation; ETT, endotracheal tube; FiO2, fraction of inspired oxygen; ICU, intensive care unit; IV, intravenous; PICU, pediatric intensive care unit; PRBC, packed red blood cells; PT, prothrombin time; SpO2, saturation of peripheral oxygen. Downloaded for Damon dr68 ([email protected]) at Hacettepe University from ClinicalKey.com by Elsevier on October 21, 2019. For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.

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SECTION V  •  Pediatric Anesthesia

Tibial tuberosity

Anterior border

90° to medial surface Fig. 79.2  Intraosseous Cannulation Technique.

recommend the use of etomidate unless it is in the format of a randomized controlled trial. Ketamine with atropine was recommended for sedation for invasive procedures in infants and children. However, due to limited experience, ketamine could not be recommended for the newborn population. The 2007 guidelines32 recommend titrating therapy to cardiac output and indicate that there are several methods by which cardiac output can be measured. The use of pulmonary arterial catheters has decreased in pediatrics over time, but other methods are available. A good review of monitoring techniques was published by Mtaweh et al. in 2013.38 Cardiac output can be monitored by newer techniques analyzing the arterial pulse wave, transpulmonary thermodilution, carbon dioxide rebreathing, echocardiography, bio-impedance of the thorax, and ultrasound continuous-wave Doppler. These techniques are less invasive than pulmonary artery catheters. However, many still require validation studies in pediatric, and they may not be available at all centers. One additional area to be addressed in the 2007 guidelines is in the area of fluid removal.32 A study published by Goldstein et al. in 2005 in pediatric patients with multiorgan failure, including acute renal failure requiring continuous renal replacement therapy (CRRT), showed improved survival in the group that had a lower percentage of fluid overload at the initiation of CRRT.39 While supporting the primary premise of fluid resuscitation, the 2007 guidelines offered new recommendation for fluid removal in patients with fluid overload and multiorgan failure.31 They recommended the use of diuretics, peritoneal dialysis, or CRRT in patients who had been adequately fluid resuscitated but were not able to maintain an even fluid balance through native urine output. Again, it should be noted that peritoneal dialysis and CRRT for pediatric patients may not be available at all centers. However, the association between fluid overload and mortality with acute renal failure has been seen in other studies and will likely be an ongoing issue in pediatric ICU care. The concern for possible adrenal insufficiency during septic shock needs to be addressed by the clinician caring for the patient. There are certain instances where limited function of the adrenal axis is anticipated. This

would include patients who have recently received glucocorticosteroids, ketoconazole, or etomidate. Further, patients with disease states such as purpura fulminans or those affecting the hypothalamus, pituitary, or adrenal glands will be at increased risk. Patients with adrenal insufficiency need supplemental corticosteroids. However, for children with septic shock but without these factors, it is not clear whether the risk of relative adrenal insufficiency or treatment with systemic steroids alter outcome. Dr. Zimmerman40 reviewed the adult and limited pediatric literature in 2007 for therapeutic steroid use in sepsis. He highlighted adult studies showing high dose short courses of steroids are associated with decreased survival. Further, data from the CORTICUS trial41 indicated that low dose steroids as a physiologic replacement during periods of vasopressor resistant shock resolve shock more quickly but there was no change in mortality. In turn, the 2007 guidelines were unchanged from 2002. Hydrocortisone treatment was only recommended for patients with absolute adrenal insufficiency or adrenal-pituitary axis failure and catecholamine-resistant shock. Absolute adrenal insufficiency was defined as peak cortisol concentration of less than 18 μg/dL obtained after corticotropin stimulation. 

Cardiovascular Pharmacology Pharmacologic support of the circulation includes positive inotropic and chronotropic agents, vasoconstrictors and vasodilators (afterload reduction), and antiarrhythmics (see Chapters 14, 18, and 86). Most currently used drugs have not been adequately tested in children, so dosage recommendations and anticipated effects must be extrapolated from adult doses and clinical experience. Positive inotropic drugs are used to augment the cardiac output of patients with circulatory failure. Most inotropic agents also affect the HR and vasomotor tone. Tachycardia in a child is usually well tolerated and is frequently beneficial.42 In a neonate whose ventricles are relatively noncompliant and whose stroke volume is less variable, tachycardia is an important means of augmenting cardiac output. Because drugs that increase the HR or contractility also increase myocardial oxygen consumption, adequate arterial oxygenation and sufficient metabolic substrates are required when these drugs are administered. The cardiovascular response to sympathomimetic amines is attenuated in the presence of severe acidosis and possibly sepsis; higher infusion rates of these drugs are required and need readjustment as the acidosis improves. Commonly used inotropes are listed with brief comments regarding their use in pediatric intensive care are provided in the following paragraphs (Table 79.1).

EPINEPHRINE Epinephrine is useful for the treatment of shock in the presence of myocardial dysfunction. Typical starting doses in children are 0.05 to 0.2 μg/kg/min; with escalating doses up to 1 to 2 μg/kg/min, there is profound vasoconstriction in the periphery and abdominal organs to shunt blood to the heart and brain.

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TABLE 79.1  Vasoactive and Inotropic Medications Drug

Effect

Dose (μg/kg/min)

Inotropy

Chronotropy

Epinephrine (Adrenalin)

α, β

0.05-2.0

++

++

Isoproterenol (Isuprel)

β1, β2

0.05-2.0

++

++

Dopamine (Intropin)

δ

1-3

β>α

5-15

β, α Milrinone

Vasodilation

Vasoconstriction ++

+ +Renal splanchnic

+

+

>15

+

+

Bolus: 50 μg/kg over 15-min period

+

+ or − + +

Infusion: 0.375-0.75 Norepinephrine

α >> β

0.05-1.0

Slight+

+

++

Nitroprusside

0.5-10

++

Nitroglycerin

1-20

++

Arterial > venous

Dopamine Dopamine is the most commonly infused inotrope in pediatric patients. Dopamine is the metabolic precursor of both NE and epinephrine. Its effects are dose dependent, with dopaminergic activity at low doses (although these low-dose dopamine effects have not been demonstrated in critically ill children); β-adrenergic activity with intermediate doses 5 to 10 μg/kg/min exhibiting chronotropic and inotropic effects; and some α-adrenergic activity at higher doses, with 10 to 20 μg/kg/min exhibiting peripheral vasoconstriction. Young children require higher doses of dopamine than adults do to produce the same effect. In one study, an infusion of 15 μg/kg/min was required to increase cardiac output above control levels after cardiac surgery.43 This may reflect the decreased releasable myocardial stores of NE in immature ventricles. Therefore, in the sick preterm infant there can be decreased dopamine clearance with a much greater vasopressor response than expected.  Vasopressin Vasopressin is a pituitary peptide hormone with method of action on the kidney and vasculature. In the kidney, vasopressin controls water reabsorption in the renal tubules, and in the vasculature, it causes vasoconstriction by stimulating smooth muscle V1 receptors. Its clinical applications include GI hemorrhage, central diabetes insipidus (DI), and as a second- or third-line agent to treat hypotension.  Isoproterenol Isoproterenol is a synthetic, potent, nonselective β-agonist with strong chronotropic effects with very low affinity to α-adrenergic receptors, and is usually well tolerated in children. However, high doses of isoproterenol can cause myocardial ischemia.44 Isoproterenol also induces vasodilation that is responsive to acute volume administration. It is often used for increasing HR in complete heart block, in the immediate postoperative period after cardiac transplantation to improve cardiac output by increasing HR in

the denervated donor heart, and as a potent pulmonary vasodilator during pulmonary hypertensive crisis via β2adrenergic receptor activity. 

Dobutamine Dobutamine provides positive inotropy and afterload reduction, β and α receptors. Its function is primarily as a inotropic agent but with less vasopressor activity compared with dopamine. It is only used as a continuous infusion of 5 to 20 μg/kg/min, and in some studies may increase myocardial oxygen In children but not in adults it causes tachycardia.45,46  Norepinephrine NE, a drug with strong α- and β-agonist effects, has had a resurgence of use in infants and children.47 Children with nearly normal cardiac function and marked peripheral vasodilation have good responses to this drug. It is especially useful in instances of warm septic shock, anaphylaxis, liver failure, and sympathetic blockade with regional anesthesia. It will increase SVR, but also limits mesenteric blood flow, including hepatic perfusion.  Milrinone Milrinone is a selective phosphodiesterase III inhibitor that increases cyclic adenosine monophosphate by inhibiting breakdown. Milrinone has both inotropic and vasodilator effects, without acting on α and β receptors. This drug has improved the outcome of children who have low cardiac output syndrome after cardiac surgery.48 The loading dose of milrinone is 25 to 75 μg/kg administered over a period of 10 minutes; the maintenance infusion rate is 0.25 to 0.75 μg/kg/min. Loading doses are often avoided in the ICU setting because of resultant hypotension. Renal failure significantly increases the elimination half-life of this drug.49,50 Outside the cardiac ICU, milrinone is used for vasoconstricted septic shock and may have a role in the treatment of pulmonary hypertension. 

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SECTION V  •  Pediatric Anesthesia

Levosimendan Levosimendan is a novel agent that increases the sensitivity of the contractile apparatus to calcium increasing inotropy by binding to cardiac myocyte troponin C. This agent will increase cardiac ejection fraction, while reducing catecholamine dose with minimal effects on blood pressure and HR. In children, the most common indications have been for cardiac failure or post–cardiac surgery, with a loading does of 612 μg/kg followed by an infusion of 0.1 to 0.2 μg/kg/ min.51,52  Nesiritide Nesiritide is a recombinant form of the human B-type natriuretic peptide, the hormone release from the cardiac ventricles in response to volume overload and increasing mechanical wall stress. The action is on guanylate cyclase with resulting venous and arterial vasodilation. In addition, B-type natriuretic peptide leads to myocardial relaxation (lusitropy) and natriuresis. In children, it has been used to decrease central venous pressure and increase urinary output.53 Usual dosing suggestions for children and adults: initial 2 μg/kg bolus followed by a continuous infusion of 0.005 to 0.01 μg/kg/min.  Digitalis Digitalis is useful for the long-term treatment of myocardial failure in children but may not be effective in neonates.54 Because of its long half-life and unpredictability, digitalis should be administered cautiously to children who have changing levels of serum potassium, calcium, and pH. In these cases, it is more appropriate to use rapid-acting, titratable inotropic agents.  Calcium When serum ionized calcium levels are below normal, administration of calcium produces a positive inotropic effect. If the patient’s ionized calcium levels are normal, less marked inotropic effects occur. Low ionized calcium levels most commonly occur in patients with DiGeorge’s syndrome, when large volumes of citrate-containing blood products are rapid administered, and in neonates with relatively unstable calcium metabolism. Calcium also has effects on the cardiac conduction system. Rapid administration of calcium can cause severe bradycardia or asystole. This effect may be exaggerated in hypokalemic children or in those receiving digitalis. The vasomotor effects of calcium are controversial, but most reports show an increase in both SVR and PVR when the drug is administered.55  Bicarbonate Therapy Severe acidosis decreases myocardial function and tissue perfusion. Correction of acidosis with 1 to 2 mEq/kg of sodium bicarbonate is indicated for a pH below 7.20 if ventilation is adequate (PCO2 100 beats/min, but persistent respiratory distress or cyanosis

Clear airway SpO2 monitoring Consider CPAP

Apnea, gasping, or HR < 100 beats/min

Bag-mask PPV SpO2 monitoring

After initiation of resuscitation (PPV), HR > 100 beats/min, effective ventilation

Post-resuscitation care

HR < 60 beats/min

Consider intubation Chest compressions Coordinate PPV

HR = 60-100 beats/min

Continue with PPV SpO2 monitoring

Acute glomerulonephritis (e.g., poststreptococcal, Henoch-­ Schönlein purpura) Hemolytic-uremic syndrome Chronic glomerulonephritis (all types) Acute and chronic pyelonephritis Congenital malformations (dysplasia, hypoplasia, cystic diseases) Tumors (e.g., Wilms, leukemic infiltrate) Post–renal transplantation status; also rejection Oliguric renal failure Trauma Obstructive uropathy After genitourinary surgery Blood transfusions in children with azotemia  Cardiovascular Coarctation of the aorta Renal artery abnormalities (e.g., stenosis, thrombosis) Takayasu’s disease  Endocrine Pheochromocytoma Neuroblastoma Adrenogenital disease Cushing syndrome Hyperaldosteronism Hyperthyroidism Hyperparathyroidism  Iatrogenic Intravascular volume overload Sympathomimetic administration (e.g., epinephrine, ephedrine) Corticosteroid administration Rapid intravenous infusion of methyldopa  Miscellaneous Immobilization (e.g., fractures, burns, Guillain-Barré syndrome) Hypercalcemia (e.g., hypervitaminosis D, metastatic disease, sarcoidosis, some immobilized patients) Hypernatremia Stevens-Johnson syndrome Increased intracranial pressure (any cause) Dysautonomia After resuscitation

Guidelines for neonatal resuscitation have been issued by many organizations, including the AHA and the American Academy of Pediatrics.66

INITIAL ASSESSMENT OF THE FETUS AT BIRTH Initial stabilization should begin with a rapid evaluation of the newborn to determine if the infant is term, breathing, or crying, and has a normal tone (Table 79.2).66 

ONGOING ASSESSMENT Ongoing assessment consists of three signs: HR, respirations, and oxygenation. The preferred method for auscultation of HR is by auscultation. All of these vital signs should be determined within the first 30 seconds. 

CPAP, Continuous positive airway pressure; HR, heart rate; PPV, positive pressure ventilation; SpO2, saturation of peripheral oxygen.

CLEARING THE AIRWAY Proper positioning by placing the infant in the sniffing position is recommended, and the practitioner must try to avoid either underextension or hyperextension, both of which will obstruct the airway. Deep sucking should be avoided even in healthy, vigorous newborns, because of risks of vagal-mediated bradycardia.67 This does not apply to newborns who may have airway obstruction or the depressed infant with meconium (covered later in this section.) 

TEMPERATURE CONTROL During the initial resuscitation period, the goal temperature for the newborn is normothermia. The initial step is to dry the infant and warm the infant to a goal axillary temperature of 36.5°C. The goal for each neonate is euthermia. Infants wrapped in polyethylene from the neck down will avoid evaporative heat loss. Controlled hypothermia should only be attempted in select tertiary centers within hours after birth in infants with hypoxic-ischemic encephalopathy (HIE). 

OXYGEN One of the recent changes in neonatal resuscitation in the 2011 Neonatal Resuscitation Program Guidelines is the recommendation of positive pressure ventilation (PPV) with room air, unless chest compressions or medications are needed during the resuscitation then the recommendation are still for PPV with 110% oxygen. It is important to place a preductal (right hand) oximeter probe on the newborn if PPV is initiated. For the preterm infant, oxygen should be blended to goal saturation targets. In summary: (1) Use room air in the baby is cyanotic or needs PPV. (2) If the baby is less than 32 weeks, titrate oxygen (Table 79.3).

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TABLE 79.3  Preterm Infant (60 breaths/min) occurs with hypoxemia, hypovolemia, metabolic and respiratory acidosis, CNS hemorrhage, pulmonary gas leaks, pulmonary disease (e.g., hyaline membrane disease, aspiration syndromes, infections), pulmonary edema, and maternal drugs (e.g., narcotics, alcohol, magnesium, barbiturates). Recommendations now are that initial breaths should be at 20 cm H2O. Ventilation should be performed at 40 to 60 breaths/min with reassessment of HR, color, and breath sounds. In the neonate, rising HR may be the best assessment of adequate ventilation. If gastric distention becomes a problem, hindering compliance, a gastric tube may be placed (8 Fr) to improve compliance. Both sides of the chest should rise equally and simultaneously with inspiration, but the amount of rise should not exceed that associated with the neonate’s normal spontaneous breathing. The presence of breath sounds may be misleading because they are well transmitted within the neonate’s small chest. A difference in breath sounds between the two sides of the chest should raise suspicion of endobronchial intubation, pneumothorax, atelectasis, or a congenital anomaly of the lung. The presence of loud breath sounds over the stomach suggests esophageal intubation or a tracheoesophageal fistula. If ventilation is adequate, the neonate will become pink, initiate rhythmic breathing, and have a normal HR. Because most asphyxiated neonates have no lung disease, they can be effectively ventilated with peak airway pressures lower than 25 cm H2O, even for the first few breaths. Those with stiff lungs (e.g., erythroblastosis fetalis, congenital anomalies of the lung, pulmonary edema, severe meconium aspiration, diaphragmatic hernia) may require

higher inspiratory pressure to ventilate their lungs and are more likely to have pulmonary gas leaks. To reduce this likelihood, the lungs should first be ventilated with an inspiratory pressure of 15 to 20 cm H2O and inspiratory rate of 150 to 200 breaths/min. If low-pressure (low-volume), high-rate ventilation does not improve the oxygenation, higher pressure and volume may be required. Failure to adequately ventilate the lungs at birth may worsen hypoxemia and lead to CNS damage or even death. If PaO2 exceeds 70 to 80 mm Hg or SaO2 exceeds 94%, the inspired oxygen concentration should be reduced (if increased concentrations of oxygen are used) until SaO2 and PaO2 are normal for age. Oxygenation is maintained at the low range of normal in neonates 34 weeks’ or less gestation to avoid the retinopathy of prematurity.68 The neonate’s HR should be monitored continuously during endotracheal intubation because the process of tracheal intubation may cause arrhythmias in hypoxic neonates. If the practitioner is having difficulty with bag mask ventilation or fails intubation, a laryngeal mask airway (LMA) should be considered.69,70 

PNEUMOTHORAX Pneumothorax occurs in 1% of all vaginal deliveries, in 10% of meconium-stained neonates, and in 2% to 3% of neonates who require mechanical ventilation in the delivery room. The hemithorax containing free air is usually hyperexpanded and moves poorly with ventilation. The point of maximum cardiac impulse is shifted toward the side without the pneumothorax. Heart tones may be muffled. If a small, high-intensity cold light is placed directly on the skin of the neonate’s chest, the involved side of the chest will glow if a pneumothorax is present.71 Pneumothoraces are relieved by needle or chest tube drainage. 

ENDOTRACHEAL INTUBATION The head should be placed in a neutral or “sniffing” position during bag-and-mask ventilation and tracheal intubation. An appropriately sized endotracheal tube (ETT) is inserted and its tip is placed 1 to 2 cm below the vocal cords, depending on the size of the neonate. Usually, this means that the distance from the tip of the tube to the gums is 7, 8, 9, or 10 cm in 1-, 2-, 3-, and 4-kg infants. A small gas leak should be present between the ETT and trachea when the ventilation pressure is 15 to 25 cm H2O. This usually entails the use of a 2.5-mm (internal diameter) tube for neonates weighing less than 1.5 kg, a 3.0-mm tube for those between 1.5 and 2.5 kg, and a 3.5-mm tube for those weighing more than 2.5 kg. Successful tracheal intubation is confirmed by observing the ETT pass through the vocal cords, by observing bilateral chest movement with each mechanical inspiration, and by observing condensation in the ETT during exhalation. Breath sounds should be much louder over the chest than over the abdomen, and the skin color, HR, and SaO2 should improve with positive-pressure ventilation. Carbon dioxide should be present during exhalation. However, the small tidal volumes and low pulmonary blood flow of some infants at birth may make it difficult to use capnography effectively. 

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Naloxone Naloxone (Narcan) is not recommended as an initial response to respiratory distress in neonatal resuscitation.66,72 Neonates should be supported on PPV, even in women who have received narcotics less than four hours prior to delivery. However, if respiratory depression continues, naloxone can be considered. In addition, naloxone should be avoided in an infant whose mother has a history of narcotic dependence due to the risk of seizures from withdrawal. 

DETECTION OF HYPOVOLEMIA

Fig. 79.3 Neonatal chest compression. For simplification, ventilation is not shown. (From Gregory GA. Resuscitation of the newborn. Anesthesiology. 1975;43:225.)

CARDIAC COMPRESSIONS Place both thumbs on the sternum and allow the fingers to support the back (Fig. 79.3). Compress the sternum to approximately one-third the depth of the chest. Three compressions should be performed with a breath in place of the fourth compression for an effective compression rate of 90 compressions and 30 breaths/min. HR should be evaluated every 45 to 60 seconds, and if after adequate ventilation and compressions for 60 seconds the HR is still less than 60 beats/min, then medications should be considered. 

MEDICATIONS Resuscitation with medications are needed only for the infant that is critically depressed or presents with significant anomalies leading to cardiovascular depression. There should be a quick reference drug list designed for each delivery room for easy access for these rare occasions, and should help with dosing based on an estimated weight of the infant at birth. IV route of administration is the preferred for administration of resuscitation medications; however, IO and umbilical venous catheters can be placed rapidly by trained individuals and may be life-saving.

Epinephrine The primary medication used in the resuscitation of a newborn is epinephrine, and should be given if the infant’s HR is less than 60 bpm, 45 to 60 seconds after the initiation of PPV and chest compressions. The recommended dose is 0.1 to 0.3 mL/kg of 1:10,000 concentration; (0.01-0.03 mg/ kg), followed by a 1 mL flush of saline. While IV administration is preferable, if venous access is not obtained, it is appropriate to give epinephrine via the ETT. In this instances the practitioner, should give a higher dose of Epinephrine: 0.5 to 1 mL/kg of 1:10,000 concentration; (0.05-0.1 mg/kg). Epinephrine can be repeated every five minutes, as needed, while re-evaluating HR every 45 to 60 seconds. 

Hypovolemia is detected by measuring arterial blood pressure and by physical examination (i.e., skin color, perfusion, capillary refill time, pulse volume, and extremity temperature). CVP measurements are useful in detecting hypovolemia and in determining the adequacy of fluid replacement. The venous pressure of normal neonates is 2 to 8 cm H2O. If CVP is less than 2 cm H2O, hypovolemia should be suspected. 

TREATMENT OF HYPOVOLEMIA Treatment of hypovolemia requires expansion of intravascular volume with blood and crystalloid. Albumin may also be used, but evidence of its effectiveness is limited. If it is suspected that the neonate will be hypovolemic at birth, Rh-negative type O packed RBCs should be available in the delivery room before the neonate is born.73 Crystalloid and blood should be titrated in 10 mL/kg and given slowly over 10 minutes, if hemodynamics allow, to limit the risk of intraventricular hemorrhage. Occasionally, enormous volumes of blood and fluid are required to raise arterial blood pressure to normal. At times, more than 50% of the blood volume (85 mL/kg in term neonates and 100 mL/kg in preterm neonates) must be replaced, especially when the placenta is transected or abrupted during birth. In most cases, less than 10 to 20 mL/ kg of volume restores mean arterial pressure to normal. 

OTHER CAUSES OF HYPOTENSION Hypoglycemia, hypocalcemia, and hypermagnesemia also cause hypotension in neonates. Hypotension induced by alcohol or magnesium intoxication usually responds to blood volume expansion or dopamine, or to both. Hypermagnesemic neonates generally respond to 100 to 200 mg/kg of calcium gluconate administered over a 5-minute period.66 

MECONIUM Meconium stained amniotic fluid (MSAF) when aspirated into the lungs during delivery or in utero can cause serious lung injury and respiratory distress syndrome (RDS). Most cases of meconium aspiration occur in utero; therefore, endotracheal intubation to suction the airway to remove MSAF should only occur if the neonate is distress: absent or depressed respirations, HR less than 100 bpm, or poor muscle tone.66,74,75 A depressed MSAF stained infant should be

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intubated as soon as possible following delivery. Suctioning is accomplished through an ETT, and if there is a significant amount of MSAF or the infant remains in extremis, they should be transferred directly to the neonatal ICU. 

Pulse oximeters permit rapid detection of changes in oxygenation and rapid reduction of fraction of inspired oxygen (FiO2). The normal SaO2 of neonates is usually 87% to 95%, which is associated with a PaO2 of 55 to 70 mm Hg. 

COLOR

PEDIATRIC CARDIAC ARREST AND RESUSCITATION

Essentially all neonates have a blue-tinged cast to their skin at birth. By 60 seconds of age, most of them are entirely pink, except for their hands and feet, which remain blue. If central cyanosis persists beyond 90 seconds of age, asphyxia, low cardiac output, pulmonary edema, methemoglobinemia, polycythemia, congenital heart disease, arrhythmias, and pulmonary disorders (e.g., respiratory distress, airway obstruction, hypoplastic lungs, diaphragmatic hernia) should be considered, especially if the infant remains cyanotic despite oxygen and controlled ventilation. Neonates who are pale at birth are often asphyxiated, hypovolemic, acidotic, or anemic, or they have congenital heart disease. A neonate whose skin is entirely pink within 2 minutes of birth may be intoxicated with alcohol or magnesium or may be alkalotic (pH >7.50). Rubrous neonates are usually polycythemic. 

RESUSCITATION EQUIPMENT Resuscitation beds should allow positioning of the neonate’s head below the level of the lungs to promote drainage of lung fluid and reduce the likelihood of aspirating gastric contents. A servo-controlled infrared heater should be used to maintain the neonate’s temperature between 36°C and 37°C, unless there is evidence of asphyxia. If asphyxia is noted, body temperature should be reduced to 34°C to 35°C for brain protection. A suction device should be available and should allow the suction pressure to be varied; pressures below −100 mm Hg should not be used. Equipment required for tracheal intubation includes 0 and 00 straight laryngoscope blades; a pencil-type laryngoscope handle; 2.5-, 3.0-, and 3.5-mm ETTs; and a suction catheter that easily fits through each size tube. The ventilation system must permit ventilatory rates of at least 150 breaths/min and make it possible to maintain positive end expiratory pressure (PEEP). One-way valves can stick in the closed position, especially when high gas flow and high RRs are used. The modified Jackson-Rees or Ayres system works well when appropriately trained people use it. Overexpansion of the lungs with large tidal volumes injures the lungs and activates inflammatory processes that may cause chronic lung disease. Gentle inflation of the lung is less injurious to the lung. Airway inflation pressures should be measured continuously during assisted or controlled ventilation in the delivery room, and excessive pressures and tidal volumes should be avoided. As in any critical care situation, patient care should be guided by information. Consequently, blood gas and pH measurements are mandatory, and the results of these tests must be available within 10 minutes of drawing the blood sample. Umbilical arterial catheters are useful for measuring arterial blood pressure and withdrawing blood for blood gas analysis and pHa. They can also be used to infuse emergency fluids. Arterial oxygen saturation (SaO2) can be measured immediately after birth by attaching a pulse oximeter to a hand or foot.76

Pediatric cardiac arrest is not a rare event. At least 16,000 American children (8-20/100,000 children/year) suffer a cardiopulmonary arrest each year.77-81 More than half of these cardiac arrests probably occur in-hospital.77-82 With advances in resuscitation science and implementation techniques, survival from pediatric cardiac arrest has improved substantially over the past 25 years.83 Outcomes from pediatric cardiac arrest have improved significantly over the past 20 years. For example, survival to discharge from pediatric in-hospital cardiac arrest has increased from less than 10% in the 1980s84,85 to greater than 25% in the 21st century. Of the pediatric patients that survive to hospital discharge, nearly three quarters will have favorable neurologic function defined by specific pediatric cerebral outcome measures and quality of life indicators.83,86-88 Factors that influence outcome from pediatric cardiac arrest include (1) the pre-existing condition of the child; (2) the environment in which the arrest occurs; (3) the initial ECG rhythm detected; (4) the duration of no-flow time (the time during an arrest without spontaneous circulation or CPR); (5) the quality of the life-supporting therapies provided during the resuscitation; and (6) the quality of the life-supporting therapies during postresuscitation. Not surprisingly, outcomes after pediatric out-of-hospital arrests are much worse than those after in-hospital arrests.78,79,89-97 This may be due to the fact that there is a prolonged period of no flow in out-of-hospital arrests, where many of the pediatric cardiac arrests are not witnessed and only 30% of children are provided with bystander CPR. As a result of these factors, less than 10% of cases of pediatric out-of-hospital cardiac arrest (OHCA) survive to hospital discharge, and for those that do survive, severe neurological injury is common. These findings are especially troublesome, given that bystander CPR more than doubles patient survival rates in adults.98 An exciting prospective, nationwide, population-based cohort study from Japan similarly demonstrates more than doubling of survival rates for children who have OHCA and receive bystander CPR either with conventional CPR (with rescue breathing) or chest compression only CPR compared with no bystander CPR.99 The same study then further stratifies outcomes for OHCA into “cardiac” and “noncardiac” causes for arrest, and defines the relative value of rescue breathing during CPR by bystanders. Pediatric patients who have OHCA with noncardiac causes and receive bystander conventional CPR (including rescue breathing) had an association with higher frequency of favorable neurologic outcomes at 1 month after arrest compared with compression-only bystander CPR or no bystander CPR. For pediatric arrests defined as “cardiac” in nature, bystander CPR (conventional or compression-only) was associated with a higher rate of favorable neurologic outcomes 1 month after arrest compared with no bystander CPR. Interestingly, the two types of bystander CPR (conventional or compression-only)

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79 • Pediatric and Neonatal Critical Care

seemed to be similarly effective for pediatric cardiac arrests with cardiac causes, consistent with animal and adult studies.99 Survival outcomes after in-hospital cardiac arrest are higher in the pediatric population compared with adults; 27% of children survive to hospital discharge compared with only 17% of adults.83 For both children and adults, outcomes are better after arrhythmogenic arrests, ventricular fibrillation (VF)/ventricular tachycardia (VT). Importantly, pediatric in-hospital arrests are less commonly caused by arrhythmias (10% of pediatric arrests vs. 25% of adult arrests), and approximately one-third of children and adults with these arrhythmogenic arrests survive to hospital discharge. Interestingly, the superior pediatric survival rate following in-hospital cardiac arrest reflects a substantially higher survival rate among children with asystole or pulseless electrical activity (PEA) compared with adults (24% vs. 11%). Further investigations have shown that the superior survival rate seen in children is mostly attributable to a much better survival rate among infants and preschool age children compared with older children.87 Although speculative, the higher survival rates in children may be due to improved coronary and cerebral blood flow (CBF) during CPR because of increased chest compliance in these younger arrest victims, with improved aortic diastolic pressure and venous return.100,101 In addition, survival of pediatric patients from an in-hospital cardiac arrest is more likely in hospitals staffed with dedicated pediatric physicians.102 

Phases of Resuscitation The four distinct phases of cardiac arrest and CPR interventions are (1) prearrest, (2) no flow (untreated cardiac arrest), (3) low flow (CPR), and (4) postresuscitation/arrest. Interventions to improve outcome of pediatric cardiac arrest should optimize therapies targeted to the time and phase of CPR, as suggested in Table 79.4.

PREARREST The prearrest phase refers to any relevant preexisting conditions of the child (e.g., neurologic, cardiac, respiratory, or metabolic problems) and precipitating events (e.g., respiratory failure or shock), uncoupling metabolic delivery and metabolic demand. Pediatric patients who suffer an in-hospital cardiac arrest often have changes in their physiological status in the hours leading up to their arrest event.103,104 Therefore, interventions during the prearrest phase focus on preventing the cardiac arrest, with special attention to early recognition and targeted treatment of respiratory failure and shock. Early recognition plays a key role in identifying a prearrest state in children, who unlike adults may be able to mount a prolonged physiologic response to a worsening clinical picture. Medical emergency teams (METs; also known as rapid response teams) are in-hospital emergency teams designed specifically for this purpose. Frontline providers, and even parents, are encouraged to initiate evaluation by METs based on physiologic protocol driven parameters or even intuition. Patients are assessed by the METs, and those at high risk of clinical decompensation

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TABLE 79.4  Phases of Cardiac Arrest and Resuscitation Phase

Interventions

Prearrest phase (protect)

Optimize patient monitoring and rapid emergency response Recognize and treat respiratory failure or shock to prevent cardiac arrest

Arrest (no-flow) phase (preserve)

Minimize interval to BLS and ACLS Organize response with clear leadership Minimize interval to defibrillation, when indicated

Low-flow (CPR) phase (resuscitate)

Push hard, push fast Allow full chest recoil Minimized interruptions in compressions Avoid overventilation Titrate CPR to optimize myocardial blood flow (coronary perfusion pressures and exhaled CO2) Consider adjuncts to improve vital organ perfusion during CPR Consider ECMO if standard CPR/ALS not promptly successful

Post-resuscitation phase: short-term

Optimize cardiac output and cerebral blood flow Treat arrhythmias, if indicated Avoid hyperglycemia, hyperthermia, hyperventilation Debrief to improve future responses to emergencies

Postresuscitation phase: long-term rehabilitation (regenerate)

Early intervention with occupational and physical therapy Bioengineering and technology interface Possible future role for stem cell transplantation

ACLS, Advanced cardiac life support; ALS, advanced life support; BLS, basic life support; CPR, cardiopulmonary resuscitation; ECMO, extracorporeal membrane oxygenation.

are transferred to a pediatric ICU if necessary, with the goal to prevent progression to full cardiac arrest or to decrease the response time to initiation of advanced life support, thereby limiting the no-flow state. Implementation of METs decreases the frequency of cardiac arrests compared with retrospective control periods before MET initiation.105-107 While early recognition protocols cannot identify all children at risk for cardiac arrest, it seems reasonable to assume that transferring critically ill children to an ICU early in their disease process for better monitoring and more aggressive interventions can improve resuscitative care and clinical outcomes. The caveat is that prearrest states must be identified to initiate monitoring and interventions that may inhibit the progression to an arrest. While a significant amount of research dollars and resources are spent on the other phases of cardiac arrest, particular focus on the prearrest state may yield the greatest improvement in survival and neurologic outcomes. 

NO FLOW/LOW FLOW Airway-Breathing-Circulation or Circulation-Airway-Breathing For OHCA victims, “compression-only” CPR has been associated with improved outcomes.108,109 This is now the recommended modality for emergency medical service dispatcher

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instructing bystander CPR.110 In a recent Japanese study, children with OHCA due to a primary cardiac etiology displayed an equivalent survival rate between compressiononly CPR and classic CPR with rescue breaths. However, only 29% of patients had a cardiac cause of OHCA. Those with noncardiac etiology in the overall cohort had a significantly worse survival rate with compression-only CPR, as compared with classic CPR with rescue breaths.111 Additionally, in another nationwide Japanese OHCA registry study, compression-only CPR was superior to no bystander CPR at all but not to conventional CPR.112 In a recent American OHCA registry study, children who received conventional bystander CPR with chest compressions and rescue breaths had improved rates of overall survival and survival with favorable outcomes as compared with those who did not receive CPR, whereas those receiving compression-only CPR did not fare any better than children not receiving CPR.113 Thus compression-only CPR is not recommended for children in either the inpatient or out-of-hospital setting, except in situations in which “rescuers are unwilling or unable to deliver breaths.”114 Regardless, the prioritization of initial interventions during CPR has shifted from airway-breathing-circulation (“A-B-C”) to circulation-airway-breathing (“C-A-B”) in order to prevent harmful delays in the initiation of chest compressions and due to the relative complexity of the tasks involved in providing assisted ventilation. This is endorsed by both the 2010 and 2015 AHA BLS Guidelines.114,115 However, a 2015 International Liaison Committee on Resuscitation consensus statement identified a paucity of pediatric-specific evidence to support this recommendation.116 In our opinion, the approach is physiologically sound, especially given the association of delayed chest compression initiation with poor outcomes. With that said, the pediatric provider must consider the predominance of asphyxia and hypoxemia as precursors to cardiac arrest.83,117 This is especially true in the ICU and operating room, where personnel and other resources frequently allow for simultaneous circulatory support with high-quality chest compressions as well as the provision of assisted ventilations by experienced personnel. In order to improve outcomes from pediatric cardiac arrest, it is imperative to shorten the no-flow phase of untreated cardiac arrest. To that end, it is important to monitor high-risk patients to allow early recognition of the cardiac arrest and prompt initiation of basic and advanced life support. Effective CPR optimizes coronary perfusion pressure (by elevating aortic diastolic pressure relative to RAP) and cardiac output to critical organs to support vital organ viability (by elevating mean aortic pressure) during the low flow phase. Important tenets of basic life support are push hard, push fast, allow full chest recoil between compressions, and minimize interruptions of chest compression. The myocardium receives blood flow from the aortic root, mainly during diastole, via the coronary arteries. When the heart arrests and no blood flows through the aorta, coronary blood flow ceases. However, during chest compressions, aortic pressure rises at the same time as RAP and with the subsequent decompression phase of chest compressions, the RAP falls faster and lower than the aortic pressure, which generates a pressure gradient that perfuses the heart with oxygenated

blood. Therefore, full elastic recoil (release) is critical to create a pressure difference between the aortic root and the right atrium. A CPP below 15 mm Hg during CPR is a poor prognostic factor for ROSC. Achieving optimal coronary perfusion pressure, exhaled carbon dioxide concentration, and cardiac output during the low flow phase of CPR is consistently associated with an improved chance for return of spontaneous circulation (ROSC) and improved short- and long-term outcome in mature animal and human studies.118-125 There is a critical need for research evaluating goal directed CPR, both in immature animal models and pediatric patients. Other measures essential for truncating the no-flow phase during VF and pulseless VT are rapid detection and prompt defibrillation. Clearly, CPR alone is inadequate for successful resuscitation from these arrhythmias. For cardiac arrests resulting from asphyxia and/or ischemia, provision of adequate myocardial perfusion and myocardial oxygen delivery are the critical elements for ROSC. 

POSTARREST/RESUSCITATION The postarrest/resuscitation phase includes coordinated, skilled management of the immediate post-resuscitation stage, the next few hours to days, and long-term rehabilitation. The immediate post-resuscitation stage is a high-risk period for ventricular arrhythmias and other reperfusion injuries. Goals of interventions implemented during the immediate post-resuscitation stage and the next few days include adequate tissue oxygen delivery, treatment of postresuscitation myocardial dysfunction, and minimizing post-resuscitation tissue injury (e.g., preventing post-resuscitation hyperthermia and hypoglycemia; and, perhaps initiating post-resuscitation therapeutic hypothermia, preventing hyperglycemia and avoiding hyperoxia). This postarrest/resuscitation phase may have the greatest potential for innovative advances in the understanding of cell injury (excitotoxicity, oxidative stress, metabolic stress) and cell death (apoptosis and necrosis), ultimately leading to novel molecular-targeted interventions. The rehabilitation stage concentrates on salvage of injured cells, and support for reengineering of reflex and voluntary communications of these cell and organ systems to improve long-term functional outcome. The specific phase of resuscitation dictates the focus of care. Interventions that improve outcome during one phase may be deleterious during another. For instance, intense vasoconstriction during the low flow phase of cardiac arrest improves coronary perfusion pressure and the probability of ROSC. The same intense vasoconstriction during the post-resuscitation phase increases left ventricular afterload and may worsen myocardial strain and dysfunction. Current understanding of the physiology of cardiac arrest and recovery allows us to only crudely manipulate blood pressure, oxygen delivery and consumption, body temperature, and other physiologic parameters in our attempts to optimize outcome. Future strategies likely will take advantage of increasing knowledge of cellular injury, thrombosis, reperfusion, mediator cascades, cellular markers of injury and recovery, and transplantation technology, including stem cells. 

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79 • Pediatric and Neonatal Critical Care

Interventions During the Cardiac Arrest (No Flow) and Cardiopulmonary Resuscitation (Low Flow) AIRWAY AND BREATHING During CPR, cardiac output and pulmonary blood flow are ∼10% to 25% of that during normal sinus rhythm; therefore, a lower minute ventilation is necessary for adequate gas exchange from the blood traversing the pulmonary circulation. Animal and adult data indicate that overventilation (“overventilation” from exuberant rescue breathing) during CPR is common and can substantially compromise venous return and subsequently cardiac output.126-128 These detrimental hemodynamic effects are compounded when one considers the effect of interruptions in CPR to provide airway management and rescue breathing and may contribute to worse survival outcomes.129-132 While overventilation is problematic, in light of the fact that most pediatric arrests are asphyxial in nature, immediate initiation of adequate ventilation is still important. The difference between arrhythmogenic and asphyxial arrests lies in the physiology. In animal models of sudden VF cardiac arrest, acceptable PaO2 and PaCO2 persist for 4 to 8 minutes during chest compressions without rescue breathing.133,134 This is in part because aortic oxygen and carbon dioxide concentrations at the onset of the arrest do not vary much from the prearrest state with no blood flow and minimal aortic oxygen consumption. The lungs act as a reservoir of oxygen during the low-flow state of CPR; therefore, adequate oxygenation and ventilation can continue without rescue breathing. Several retrospective studies of witnessed VF cardiac arrest in adults have also shown that outcomes are similar after bystander-initiated CPR with either chest compressions alone or chest compressions plus rescue breathing.135 However, during asphyxial arrest, peripheral and pulmonary blood flow continues during the prearrest, state resulting in significant arterial and venous oxygen desaturation, elevated lactate levels, and depletion of the pulmonary oxygen reserve. Therefore, at the onset of CPR, there is substantial arterial hypoxemia and resulting acidemia. In this circumstance, rescue breathing with controlled ventilation can be a life-saving maneuver. In contrast, the adverse hemodynamic effects from overventilation during CPR combined with possible interruptions in chest compressions to open the airway and deliver rescue breathing are a lethal combination in certain circumstances such as VT/VF arrests. In short, the resuscitation technique should be titrated to the physiology of the patient to optimize patient outcome. 

CIRCULATION: OPTIMIZING BLOOD FLOW DURING LOW FLOW CARDIOPULMONARY RESUSCITATION: PUSH HARD, PUSH FAST When the heart arrests, no blood flows to the aorta and coronary blood flow ceases immediately.135 At that point, provision of high quality CPR (PUSH HARD, PUSH FAST) is vital to reestablish coronary flow. The goal during CPR is to

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maximize the myocardial perfusion pressure (MPP). Related by the following equation: MPP = aortic diastolic blood pressure (AoDP) minus RAP, myocardial blood flow improves as the gradient between AoDP and RAP increases. During downward compression phase, aortic pressure rises at the same time as RAP with little change in the MPP. However, during the decompression phase of chest compressions, the RAP falls faster and lower than the aortic pressure, which generates a pressure gradient perfusing the heart with oxygenated blood during this artificial period of “diastole.” Several animal and human studies have demonstrated, in both VT/VF and asphyxial models, the importance of establishing MPP as a predictor for short-term survival outcome (ROSC).124,136-139 Because there is no flow without chest compressions, it is important to minimize interruptions in chest compressions. To allow good venous return in the decompression phase of external cardiac massage, it is also important to allow full chest recoil and to avoid overventilation (preventing adequate venous return because of increased intrathoracic pressure). Based on the provided equation, MPP can be improved by strategies that increase the pressure gradient between the aorta and the right atrium. As an example, the inspiratory impedance threshold device (ITD) is a small, disposable valve that can be connected directly to the tracheal tube or face mask to augment negative intrathoracic pressure during the inspiratory phase of spontaneous breathing and the decompression phase of CPR by impeding airflow into the lungs. Application in animal and adult human trials of CPR has established the ability of the ITD to improve vital organ perfusion pressures and myocardial blood flow140-145; however, in the only randomized trial during adult CPR, mortality benefit was limited to the subgroup of patients with PEA.145 Additional evidence that augmentation of negative intrathoracic pressure can improve perfusion pressures during CPR comes from the active compression-decompression device (ACD). The ACD is a handheld device that is fixed to the anterior chest of the victim by means of suction similar to a household plunger that can be used to apply active decompression forces during the release phase, thereby creating a vacuum within the thorax. By actively pulling during the decompression phase, blood is drawn back into the heart by the negative pressure.146 Animal and adult studies have demonstrated that the combination of ACD with ITD act in concert to further improve perfusion pressures during CPR compared with ACD alone.142 In the end, while novel interventions such as the ITD and ACD are promising adjuncts to improve blood flow during CPR, the basic tenants of PUSH HARD, PUSH FAST, ALLOW FULL CHEST WALL RELEASE, MINIMIZE INTERRUPTIONS, and DON’T OVERVENTILATE are still the dominate factors to improve blood flow during CPR and chance of survival. 

CHEST COMPRESSION DEPTH The pediatric chest compression depth recommendation of at least one-third anterior-posterior chest depth (approximately 4 cm in infants and 5 cm in children) is based largely upon expert clinical consensus, using data extrapolated from animal, adult, and limited pediatric data. In a small study of six infants, chest compressions targeted to one half

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anterior-posterior chest depth resulted in improved systolic blood pressures, compared with those targeted at one-third anterior-posterior chest depth.147 While only a small series with qualitatively estimated chest compression depths, this is the first study to collect actual data from children supporting the existing chest compression depth guidelines. On the contrary, two recent studies using computer automated tomography (CT)148,149 suggest that depth recommendations based on a relative (%) anterior-posterior chest compression depth are deeper than that recommended for adults, and that a depth of one half anterior-posterior chest depth will result in direct compression to the point of fully emptying the heart and requisite shifting of heart because of inadequate AP diameter reserve in most children. Future studies that collect data from actual children and that associate quantitatively measured chest compression depths with short- and long-term clinical outcomes (arterial blood pressure, end tidal carbon dioxide, ROSC, survival) are needed. 

CIRCUMFERENTIAL VERSUS FOCAL STERNAL COMPRESSIONS

COMPRESSION/VENTILATION RATIOS

OPEN-CHEST CARDIOPULMONARY RESUSCITATION

The amount of ventilation provided during CPR should match, but not exceed, perfusion and should be titrated to the amount of circulation during the specific phase of resuscitation, as well as the metabolic demand of the tissues. Therefore, during the low flow state of CPR when the amount of cardiac output is roughly 10% to 25% of normal, less ventilation is needed.150 However, the best ratio of compressions to ventilations in pediatric patients is largely unknown and depends on many factors, including the compression rate, the tidal volume, the blood flow generated by compressions, and the time that compressions are interrupted to perform ventilation. Recent evidence demonstrates that a compression/ventilation ratio of 15:2 delivers the same minute ventilation and increases the number of delivered chest compressions by 48% compared with CPR at a compression/ventilation ratio of 5:1 in a simulated pediatric arrest model.151,152 This is important because when chest compressions cease, the aortic pressure rapidly decreases and coronary perfusion pressure falls precipitously, thereby decreasing myocardial oxygen delivery.135 Increasing the ratio of compressions to ventilations minimizes these interruptions, thus increasing coronary blood flow. The benefits of PPV (increased arterial content of oxygen and carbon dioxide elimination) must be balanced against the adverse consequence of decreased circulation. These findings are in part the reason the AHA now recommends a pediatric compression/ventilation ratio of 15:2. 

DUTY CYCLE In a model of human adult cardiac arrest, cardiac output and coronary blood flow are optimized when chest compressions last for 30% of the total cycle time (approximately 1:2 ratio of time in compression to time in relaxation).153 As the duration of CPR increases, the optimal duty cycle may increase to 50%. In a juvenile swine model, a relaxation period of 250 to 300 milliseconds (duty cycle of 40%-50% at a compression rate of 120/min) correlates with improved cerebral perfusion pressures (CPPs) compared with shorter duty cycles of 30%.154 

In adult and animal models of cardiac arrest, circumferential (vest) CPR has been demonstrated to dramatically improve CPR hemodynamics.155 In smaller infants, it is often possible to encircle the chest with both hands and depress the sternum with the thumbs, while compressing the thorax circumferentially (thoracic squeeze). In an infant animal model of CPR, this “two-thumb” method of compression with thoracic squeeze resulted in higher systolic and diastolic blood pressures and a higher pulse pressure than traditional two-finger compression of the sternum.156 Although not rigorously studied, our clinical experience indicates that it is very difficult to attain adequate chest compression force and adequate aortic pressures with the two-finger technique, so we fully support the AHA Guidelines for health care providers to perform CPR on infants with the two-thumb-encircling hands technique.157 

In animal models, high quality standard, closed-chest CPR generates myocardial blood flow that is greater than 50% of normal, CBF that is approximately 50% of normal, and cardiac output ∼10% to 25% of normal.135,155,158,159 By contrast, open-chest CPR can generate myocardial and CBF that approaches normal. Although open-chest massage improves coronary perfusion pressure and increases the chance of successful defibrillation in animals and humans,160-162 performing a thoracotomy to allow openchest CPR is impractical in many situations. A retrospective review of 27 cases of CPR following pediatric blunt trauma (15 with open-chest CPR and 12 with closed-chest CPR) demonstrated that open-chest CPR increased hospital cost without altering rates of ROSC or survival to discharge. However, survival in both groups was 0%, indicating that the population may have been too severely injured or too late in the process to benefit from this aggressive therapy.163 Open-chest CPR is often provided to children after openheart cardiac surgery and sternotomy. Earlier institution of open-chest CPR may warrant reconsideration in selected special resuscitation circumstances. 

MEDICATIONS USED TO TREAT CARDIAC ARREST While animal studies have indicated that epinephrine can improve initial resuscitation success after both asphyxial and VF cardiac arrests, there are no prospective studies to support the use of epinephrine or any other medication to improve survival outcome from pediatric cardiac arrest. A variety of medications are used during pediatric resuscitation attempts, including vasopressors (epinephrine and vasopressin), antiarrhythmics (amiodarone and lidocaine), and other drugs such as calcium chloride and sodium bicarbonate. Each will be discussed separately as follows.

Vasopressors Epinephrine (adrenaline) is an endogenous catecholamine with potent α- and β-adrenergic stimulating properties. The

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79 • Pediatric and Neonatal Critical Care

α-adrenergic action (vasoconstriction) increases systemic and PVR. The resultant higher aortic diastolic blood pressure improves coronary perfusion pressure and myocardial blood flow, even though it reduces global cardiac output during CPR; as noted previously, adequacy of myocardial blood flow is a critical determinant of ROSC. Epinephrine also increases CBF during good quality CPR because peripheral vasoconstriction directs a greater proportion of flow to the cerebral circulation.164-166 However, recent evidence suggests that epinephrine can decrease local cerebral microcirculatory blood flow at a time when global cerebral flow is increased.167 The β-adrenergic effect increases myocardial contractility and HR, and relaxes smooth muscle in the skeletal muscle vascular bed and bronchi; however, the β-adrenergic effects are not observed in the peripheral vascular beds secondary to the high dose used in cardiac arrest. Epinephrine also increases the vigor and intensity of VF, increasing the likelihood of successful defibrillation. Highdose epinephrine (0.05-0.2 mg/kg) improves myocardial and CBF during CPR more than standard-dose epinephrine (0.01-0.02 mg/kg) in animal models of cardiac arrest and may increase the incidence of initial ROSC.168,169 However, prospective and retrospective studies have indicated that the use of high-dose epinephrine in adults or children does not improve survival and may be associated with worse neurologic outcome.170,171 A randomized, blinded, controlled trial of rescue high-dose epinephrine versus standard-dose epinephrine after failed initial standard dose epinephrine in pediatric in-hospital cardiac arrest demonstrated a worse 24-hour survival in the high-dose epinephrine group (1 of 27 survivors vs. 6 of 23 survivors, P < .05).172 Based on these clinical studies, high-dose epinephrine cannot be recommended routinely for either initial or rescue therapy. Importantly, these studies indicate that high-dose epinephrine can worsen a patient’s post-resuscitation hemodynamic condition and likelihood of survival. Vasopressin is a long-acting endogenous hormone that acts at specific receptors to mediate systemic vasoconstriction (V1 receptor) and reabsorption of water in the renal tubule (V2 receptor). Vasoconstrictive properties are most intense in the skeletal muscle and skin vascular beds. Unlike epinephrine, vasopressin is not a pulmonary vasoconstrictor. In experimental models of cardiac arrest, vasopressin increases blood flow to the heart and brain and improves long-term survival compared with epinephrine. However, vasopressin can decrease splanchnic blood flow during and following CPR and can increase afterload in the post-resuscitation period placing further strain on the left ventricle.158,173-176 Adult randomized, controlled trials suggest that outcomes are similar after use of vasopressin or epinephrine during CPR.177,178 During pediatric arrest, a case series of four children who received vasopressin during six prolonged cardiac arrest events suggested that the use of bolus vasopressin may result in ROSC when standard medications have failed.179 However, a more recent retrospective study of 1293 consecutive pediatric arrests from the National Registry of CPR (NPCRP) found that vasopressin use, while infrequent (administered in only 5% of events), was associated with a lower likelihood of ROSC. Therefore, it is unlikely that vasopressin will replace epinephrine as a first-line agent in pediatric cardiac arrest. However, the available data suggest that its use in conjunction with

2533

epinephrine may deserve further investigation, especially in prolonged arrest unresponsive to initial epinephrine resuscitation. 

Antiarrhythmic Medications Calcium. Calcium is used frequently in cases of pediatric cardiac arrest, despite the lack of evidence for efficacy. In the absence of a documented clinical indication (i.e., hypocalcemia, calcium channel blocker overdose, hypermagnesemia, or hyperkalemia), administration of calcium does not improve outcomes from cardiac arrest.180-188 To the contrary, three pediatric studies have suggested a potential for harm, as routine calcium administration was associated with decreased survival rates and / or worse neurological outcomes.180-188 Despite limited clinical data to support the use of calcium during CPR, it is reasonable to consider calcium administration during CPR for cardiac arrest patients at high risk of hypocalcemia (e.g., renal failure, shock associated with massive transfusion, etc.).  Buffer Solutions. There are no randomized controlled studies in children examining the use of sodium bicarbonate for management of pediatric cardiac arrest. Two randomized controlled studies have examined the value of sodium bicarbonate in the management of adult cardiac arrest189 and in neonates with respiratory arrest in the delivery room.190 Neither study was associated with improved survival. In fact, one multicenter retrospective in-hospital pediatric study found that sodium bicarbonate administered during cardiac arrest was associated with decreased survival, even after controlling for age, gender and first documented cardiac rhythm.187 Therefore, during pediatric cardiac arrest resuscitation, the routine use of sodium bicarbonate is not recommended. Clinical trials involving critically ill adults with severe metabolic acidosis do not demonstrate a beneficial effect of sodium bicarbonate on hemodynamics despite correction of acidosis.191-192 This is somewhat surprising in light of data that severe acidosis may depress the action of catecholamines and worsen myocardial function.193,194 Nevertheless, the common use of sodium bicarbonate during CPR is not supported by clinical data. Pediatric patients with implanted cardiac pacemakers may have an increased threshold for myocardial electrical stimulation when acidotic195; therefore, administration of bicarbonate or another buffer is appropriate for management of severe documented acidosis in these children. Administration of sodium bicarbonate also is indicated in the patient with a tricyclic antidepressant overdose, hyperkalemia, hypermagnesemia, or sodium channel blocker poisoning. The buffering action of bicarbonate occurs when a hydrogen cation and a bicarbonate anion combine to form carbon dioxide and water. Carbon dioxide must be cleared through adequate minute ventilation; thus, if ventilation is impaired during sodium bicarbonate administration, carbon dioxide buildup may negate the buffering effect of bicarbonate. Because carbon dioxide readily penetrates cell membranes, intracellular acidosis may paradoxically increase after sodium bicarbonate administration without adequate ventilation. Therefore, bicarbonate should not be used for management of respiratory acidosis. Unlike sodium bicarbonate, tromethamine (THAM) buffers excess protons without generating carbon dioxide; in

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SECTION V  •  Pediatric Anesthesia

fact, carbon dioxide is consumed following THAM administration. In a patient with impaired minute ventilation, tromethamine may be preferable when buffering is necessary to mitigate severe acidosis. Tromethamine undergoes renal elimination, and renal insufficiency may be a relative contraindication to its use. Carbicarb, an equimolar combination of sodium bicarbonate and sodium carbonate, is another buffering solution that generates less carbon dioxide than sodium bicarbonate. In a canine model of cardiac arrest comparing animals given normal saline, sodium bicarbonate, THAM, or Carbicarb, the animals given any buffer solution had a higher rate of ROSC than the animals given normal saline. In the animals given sodium bicarbonate or Carbicarb, the interval to ROSC was significantly shorter than in animals given normal saline. However, at the end of the 6-hour study period, all resuscitated animals were in a deep coma, so no inferences regarding meaningful survival can be drawn.196 It is premature to recommend either THAM or Carbicarb during CPR at this time. 

POST-RESUSCITATION INTERVENTIONS Temperature Management Two seminal articles197,198 have established that induced hypothermia (32°C-34°C) could improve outcome for comatose adults after resuscitation from VF cardiac arrest. In both randomized, controlled trials, the inclusion criteria were patients older than 18 years who were persistently comatose after successful resuscitation from nontraumatic VF.199,200 However, in a recent randomized control trial with unconscious adult survivors of OHCA, a targeted temperature of 33°C did not confer a benefit as compared with the targeted temperature of 36°C.201 Interpretation and extrapolation of these studies to children is difficult; however, fever within the first 48 hours following cardiac arrest, brain trauma, stroke, and ischemia is associated with poor neurologic outcome. Emerging neonatal trials of selective brain cooling and systemic cooling show promise in neonatal HIE, suggesting that induced hypothermia may improve outcomes.202,203 The efficacy of therapeutic hypothermia following pediatric cardiac arrest is being evaluated in a randomized controlled trial (clinicaltrials.gov identifier NCT00880087); THAPCA: Therapeutic Hypothermia After Pediatric Cardiac Arrest (www.thapca.org). At a minimum, it is advisable to avoid hyperthermia in children following CPR. Using an approach of “therapeutic normothermia” with scheduled administration of antipyretic medications and the use of external cooling devices, while monitoring core temperature, may be necessary to prevent hyperthermia in this population. Notably, preventing hyperthermia is not easy. Many children become hyperthermic post-arrest despite the intent to prevent hypothermia.198  Glucose Control Both hyperglycemia and hypoglycemia following cardiac arrest is associated with worse neurologic outcome.204-207 While it seems intuitive that hypoglycemia would be associated with worse neurologic outcome, whether hyperglycemia per se is harmful or is simply a marker of the severity of the stress hormone response from prolonged ischemia is not clear. A recent randomized control trial suggests

that tight glycemic control in critically ill children had no effect on major clinical outcomes, but was associated with a higher incidence of hypoglycemia.208 In summary, there is insufficient evidence to formulate a strong recommendation on the management of hyperglycemia in children with ROSC following cardiac arrest. If hyperglycemia is treated following ROSC in pediatric patients, blood glucose concentrations should be carefully monitored to avoid hypoglycemia. 

Blood Pressure Management A patient with ROSC may have substantial variability in blood pressure following cardiac arrest. Postarrest/resuscitation myocardial dysfunction is very common and is often associated with hypotension (discussed later).199,200,209-218 In addition, hypertension may occur, especially if the patient receives vasoactive infusions for postarrest myocardial dysfunction. Optimization of blood pressure postarrest is critical to maintain adequate perfusion pressure to vital organs that may have already been injured from the “no flow” and “low blood flow” states during initial cardiac arrest and CPR. Cerebral blood flow in healthy patients is tightly controlled over a wide range of mean arterial blood pressure via cerebral neurovascular bundle (autoregulation); however, adults resuscitated from cardiac arrest have demonstrated impaired autoregulation of CBF, and this may also be the case in children.219 Dysautoregulation of the cerebral neurovascular bundle following cardiac arrest may limit the brain’s ability to regulate excessive blood flow and microvascular perfusion pressure, thereby leading to reperfusion injury during systemic hypertension. However, in animal models, brief induced hypertension following resuscitation results in improved neurologic outcome compared with normotensive reperfusion.220,221 Conversely, systemic hypotension may perpetuate neurologic metabolic crisis following ischemic injury by uncoupling bioenergetic demand and delivery. Therefore, a practical approach to blood pressure management following cardiac arrest is to attempt to minimize blood pressure variability in this highrisk period following resuscitation. 

Post-resuscitation Myocardial Dysfunction Postarrest myocardial stunning and arterial hypotension occur commonly after successful resuscitation in both animals and humans.199,200,209-218 Animal studies demonstrate that postarrest myocardial stunning is a global phenomenon with biventricular systolic and diastolic dysfunction. Postarrest myocardial stunning is pathophysiologically and physiologically similar to sepsis-related myocardial dysfunction and postcardiopulmonary bypass myocardial dysfunction, including increases in inflammatory mediators and NO production.212,215,218,216 Because cardiac function is essential to reperfusion following cardiac arrest, management of postarrest myocardial dysfunction may be important to improving survival. The classes of agents used to maintain circulatory function (i.e., inotropes, vasopressors, and vasodilators) must be carefully titrated during the post-resuscitation phase to the patient’s cardiovascular physiology. Although the optimal

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79 • Pediatric and Neonatal Critical Care

management of post–cardiac arrest hypotension and myocardial dysfunction has not been established, data suggest that aggressive hemodynamic support may improve outcomes. Controlled trials in animal models have shown that dobutamine, milrinone, levosimendan can effectively ameliorate post–cardiac arrest myocardial dysfunction.209,210,222,223 In clinical observational studies, fluid resuscitation has been provided for patients with hypotension and concomitant low central venous pressure, and various vasoactive infusions, including epinephrine, dobutamine, and dopamine, have been used to treat the myocardial dysfunction syndrome.199,200,213-217 In the end, optimal use of these agents involves close goal-directed titration, and the use of invasive hemodynamic monitoring may be appropriate. General critical care principles suggest that appropriate therapeutic goals are adequate blood pressures and adequate oxygen delivery. However, the definition of “adequate” is elusive. Reasonable interventions for vasodilatory shock with low central venous pressure include fluid resuscitation and vasoactive infusions. Appropriate considerations for left ventricular myocardial dysfunction include euvolemia, inotropic infusions, and afterload reduction.

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in animal models may potentiate oxidative injury to key mitochondrial enzymes (pyruvate dehydrogenase or manganese superoxide) or mitochondrial lipids (cardiolipin), and is associated with worse neurologic outcomes.235-238 Experimental protocols in large animals using peripheral pulse-oximetry to titrate oxygenation in the post-resuscitation phase can reduce post-resuscitation hyperoxia and significantly improve neuropathology and neurobehavioral outcomes.239 Consistent with these experimental findings, arterial hyperoxia (PaO2 ≥ 300 mm Hg) was independently associated with in-hospital mortality compared with either hypoxia or normoxia in an observational study among critically ill adult patients admitted to the ICU within 24 hours of a cardiac arrest.240 We believe it is prudent to titrate oxygenation during and following pediatric cardiac arrest. Although the optimal SpO2 is not known, we recommend titration of FiO2 to the lowest amount necessary to assure SpO2 >94%. Perhaps the future of post-arrest care will include more aggressive neurocritical care monitoring, such as near infrared spectroscopy, cerebral microdialysis, PbtO2, CBF, and even bedside analysis of mitochondrial dysfunction. 

NEUROMONITORING

QUALITY OF CARDIOPULMONARY RESUSCITATION

Continuous neuromonitoring and goal-directed intervention following cardiac arrest is an exciting frontier with great promise in improving neurologic outcomes post–­ cardiac arrest.224 Continuous electroencephalogram (cEEG) monitoring is an increasingly instituted modality for neuromonitoring of critically ill patients, especially to diagnose nonconvulsive seizures (NCS) and seizures in patient’s receiving muscle relaxants. cEEG monitoring is noninvasive, performed at the bedside, and permits continuous assessment of cortical function. Interpretation of continuous electroencephalogram (EEG) is usually performed by a neurologist from a remote location, and not bedside critical care physicians. However, advances in quantitative EEG tools may allow bedside caregivers to identify important electrographic events, such as seizures or abrupt background changes, to potentially permit real-time analysis and intervention.225 In a prospective study of cEEG in children, NCS were detected in 39% (12 of 31) children following cardiac arrest.226 In a partially overlapping cohort of 19 children, NCS were common in children undergoing therapeutic hypothermia after cardiac arrest.226 NCS seems to be a common occurrence following cardiac arrests in children. Although the relationship of NCS to worse outcomes has not been established in pediatric patients following cardiac arrest, it has been associated with worse outcomes among critically ill adults and neonates.227-233 We believe that cEEG should be considered for children post–cardiac arrest and that patients with NCS (especially status epilepticus with NCS) should be treated with anticonvulsant medication. Further study is warranted to better establish frequency of NCS and potential benefit in outcomes with anticonvulsant therapy. Oxidative injury may be greatest in the early phases of post-resuscitation therapy following cardiac arrest.234 Interestingly, the use of 100% oxygen (compared with room air) during and immediately following resuscitation

Despite evidence-based guidelines, extensive provider training, and provider credentialing in resuscitation medicine, the quality of CPR is typically poor. CPR guidelines recommend target values for selected CPR parameters related to rate and depth of chest compressions and ventilations, avoidance of CPR-free intervals, and complete release of sternal pressure between compressions.241 Slow compression rates, inadequate depth of compression, and substantial pauses are the norm. An approach to Push Hard, Push Fast, Minimize Interruptions, Allow Full Chest Recoil, and Don’t Overventilate can markedly improve myocardial, cerebral, and systemic perfusion, and will likely improve outcomes.131 Quality of post-resuscitative management has also been demonstrated to be critically important to improve resuscitation survival outcomes.213 Measuring the quality of CPR and avoiding overventilation during cardiac arrest resuscitation have recently been reemphasized by consensus of the International Liaison Committee on Resuscitation and the AHA.242 Although the correct amount, timing, intensity, and duration of ventilation that is required during CPR is controversial, there is no controversy that measurement and titration of the amount of ventilation to the amount of blood perfusion are desirable. Thus additional technology that is safe, accurate, and practical would improve detection and feedback of the “quality of CPR.” Recent technology has been developed that monitors quality of CPR by force sensors and accelerometers, and can provide verbal feedback to the CPR administrator regarding the frequency and depth of chest compressions and the volume of ventilations. Recent pediatric data illustrates that intensive training and real-time corrective feedback can help chest compression quality approach age-specific AHA CPR guideline targets.243-245 Moreover, improvements in post-resuscitation care can improve resuscitation survival outcomes.213 

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SECTION V  •  Pediatric Anesthesia

EXTRACORPOREAL MEMBRANE OXYGENATIONCARDIOPULMONARY RESUSCITATION The use of extracorporeal membrane life-saving (ECLS) devices as a rescue therapy for refractory cardiac arrest (ECPR) is an exciting topic in resuscitation science. In children with medical or surgical cardiac diseases, ECPR has been shown to improve survival to hospital discharge246 and can be effective after even greater than 50 minutes of CPR.247 However, at this time, observational data has not consistently demonstrated a survival benefit of ECPR compared with conventional CPR across broad populations.248,249 Children with primary cardiac disease may have a survival advantage, due to these disease processes being amenable to a bridge with ECLS—whether to recovery, surgery, or transplantation. There may be an underlying advantage for these patients as well, stemming from predominantly single-organ failure compared with patients with noncardiac etiologies of cardiac arrest, allowing for a greater chance of full recovery after resuscitation.250 Importantly, in these observational studies, ECPR is used as a rescue therapy in patients who likely would have died with continued conventional resuscitation efforts.250 In fact, in a GWTG-R study that looked at both cardiac and noncardiac patients with greater than 10 minutes of CPR, those who received ECPR had improved survival and favorable neurologic outcome at discharge.251 A lack of survival advantage, even when controlling for confounding factors, is flawed by the nature of these studies.252 In the absence of randomized controlled trials that specifically compare early initiation of ECPR and conventional CPR, it is probably reasonable to consider ECPR as a rescue therapy in patients with potentially reversible underlying disease processes. However, as noted in PALS guidelines, any reasonable chance of success requires a setting with “existing ECMO protocols, expertise, and equipment,”253 and dedicated teams that train for efficient cannulation under difficult circumstances. Therefore, timely, quality E-CPR may be an exciting adjuvant to conventional CPR for pediatric patients. Future frontiers will define patient populations and optimize the clinical approach to extracorporeal support; however, clinicians providing CPR should consider E-CPR early in the course of a resuscitation not responding to conventional CPR. Perhaps after failure to attain ROSC within 5 minutes, clinicians should ask themselves: (1) does the patient have a potentially reversible process, (2) would ECMO be a “bridge” to a potentially good outcome, and (3) do we have the personnel and resources to provide EMCO promptly? If the answer to all three are “yes,” prompt implementation of E-CPR should be considered. We believe that patients arriving with a witnessed arrest with immediate initiation of CPR and evidence of quality CPR should be considered E-CPR candidates. 

Ventricular Fibrillation and Ventricular Tachycardia in Children Pediatric VF, or VT, has been an underappreciated pediatric problem. Recent studies indicate that VF and VT (i.e., shockable rhythms) occur in 27% of in-hospital cardiac arrests

at some time during the resuscitation.254 In a population of pediatric cardiac ICU patients, as many as 41% of arrests were associated with VF or VT.255 According to the National Registry of Cardiopulmonary Resuscitation (NRCPR) database, 10% of children with in-hospital cardiac arrest had an initial rhythm of VF/VT. In all, 27% of the children had VF/ VT at some time during the resuscitation.254 The incidence of VF varies by setting and age.256 In special circumstances, such as tricyclic antidepressant overdose, cardiomyopathy, post–cardiac surgery, and prolonged QT syndromes, VF and pulseless VT are more likely. The treatment of choice for short-duration VF is prompt defibrillation. In general, the mortality rate increases by 7% to 10% per minute of delay to defibrillation. Because VF must be considered before defibrillation can be provided, early determination of the rhythm by ECG is critical. An attitude that VF is rare in children can be a self-fulfilling prophecy with a uniformly fatal outcome. The recommended defibrillation dose is 2 J/ kg, but the data supporting this recommendation are not optimal and are based on old monophasic defibrillators. In the mid-1970s, authoritative sources recommended starting doses of 60 to 200 J for all children. Because of concerns for myocardial damage and animal data suggesting that shock doses ranging from 0.5 to 1 J/kg were adequate for defibrillation in a variety of species, Gutgesell et al. evaluated the efficacy of their strategy to defibrillate with 2 J/kg monophasic shocks.257 Seventy-one transthoracic defibrillations in 27 children were evaluated. Shocks within 10 J of 2 J/kg resulted in successful defibrillation (i.e., termination of fibrillation) in 91% of defibrillation attempts. More recent data demonstrate that an initial shock dose of 2 J/kg terminates fibrillation in less than 60% of children, suggesting that a higher dose may be needed.93,258-260 Interestingly, retrospective observational NRCPR data demonstrate that higher initial doses of 4 J/kg were associated with worse short-term survival (i.e., immediate survival of the cardiac arrest event with a spontaneous rhythm). Despite 5 decades of clinical experience with pediatric defibrillation, the optimal dose remains unknown.

ANTIARRHYTHMIC MEDICATIONS: LIDOCAINE AND AMIODARONE Administration of antiarrhythmic medications should never delay administration of shocks to a patient with VF. However, after an unsuccessful attempt at electrical defibrillation, medications to increase the effectiveness of defibrillation should be considered. Epinephrine is the current first-line medication for both pediatric and adult patients in VF. If epinephrine and a subsequent repeat attempt to defibrillate are unsuccessful, lidocaine or amiodarone should be considered. Lidocaine traditionally has been recommended for shockresistant VF in adults and children. However, only amiodarone improved survival to hospital admission in the setting of shock-resistant VF compared with placebo.261 In another study of shock-resistant out-of-hospital VF, patients receiving amiodarone had a higher rate of survival to hospital admission than patients receiving lidocaine.262 Neither study included children. Because there is moderate experience with amiodarone use as an antiarrhythmic agent in children and because of the adult studies, it is rational to use amiodarone similarly in children with shock-resistant VF/VT.

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79 • Pediatric and Neonatal Critical Care

The  recommended dosage is 5 mg/kg by rapid IV bolus. There are no published comparisons of antiarrhythmic medications for pediatric refractory VF. Although extrapolation of adult data and electrophysiologic mechanistic information suggest that amiodarone may be preferable for pediatric shock-resistant VF, the optimal choice is not clear. 

PEDIATRIC AUTOMATED EXTERNAL DEFIBRILLATORS Automated external defibrillators (AEDs) have improved adult survival from VF.263,264 AEDs are recommended for use in children 8 years or older with cardiac arrest.157,265 The available data suggest that some AEDs can accurately diagnose VF in children of all ages, but many AEDs are limited because the defibrillation pads and energy dosage are geared for adults. Adapters having smaller defibrillation pads that dampen the amount of energy delivered have been developed as attachments to adult AEDs, allowing their use in children. However, it is important that the AED diagnostic algorithm is sensitive and specific for pediatric VF and VT. The diagnostic algorithms from several AED manufacturers have been tested for such sensitivity and specificity and therefore can be reasonably used in younger children. 

WHEN SHOULD CARDIOPULMONARY RESUSCITATION BE DISCONTINUED? Several factors determine the likelihood of survival after cardiac arrest including the mechanism of the arrest (e.g., traumatic, asphyxial, progression from circulatory shock), location (e.g., in-hospital or out-of-hospital), response (i.e., witnessed or unwitnessed, with or without bystander CPR), underlying pathophysiology (i.e. cardiomyopathy, congenital defect, drug toxicity or metabolic derangement), and the potential reversibility of underlying diseases. These factors should all be considered before deciding to terminate resuscitative efforts. Continuation of CPR has been traditionally considered futile beyond 15 minutes of CPR or when more than 2 doses of epinephrine are needed.266 Presumably in part because of improvements in CPR quality and postresuscitation care, improved outcomes from in-hospital CPR efforts beyond 15 minutes or 2 doses of epinephrine are increasingly the norm.83,86 The potential for excellent outcomes despite prolonged CPR has been highlighted by the ECPR data noted above.267-271 Conversely, the decision to discontinue CPR prematurely is final and cannot be rescinded. In the first decade of the 21st century, there is no simple answer to the important clinical question: when should CPR be discontinued? 

Respiratory System STRUCTURAL AND FUNCTIONAL DEVELOPMENT: AGE-DEPENDENT VARIABLES Airways and Alveoli The lungs appear in the fourth to eighth weeks of gestation. At this time, the lung buds divide into the mainstem

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bronchi; by 6 weeks all subsegmental bronchi are present; and by 16 weeks, the number of airway generations is similar to that of adults. When airway development is complete, the terminal airways remodel and multiply to form a cluster of large saccules, or alveolar precursors, that can support gas exchange. True alveoli appear before and after birth, and the respiratory saccules are thin and septate during postnatal growth. At birth, children have approximately 24 million alveoli; by 8 years of age, the number has increased to 300 million (Table 79.5). After that, further lung growth is primarily the result of increased alveolar size. There is less elastic tissue in the neonatal lung than in the lungs of adults, and the elastin extends only to the alveolar duct. By 18 years of age, elastin extends to the alveolus and is at its maximum. It then slowly decreases over the next 5 decades. Lung compliance is integrally related to the amount of elastin; hence, compliance peaks in adolescence. It is lower in the very young and the very old. Airways close in the tidal volume range until about 5 years of age. 

Pulmonary Circulation The main axial arteries of the lungs are present at 14 weeks’ gestation. By 20 weeks’ gestation, the pattern of branching is similar to that of adults, and collateral supernumerary vessels are present. During fetal life, additional arteries develop to accompany the respiratory airways and saccules. Bronchial arteries appear between the 9th and 12th weeks of gestation. The arterial wall develops a fine elastic lamina by 12 weeks’ gestation, and muscle cells are present as early as 14 weeks of gestation. By 19 weeks, the elastic tissue extends to the seventh generation of arterial branching, and muscularization extends distally. In the fetus, muscularization of the arteries ends at a more proximal level than in children and adults. The muscularized arteries have thicker walls than arteries of similar size in adults. The pulmonary arteries are actively constricted until the latter part of gestation. In the fetal lamb, pulmonary blood flow is only 3.5% of the combined ventricular output at 0.4 to 0.7 of gestation and is just 7% near term. Immediately after birth, pulmonary blood flow increases to near adult levels. Development of the pulmonary venous system mirrors that of the arterial system. The pulmonary arteries continue to develop after birth; new artery formation follows airway branching up to about 19 months of age, and supernumerary arteries continue to grow until 8 years of age. As alveolar size increases, the acinar branching pattern becomes more extensive and complex. The arterial structure also changes as preexisting arteries increase in size; the thickness of the muscular arteries decreases to adult levels during the first year of life.  Biochemical Development By 24 weeks of gestation, the alveolar cuboidal epithelium flattens, and type I pneumocytes become the lining and supporting cells for the alveoli. The larger type II cells, which manufacture and store surfactant, also develop at this time. Surfactant initially appears at 23 to 24 weeks’ gestation in humans and increases in concentration during the last 10 weeks of gestational life.68 Surfactant is released into the alveoli at about 36 weeks’ gestation, thus making normal extrauterine life possible. 

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SECTION V  •  Pediatric Anesthesia

TABLE 79.5  Age-dependent Respiratory Variables: Normal Values Newborn

6 months

12 months

3 years

5 years

12 years

Adult

Respiratory rate (breaths/min)

50 ± 10

30 ± 5

24 ± 6

24 ± 6

23 ± 5

18 ± 5

12 ± 3

Tidal volume (mL)

21

45

78

112

270

480

575

Minute ventilation (L/min)

1.05

1.35

1.78

2.46

5.5

6.2

6.4

Alveolar ventilation (mL/min)

385

—

1245

1760

1800

3000

3100

Dead space–tidal volume ratio

0.3

0.3

0.3

0.3

0.3

0.3

0.3

Oxygen consumption (mL/kg/min)

6 ± 1.0

5 ± 0.9

5.2 ± 0.9

—

6.0 ± 1.1

3.3 ± 0.6

3.4 ± 0.6

Vital capacity (mL)

120

—

—

870

1160

3100

4000

Functional residual capacity (mL)

80

—

—

490

680

1970

3000

Total lung capacity (mL)

160

—

—

1100

1500

4000

6000

Closing volume as percentage of vital capacity

—

—

—

—

20

8

4

Number of alveoli (saccules) × 106

30

112

129

257

280

—

300

Specific compliance: CL/FRC (mL/cm H2O/L)

0.04

0.038

—

—

0.06

—

0.05

Specific conductance of small airways (mL/s/cm H2O/g)

0.02

—

3.1

1.7

0.12

8.2

13.4

Hematocrit

55 ± 7

37 ± 3

35 ± 2.5

40 ± 3

40 ± 2

42 ± 2

43-48

pHa

7.30 ± 7.40

—

7.35-7.45

—

—

—

7.35-7.45

Paco2 (mm Hg)

30-35

—

30-40

—

—

—

30-40

Pao2 (mm Hg)

60-90

—

80-100

—

—

—

80-100

From O’Rourke PP, Crone RK. The respiratory system. In: Gregory G, ed. Pediatric Anesthesia. 2nd ed. New York: Churchill Livingstone; 1989;63.

Respiratory Transition: Placenta to Lung By approximately 24 weeks’ gestation, the lungs are capable of extrauterine gas exchange. However, several important circulatory and mechanical changes must occur immediately after birth for pulmonary gas exchange to be adequate. Ventilation begins to match perfusion within the first hours of life. Initially, there is right-to-left intrapulmonary shunting through atelectatic areas of the lung, as well as left-to-right shunting through the ductus arteriosus and some right-to-left shunting through the foramen ovale. The resultant PaO2 of 50 to 70 mm Hg indicates a right-to-left shunt that is three times that of normal adults. Transition from fetal to neonatal respiration and circulation is dynamic. Postnatally, the pulmonary vascular bed remains constricted if it is exposed to acidosis, cold, or hypoxia. If pulmonary artery constriction occurs, right-toleft shunting of desaturated blood through the foramen ovale and ductus arteriosus increases and consequently reduces pulmonary blood flow. Maintenance of this active pulmonary vasoconstriction is called persistent pulmonary hypertension of the newborn or persistent fetal circulation.  Mechanics of Breathing For ventilation of the lungs, the respiratory muscles must overcome the lung’s static-elastic and dynamic-resistive

forces. Changes in these opposing forces during postnatal development affect lung volume, the pattern of respiration, and the work of breathing. 

Lung Compliance Versus Age Lung compliance changes with age because of the changing alveolar structure, amount of elastin, and amount of surfactant. At birth, compliance is low because alveolar precursors have thick walls and decreased amounts of elastin. A deficiency of surfactant (e.g., hyaline membrane disease) further decreases lung compliance. The improved lung compliance occurring over the first years of life is the result of continued development of alveoli and elastin.  Chest Wall The chest wall of infants is very compliant because their ribs are cartilaginous. Because of the box-like configuration of an infant thorax, there is less elastic recoil than there is with the dorsoventrally flattened thoracic cage of adults. Adults have a high proportion of slow-twitch, highoxidative, fatigue-resistant fibers in their diaphragm and intercostal muscles. Whereas adults have 65% of these fibers in the intercostal muscles and 60% in the diaphragmatic muscles, neonates have only 19% to 46% of these

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79 • Pediatric and Neonatal Critical Care

fibers in their intercostal muscles and 10% to 25% in the diaphragm.70 Consequently, infants are more vulnerable to muscle fatigue and decreased stability of the chest wall. The net effect of the compliant chest wall and the poorly compliant lungs is alveolar collapse and lower resting lung volume (FRC). Despite this tendency for lung collapse, a child maintains a large dynamic FRC via rapid RRs, laryngeal breaking, and stabilization of the chest wall with increased intercostal tone during exhalation. 

Upper Airway The upper airways of children and adults have several anatomic differences that affect their ability to maintain a patent airway. The more anterior and cephalad position of the larynx in children makes the “sniffing position” ideal for mask ventilation and endotracheal intubation. Extreme neck extension can actually obstruct the airway. The narrowest part of the adult airway is the vocal cords. Up to the age of 5 years, the narrowest portion of a child’s airway is at the cricoid cartilage, because the posterior larynx is positioned more cephalad than the anterior larynx, which causes the cricoid ring to be an ellipse rather than a circle. By 5 years of age, the posterior larynx has descended to the adult level.272 An ETT that passes easily through the vocal cords of a young child may cause ischemic damage to the distal airway. The cricoid narrowing and very pliant tracheal cartilage provide an adequate seal around an uncuffed ETT. Children younger than 5 years rarely require a cuffed ETT, although some practitioners use cuffed tubes regularly in these patients.273  Closing Capacity The elastic properties of the lung closely correlate with closing capacity. Closing volume is the lung volume at which the terminal airways close and gas is trapped behind the closed airways. Large closing volumes increase dead space ventilation, which leads to atelectasis and right-to-left shunting of blood. Elastic tissues help keep the airways open, so the greater the elastic stroma in the small airways, the lower the lung volume required to close small, noncartilaginous airways. Closing volume is small in late adolescence and relatively large in the elderly and the very young. Children overcome the complications of large closing volumes and secondary atelectasis by breathing rapidly, by constant activity, and by crying. Closing volume becomes a significant problem in infants who are inactive, sedated, or anesthetized.  Resistive Forces Neonates have small airways with high resistance or low conductance (conductance = 1/resistance). The diameter of the small airways does not significantly increase until about 5 years of age; hence, young children have elevated airway resistance at baseline and are particularly vulnerable to diseases that cause further narrowing of the airways (i.e., smooth muscle constriction, airway edema/inflammation). The normal high airway resistance of neonates and young children helps maintain FRC.  Control of Breathing The newborn’s respiratory control is unique. Hypoxia initially increases ventilation for a short time. This increase

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is followed by a sustained decrease in ventilation.77 The response is more exaggerated in preterm neonates. In fullterm infants, it disappears after several weeks. Periodic breathing is also more common in infants, particularly preterm infants, and is probably due to inadequate development of the medullary respiratory centers. 

Oxygen Transport: Oxygen Loading and Unloading Fetal hemoglobin has low levels of 2,3-diphosphoglycerate and an oxygen half-saturation pressure of hemoglobin (P50) of 18 mm Hg, which is much lower than the 27 mm Hg in adults. This lower P50 allows the fetus to load more oxygen at low placental oxygen tension, but it makes unloading oxygen in tissues more difficult. Three to 6 months after birth, fetal hemoglobin has been replaced with adult hemoglobin. The increased oxygen content of fetal hemoglobin and the increased fetal hemoglobin concentration are advantageous to the fetus because it allows an oxygen content of 20 mL of oxygen/100 mL of blood to be delivered to the brain and heart. This is the same oxygen content that adults have when breathing room air. The oxygen concentration of neonates at birth is 6 to 8 mL/kg/min. It decreases to 5 to 6 mL/kg/min over the first year of life. The decreased ventilation-perfusion ratio, the decreased P63 of fetal hemoglobin, and the progressive anemia characteristic of infants can make it difficult to deliver adequate oxygen during the first few months of life. Infants compensate by having a cardiac output of approximately 250 mL/kg/min for the first 4 to 5 months of life. 

RESPIRATORY FAILURE Respiratory failure is the inability of the lungs to adequately oxygenate and remove CO2 from pulmonary arterial blood. There are many causes of respiratory failure, including a low environmental oxygen concentration, parenchymal lung disease, and pulmonary vascular disease. A complete history of the severity and chronicity of the respiratory problem helps formulate a differential diagnosis and an approach to treatment. Specific data should include a history of prematurity, previous airway instrumentation, previous mechanical ventilation, nonpulmonary organ dysfunction, and a family history of respiratory disease. A detailed feeding history and up-to-date growth chart may provide valuable information because growth failure may increase the need for oxygen. Usually, 1% to 2% of the total oxygen consumed is used for breathing. During respiratory illnesses, as much as 50% of the total oxygen consumption may be used for breathing. Infants and children with respiratory failure often have intercostal and suprasternal retractions, signs that the work of breathing and oxygen consumption are increased. Patients grunt during expiration in an attempt to maintain FRC. Most infants and children have tachypnea, which also helps maintain FRC by decreasing the time for exhalation. Less energy is required to breath rapidly and shallowly than to take deep breaths. Infants with respiratory failure often have cyanotic lips, skin, and mucous membranes. However, it is often difficult to recognize skin color changes unless the PaO2 is below 70 mm Hg. Symmetry of chest movement should be noted. Differences in movement may indicate pneumothorax or

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blockage of a bronchus. The small thoracic volume allows easy transmission of breath sounds from one side to the other. Breath sound may be normal, even when pneumothorax is present. Abdominal distention can dramatically impede breathing in infants and young children. 

MONITORING OF RESPIRATORY FUNCTION An arterial blood gas is considered the gold standard to measure oxygenation, as PaO2 is measured directly from blood. The percent oxygen saturation of hemoglobin can be measured directly or calculated from PaO2, pH, PaCO2, and temperature. Venous and capillary blood gases do not predict PaO2. Use of arterial lines has decreased in pediatric ICUs over time.274 Pulse oximeters are ubiquitous. Pulse oximeters can provide continuous estimations of SaO2 when the saturation is less than 97%. This is due to the shape of the oxygen dissociation curve. Pulse oximeters pass at least two wavelengths of light through the patient and the change in the absorbance of light is compared with an algorithm that produces the oxygen saturation. In the saturation range of 91 to 97%, pulse oximeters have been shown to read higher than measured arterial saturations by approximately 1%.275 However, in the saturation range of 76% to 90%, pulse oximeters read higher than measured arterial saturations by approximately 5% with very wide confidence intervals.275 Pulse oximeters may also have poorer performance when there is decreased perfusion to the extremity with the sensor. Lastly, most pulse oximeters have difficulty detecting abnormal forms of hemoglobin, such as methemoglobin or carboxyhemoglobin, and will produce erroneous results in their presence. Umbilical artery cannulation is common in neonates, so those caring for such children can obtain arterial blood and continuously measure arterial blood pressure. These catheters are relatively simple to insert and reasonably easy to maintain.276-278 The tip of the catheter ideally should be at or just above the level of the aortic bifurcation and below the level of the renal arteries (L2). Once the child’s condition is stable, a peripheral artery catheter should be inserted and the umbilical artery catheter should be removed. All intraarterial catheters have the potential to cause distal thromboembolic disease. Care must be taken to flush arterial catheters gently to prevent cerebral or cardiac emboli. With proper insertion and maintenance, serious complications of arterial lines are rare. They have been shown to be relatively safe for short term use.279 Although arteries that are cannulated for a long time may develop thrombosis in a small study by Ergaz et al. all of the infants that developed thrombosis had spontaneous resolution with sequela.280 PaCO2 is used as a measure of ventilation. An arterial blood gas may be the gold standard, PaCO2 obtained from capillary or venous blood gases can provide valuable information. CO2values obtained from capnography or transcutaneous CO2(TCOM) can provide continuous information in a manner similar to pulse oximeters.281 Capnographs produce a waveform displaying exhaled CO2that can be either time-based or volumetric. Time-based capnography is much more common. Capnographs can either be an aspirating or nonaspirating system. An aspirating system takes gas from the ventilator circuit and measure the CO2. A nonaspirating system has an exhalation chamber placed in

line with the ventilator circuit. The system uses an infrared light source and detector which measures the exhaled CO2. There is a great amount of information that can come from capnography, including the end-tidal CO2(ETCO2) value, RR, dead space calculations, cardiac output, and detection of obstruction of the airways. For time-based capnography, the plateau of the slope will always be lower than PaCO2. Elevations in ETCO2 must be investigated as they signal a change in ventilation. For individuals with healthy lungs, this ETCO2 to PaCO2 gradient is usually 2 to 5 mm Hg. The gradient increases with increased dead space, abnormalities in the pulmonary vasculature, decreased cardiac output, and pulmonary over distension. ETCO2 from capnography can be used clinically to calculate the approximate alveolar dead space by the alveolar dead space fraction (AVDSf). AVDSf = (PaCO2 − PETCO2)/ PaCO2. AVDSf is a reasonable indicator of alveolar dead space282 and has been shown in several pediatric patients with acute hypoxemic respiratory failure to be associated with mortality.283-285 Other valuable information is available from the waveform produced by time-based capnography. As an example, a rising upslope to the exhalation phase can indicate obstructive airways disease. Time-based capnography is more accurate with slower RRs and when there is a minimal leak around the ETT. Volumetric capnography traces the CO2 concentration against the exhaled volume and is appearing as a feature on some ventilators. Free-standing monitors that provide the same measure are also available. Volumetric capnography provides direct information for dead space calculations. Clinically volumetric capnography is helpful in setting the optimal PEEP. In this way, PEEP can be titrated to balance improved oxygenation through alveolar recruitment and decreased dead space by not causing overdistension. Volumetric capnography can also be used to demonstrate a response to bronchodilator therapy. In circumstances such as high frequency ventilation (HFV), the use of transcutaneous CO2monitoring (TCOM) provides a continuous measure of ventilation. The TCOM module heats the skin underneath a small sensor. There is increased diffusion of CO2across the skin as the capillary bed dilates from the heat. The diffused CO2is then measured. When the TCOM is first set up, it should be calibrated against a capillary or arterial blood gas. There can be drift of calibration over time, but newer modules have improved stability. A recent study by Bhalla et al. demonstrated that transcutaneous CO2monitoring provides an acceptable estimate of PaCO2, even with low cardiac output or increased subcutaneous tissue.281 In their study, it did not perform well in patients with cyanotic heart disease. The effort of breathing with or without a ventilator can be obtained by the objective measurement value of the pressure-rate-product (PRP). The pressure measure by a balloon-tipped catheter placed into the distal third of the esophagus can be used as a surrogate for pleural pressure. The PRP is the change in esophageal pressure (Pes) multiplied by the RR. PRP = Pes × RR. The PRP has been used as an objective measure of effort of breathing in studies: before and after extubation,286,287 with PEEP and obstructed airways disease,277 evaluating increasing inspiratory load;278 pressure-rate product and phase angle as measures of acute inspiratory upper airway obstruction in rhesus monkeys,

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79 • Pediatric and Neonatal Critical Care

evaluating effectiveness of high-flow nasal cannula;288,289 and evaluating effectiveness of noninvasive ventilation (NIV) in infants.290 Some ventilators can measure esophageal pressure, or it can be obtained with separate devices. We have found that the accuracy of PRP measurements is sensitive to the volume of air used to fill the esophageal catheter.291 In addition to measuring the PRP, the esophageal pressure is very important in measuring the pressure across the lungs or the transpulmonary pressures. Many adult studies are appearing demonstrating the benefits of titrating ventilator settings to trans-pulmonary pressure for patients with acute respiratory distress syndrome (ARDS).292-294 The transpulmonary pressure may have particular benefit in patients who are obese and requiring mechanical ventilation for respiratory failure,295-298 where the decreased compliance of the chest wall may cause practitioners to limit ventilator pressures. For adult medicine, the field of esophageal pressure monitoring and the titration of mechanical ventilation to transpulmonary pressure has recently grown significantly. The need for and goals of this type of monitoring can be best summarized in a few review articles,299,300 including one from the PleUral pressure working Group (PLUG-Acute Respiratory Failure section of the European Society of Intensive Care Medicine).301 The phase of breathing or the synchrony between movement of the abdomen and the chest wall can be measured with respiratory inductance plethysmography (RIP).302 This noninvasive measure uses elastic bands placed around the abdomen and chest. Movement of the abdomen and chest changes the inductance of a small wire in the bands. Movement of the abdomen relative to the chest can be presented graphically or measured as the phase angle. When there is obstruction to breathing, such as with upper airway obstruction, there is a lag in the movement of the abdomen and chest wall, which is identified as an increasing phase angle. The phase angle obtained by RIP is an objective measure of the degree of upper airway obstruction278,302,303 and can be used to evaluate the effectiveness of therapy.304-306 This is a valuable tool for research in the area of causes and treatment of upper airway obstruction, as there is great interobserver variability in the clinician’s assessment of this process.307 RIP can easily be measured with free-standing devices and may have an increased role in future pediatric studies. A great deal of information on the respiratory effort of patients receiving mechanical ventilation can be obtained from respiratory spirometry. Spirometry can display flowvolume loops, pressure-volume loops, in addition to graphs of flow-time, pressure-time, and volume-time. The characteristic shape of some respiratory flow-volume loops can help with the diagnosis of various respiratory diseases. There is a classic scooped out appearance to the exhalation portion of a flow-volume curve with obstructive lung disease. The pressure-volume loops obtained on the ventilator can be used to increase PEEP to keep lung tissue recruited above an area of potential atelectasis. This can be seen graphically as a lower inflection point on the inspiratory curve. This is where the curve moves from a flat area to an area of maximal compliance where there is the greatest change in volume for a given change in pressure. There is also an upper inflection point on pressure volume loops where overdistension of the lungs can be identified if the inspiratory pressure or volume is too great. The pressure-volume curve with

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over-distension looks like a bird’s beak and ventilator settings should be reduced. There are multiple noninvasive techniques that can provide additional information on the patient’s respiratory status. Radiologic evaluation of the nasopharynx, neck, and thorax can provide meaningful information regarding the cause and severity of the respiratory dysfunction. Fluoroscopy can be used to evaluate the airways and movement of the diaphragm in an uncooperative child. Electrical impedance tomography (EIT) is a noninvasive technique that does not use ionizing radiation that can provide information on regional lung ventilation. The technique uses electrodes placed on the chest wall to measure the electrical conductivity and impedance of the lung to form a tomographic image. The images are used to determine which areas of the lungs have atelectasis, normal ventilation, or overdistension. At the moment, there is much more adult data showing uses of and management strategies with EIT,308-311 as compared with pediatrics.312-314 However, as more companies produce the machines and more adult manuscripts are published, we expect there will be an increased use of EIT in pediatric mechanical ventilation monitoring. Finally, there is a rapid growth of point of care ultrasound use in pediatrics. This has multiple benefits for the patient, as it can be provided at the bedside and does not use ionizing radiation. Lung ultrasound offers the ability to identify pneumothorax, alveolar consolidation, pneumonia, atelectasis, pulmonary edema, pleural effusions, and diaphragm movements and thickness. There are an increasing number of pediatric manuscripts identifying the benefits of lung ultrasound.315-318 In the near future, ultrasound diaphragm thickness and how it changes over time may be used to guide mechanical ventilation strategies and help predict extubation success.319-322 

RESPIRATORY FAILURE The cause of respiratory failure depends to some degree on the age of the patient. Newborn respiratory failure is often the result of congenital anomalies and immaturity of the lungs and their blood vessels. Congenital anomalies can include airway malformations, dysgenesis or malfunction of the lung or nonpulmonary organs, and abnormalities of the pulmonary vessels. Lesions of immaturity include apnea of prematurity, hyaline membrane disease, and abnormalities of surfactant production and secretion. During the perinatal period, neonates are subject to infections and stress. Persistent pulmonary hypertension can complicate neonatal pulmonary and nonpulmonary problems. These and other important causes of respiratory failure in the newborn are listed in Table 79.6. A wide variety of disorders cause respiratory failure in older children (Box 79.3). Regardless of the specific cause, respiratory failure can be categorized as hypoventilation syndromes in patients with normal lungs, intrinsic alveolar and interstitial disease, and obstructive airway disease.

HYPOVENTILATION SYNDROMES IN CHILDREN WITH NORMAL LUNGS Causes of hypoventilation include neuromuscular disease, central hypoventilation, and structural/anatomic impairment of lung expansion (i.e., upper airway obstruction,

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TABLE 79.6  Causes of Neonatal Respiratory Distress Location

Congenital Abnormalities

Developmental Immaturity

Specific Neonatal Stress

Impaired control of ventilation

Central nervous system dysgenesis Ondine’s curse

Apnea of prematurity Intracranial hemorrhage

Drug intoxication (note maternal drugs) Sepsis Central nervous system infection Seizures

Neuromuscular disorders

Congenital myopathies

High cervical cord injuries

Structural impairment

Thoracic deformities Lung hypoplasia Diaphragmatic hernia Potter syndrome Abdominal malfunction Gastroschisis Omphalocele

Severe abdominal distention Pneumothorax or other leak

Airway obstruction

Choanal atresia

Massive meconium aspiration

Upper airway

Pierre Robin syndrome Laryngeal web/cleft Congenital tracheal/laryngeal stenosis Recurrent laryngeal palsy Hemangioma Lymphangioma

Vocal cord paralysis is secondary to myelodysplasia

Lower airway

Tracheoesophageal fistula Lobar emphysema

Meconium/blood aspiration

Alveolar disorders

Respiratory distress syndrome

massive abdominal distention). These clinical conditions are characterized by inadequate lung expansion, secondary atelectasis, intrapulmonary right-to-left shunting, and systemic hypoxia. Atelectasis and the secondary reduction in FRC increase the work of breathing. The child’s response to the increased work of breathing and lower lung volumes is to breathe faster with a smaller tidal volume. This pattern of breathing eventually increases the amount of atelectasis and shunting. As a result, children with intrinsically normal lungs and hypoventilation syndromes exhibit tachypnea, small tidal volumes, increased work of breathing, and cyanosis. Chest radiographs reveal small lung volumes and miliary or lobar atelectasis. Positive-pressure ventilation and PEEP quickly reverse the pathologic processes.

Primary Pulmonary Alveolar or Interstitial Disorders Intrinsic lung disease involving the alveoli or pulmonary interstitium decreases lung compliance and increases airway closure, both of which cause atelectasis and increase the work of breathing. Edema or inflammation of the alveoli or fibrosis of the interstitium decreases lung compliance. The stiffer lung requires a greater negative intrapleural pressure for air movement, thereby increasing the work of breathing and the risk for pneumothorax.  Obstructive Airway Disease Airway obstruction can be extrinsic or intrinsic. Intrinsic small airway obstruction commonly occurs with bronchiolitis, bronchopneumonia, asthma, and bronchopulmonary dysplasia (BPD). Airway obstruction decreases conductance and increases airway resistance and the work of breathing. Partial obstruction impedes expiration more than inspiration and causes gas trapping or regional emphysema. Complete airway obstruction results in atelectasis and

Bronchopulmonary dysplasia

right-to-left shunting of blood within the lung. Patients with disease of the small airways usually have a mixture of total and partial airway obstruction and inhomogeneous collapse and overdistention of the lung. The areas of collapse cause intrapulmonary right-to-left shunting of blood, and the overdistended areas increase the amount of dead space. If the entire lung is overdistended, compliance is decreased and the work of breathing is increased. The clinical and radiographic picture varies with the different degrees of collapse and overdistention of the lung. In summary, all causes of respiratory failure share similar pathophysiology: atelectasis and decreased FRC with intrapulmonary right-to-left shunting of blood or alveolar overdistention with increased dead space and decreased CO2 elimination, or both. The increased work of breathing associated with all forms of respiratory dysfunction can cause fatigue and a breathing pattern that further complicates the initial process. It may also lead to apnea, hypoxia, and cardiac arrest in young children if the increased work of breathing is not quickly detected and treated. 

RESPIRATORY CARE A patient’s FiO2 can be increased by a number of means including nasal cannula or mask. The FiO2 can be increased up to approximately 40% with nasal cannula oxygen at 5 L flow/min. However, this high rate of flow can become uncomfortable. As room air is entrained around the cannula during inspiration the FiO2 cannot be increased further with nasal cannula. It should be noted that the size of the patient correlates with the inspiratory volume with each breath. The larger the patient, the greater inspiratory volume is relative to flow from the cannula and the greater volume of room air that is entrained. In turn, the smaller a patient the less room air is entrained and there may be a greater impact on FiO2.

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BOX 79.3  Causes of Respiratory Failure in Children 1. Impaired control of ventilation □ Head trauma □ Intracranial hemorrhage □ Increase intracranial pressure secondary to tumor, edema, hydrocephalus, Reye syndrome □ Central nervous system infections □ Drug intoxication □ Status epilepticus 2. Neuromuscular disorders □ High cervical cord injury □ Poliomyelitis □ Guillain-Barré syndrome □ Neurodegenerative disease (e.g., Werdnig-Hoffman syndrome) □ Muscular dystrophies and myopathies □ Myasthenia gravis □ Botulism □ Tetanus □ Phrenic nerve injury 3. Structural impairment □ Severe kyphoscoliosis □ Flail chest □ Large intrathoracic tumor □ Pneumothorax or pneumomediastinum □ Large pleural effusion, hemothorax, empyema □ Severe abdominal distention □ Severe obesity (pickwickian syndrome)

The FiO2 can be increased further with a properly fitted face mask. The open holes of a venture or simple face mask allow for greater entrainment of room air as compared with a nonrebreather face mask that has no holes. A FiO2 approaching 1.0 can be obtained with a non-rebreather face mask with an oxygen reservoir and one-way valve. Patients with respiratory distress while on the pediatric ward may temporarily require a non-rebreather mask at high flows. If there is no significant improvement to immediate interventions, arrangements should be made to transfer the patient to the PICU. Non-rebreathing mask systems can be humidified for comfort, but they don’t provide any positive pressure to the airways. High flow humidified nasal cannula (HFHNC) oxygen can provide a higher FiO2 and is more easily tolerated as compared with standard nasal cannula. The gas in HFHNC is heated to body temperature and near completely humidified with water vapor. HFHNC can be delivered with flow rates in pediatrics up to 2 L/kg/min. HFHNC has been shown in a number of studies to decrease the effort of breathing in critically ill children.323-325 HFHNC has been used frequently to support patients with bronchiolitis.324-328 Weiler et al. demonstrated that the lowest effort of breathing for toddlers with bronchiolitis was at greater than 1.5 L/kg/min of flow.324 It is unclear whether the significant benefits of HFHNC come from washing out carbon dioxide from the airways,329,330 from the generation of positive pressure,331 or from increases in end expiratory lung volumes.332 The potential for complications exists with higher gas flow rates. Air leak syndrome was reported in three patients by Hegde et al.333 As the use of HFHNC increases, other problems may be identified. Given that the amount of FiO2 delivered approaches 1.0, HFHNC outside of an ED or ICU setting should be used with caution. The high degree of respiratory support provided can mask a significant degree of respiratory distress.

4. Airway obstruction □ Upper airway □ Congenital anomalies □ Tumor, intrinsic or extrinsic □ Epiglottitis □ Croup (laryngotracheobronchitis) □ Foreign body □ Postintubation edema, granulation tissue, or scarring □ Vocal cord paralysis □ Burns □ Vascular ring □ Lower airway □ Asthma □ Bronchiolitis □ Foreign body □ Lobar emphysema □ Cystic fibrosis 5. Alveolar disorders, pneumonia □ Infectious: bacteria, virus, fungus, Pneumocystis species □ Chemical: aspiration, hydrocarbon, smoke inhalation □ Pulmonary edema: cardiogenic, near-drowning, capillary leak syndrome 6. Massive atelectasis 7. Oxygen toxicity 8. Pulmonary confusion 9. Pulmonary hemorrhage

However, with appropriate monitoring and protocols, it is possible to provide HFHNC on a general ward to specific populations such as stable patients with bronchiolitis. Franklin et al.326 recently published a study of children younger than 12 months of age with bronchiolitis. The use of HFHNC significantly reduced the risk of escalation of care (12%) as compared with regular nasal cannula (23%). NIV can be supplied with continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP). This is typically delivered with a tight fitting nasal or face mask that allows for the development of positive airway pressure. Most modern ventilators can be set to deliver this therapy, but specific free-standing BiPAP machines are more often used. BiPAP therapy is best for short-term use and in patients who have the ability to cough and protect their airway. It is not an absolute that the patient initiates every breath as a back-up rate can be set. However, if the patient is completely reliant on the rate set on the machine, intubation should be considered. Other indications for conversion from BiPAP to endotracheal intubation include pressure related tissue breakdown on the face from constantly wearing the mask and the need to initiate enteral feedings, as patients are typically NPO on BiPAP, increasing pressure settings on the BiPAP machine. CPAP reduces the patient’s work of breathing by providing airway pressure, reducing atelectasis, decreasing dead space, and improving the balance of ventilation to perfusion. An initial CPAP pressure is typically 4 to 6 mm Hg and is then increased as needed and as the patient tolerates the therapy. Given that the feeling of positive airway pressure is a bit foreign, starting with lower pressures and increasing gives the patient a chance to adapt. We typically start patients on CPAP therapy for several minutes even if they will ultimately receive BiPAP. For BiPAP, the expiratory

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SECTION V  •  Pediatric Anesthesia

pressure is also initially at 4 to 6 mm Hg and the inspiratory pressure is set at 4 to 6 mm Hg above that. The inspiratory and expiratory pressures are adjusted, as well as the rise time to inspiratory flow. All of these changes can help the patients tolerate therapy. Given the tight seal, a FiO2 of 1.0 can be delivered. With use of the full face mask, patients are at risk for aspiration if they vomit. BiPAP therapy is being used in status asthmaticus,334,335 and it may provide a more effective means of delivering aerosolized medication. The use of BiPAP therapy for this indication may increase over time as it is being recommended in current guidelines.336,337 BiPAP can also be used as an ongoing therapy for chronic respiratory failure for such things as central hypoventilation or restrictive lung disease. These patients may be able to receive their therapy at home and are typically followed by the hospital’s pulmonary service. The size of ETT required should be selected carefully. One formula that estimates the appropriately sized tube for children older than 2 years is (age + 16)/4. This formula provides the internal diameter of the appropriately sized ETT. The correct size should have a slight air leak when a positive pressure of 20 to 30 cm H2O is applied. Serious lifelong laryngeal and subglottic damage can result from using inappropriately large ETTs, particularly in children with inflammatory lesions of the upper airway such as laryngotracheobronchitis. Because of the more flexible tracheal cartilage and the relative subglottic narrowing of children, uncuffed ETTs generally provide an adequate seal in those younger than 5 years. However, if the patient has lung disease that requires high ventilation pressure, a cuffed tube is more appropriate. Small cuffed ETTs are frequently used in the ICU in younger patients,338 but care should be taken to ensure that there is a small leak of air at 25 to 30 cm H2O. Cuffed tubes will usually eliminate the air leak around an ETT, but overinflation of the cuff may occlude venous flow and injure the airway. There are presently no data on the long-term safety of using cuffed ETTs in young children. However, there has been work by Khemani et al.339 that showed risk factors associated with the development of postextubation subglottic upper airway obstruction included low cuff leak volume or high preextubation leak pressure. We should take care to make sure that ETT cuffs are appropriately inflated. With endotracheal intubation, it is important to correctly position the ETT. If correctly positioned, chest movements should be symmetric, and breath sounds should be equal when auscultated in the axillae. An electronic or colorimetric CO2detection system helps confirm whether the ETT is in the trachea or the esophagus.340 If the double lines on the ETT are at the level of the vocal cords, the ETT is usually in the correct position. Another way to correctly position the ETT is to advance it into the right mainstem bronchus and listen for breath sounds in the left axilla. Breath sounds will be diminished. Withdraw the ETT slowly. When breath sounds are heard on the left, pull the tube out an additional 1 to 2 cm, depending on the size of the child. If the breath sounds are equal, fix the tube in place. The tip of the ETT should be midway between the vocal cords and the carina on the chest radiograph. In small infants, the distance between the carina and the vocal cords is very short. It is easy to inadvertently place the ETT in the right mainstem bronchus in small infants because of this short distance. Flexion

of the head moves the ETT into the airway. Extension moves it toward the vocal cords. Turning the head to the side may obstruct the tip of the ETT if it comes in contact with the tracheal wall, which may cause CO2retention or hypoxemia, or both (unpublished data). It is common to leave a child’s trachea intubated for 2 weeks or longer before performing a tracheostomy. This is possible with proper humidification of the inspired gases, improved endotracheal suctioning and monitoring (SaO2), and excellent nursing care. Everyone caring for the child must be constantly alert to the possibility that the ETT will become obstructed by secretions or that accidental extubation or mainstem bronchus intubation will occur. Tracheostomy is indicated when children require a long-term artificial airway for mechanical ventilation, for endotracheal suctioning, or to bypass an upper airway obstruction. Accidental dislodgement of the tracheostomy tube before the tract is well healed can be life threatening. Reinsertion of a tracheostomy tube during the first 72 hours after insertion can be very difficult and can create false passages that can make it impossible to ventilate the lungs or can cause pneumothorax. Intubation and mechanical ventilation can provide significant elevations in airway pressure as compared with NIV and a FiO2 of 1.0. There can be regional variation to the mode of mechanical ventilation chosen, but there is likely a greater use of pressure controlled ventilation rather than volume controlled ventilation in pediatric ICUs. However, as there are no studies looking at outcomes with mode of ventilation, we cannot recommend one mode over another. With pressure-controlled ventilation, pressure is set and the tidal volume may change as the pulmonary compliance changes. With volume-controlled ventilation, tidal volume is set, and the pressure needed to deliver that may change as the pulmonary compliance changes. These are likely the two main modes of mechanical ventilation in pediatric ICUs. For the majority of intubated children who have reasonable pulmonary compliance, there are little differences between the two modes. One potential advantage of pressure-controlled ventilation for patients who are sicker with poorer pulmonary compliance is that most ventilators in this mode use a decelerating inspiratory flow pattern. This means that the flow of gas is greatest early in inspiration and then decelerates to zero flow when the peak pressure is achieved. This can result in the delivery of a larger tidal volume for a lower peak pressure as compared with the same pressure that might be required in a tidal volume mode. There are additional modes available on modern ventilators that may have benefit for patients with lung injury. The names of the modes will differ between the ventilator manufacturers. Many will have a mode where a desired tidal volume is guaranteed and the lowest pressure necessary to achieve that is used. Terms usually given to define this mode are pressure-regulated volume control and volume guarantee. These modes may reduce the pressure used, but they work best when the patient is well sedated and not competing with the ventilator. Neurally adjusted ventilatory assist is a newer method of triggering ventilator synchrony available on the Servo-i ventilators by Maquet. This uses a small esophageal probe that can sense the electrical activity of the diaphragm and use that activity to synchronize the ventilator. The potential benefits of improved triggering such as improved

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79 • Pediatric and Neonatal Critical Care

comfort, lower ventilator settings, and increased minute ventilation have been shown in some studies.341,342 Some degree of expertise is necessary with the mode, as the electrical activity of the heart can also cause auto-triggering of the ventilator.343 Airway pressure release ventilation (APRV) is a mode of mechanical ventilation that is less common than pressure control or volume control. There is adult data that was recently published by Zhou et  al.344 that early use of APRV can reduce length of mechanical ventilation. As we do know, however, children are just little adults. Lalgudi et  al.345 recently published the results of a randomized controlled trial of APRV in children with ARDS. The trial was stopped early for increased mortality in the APRV arm. There are few published pediatric studies using this mode,346-349 and its benefits and limitations continue to be explored. Like other modes of ventilation, its use appears to be regional, and some will only consider this as rescue therapy when patients fail conventional ventilation. To describe its use, APRV is essentially CPAP with brief, intermittent release coupled with spontaneous ventilation. The high CPAP level (Phigh) maintains alveolar recruitment and aids in oxygenation over a period of time (Thigh), and the timed release to a low pressure (Plow) minimizes resistance to expiratory flow and carbon dioxide removal. In addition, the patient is able to spontaneous breath during all phases, Phigh and Plow, potentially allowing for improved pulmonary mechanics and gas exchange. APRV differs from other modes of ventilation because it relies on an intermittent decrease in airway pressure, instead of an increase in airway pressure to maintain an open lung strategy for ventilation. Therefore, the release time (Tlow) should be set long enough to allow for an adequate tidal volume (6-8 mL/kg), but short enough to avoid alveolar collapse and atelectrauma. In summary, the operatorcontrolled parameters in APRV are: Phigh, Thigh, Plow, Tlow, and FiO2. Recommendations for implementing APRV are limited in pediatrics, and thus extrapolated from adult recommendations.350 Plow is initially set a zero. Phigh can be set by several methods such plateau pressures or 75% of peak inspiratory pressure; however, when transitioning from conventional modes of ventilation, Phigh is often determined by mPAW pressure formula where the mPAW is set 2 to 3 cm H2O above conventional mPAW: (Phigh × Thigh) + (Plow × Tlow) / (Thigh + Tlow). To determine Thigh and Tlow, first determine the total cycle time according to a normal RR range for the patient’s age (i.e., a RR of 20 yields a total cycle time of 3 seconds). Thigh will be the total cycle time minus a Tlow of 0.2 to 0.6 seconds, initially starting at 0.4 seconds (i.e., total cycle time of 3 seconds yields a Thigh of 2.6 seconds and Tlow of 0.4 seconds), or Number of cycles (RR) = 60 seconds/(Thigh + Tlow). Transitioning to APRV, like transitioning to HFOV, will take time for optimal lung recruitment. After several hours, if the patient continues to have severe hypoxemia, Thigh can be increased to aid in oxygenation. Once established Plow and Tlow usually do not require further changes; however, as lung compliance improves, Phigh and Thigh can be decreased and increased, respectively, to wean a patient toward a target of a continual CPAP of 5 to 6 cm H2O in preparation for extubation. APRV may be advantageous to other modes of advanced mechanical ventilation because of

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the patient’s ability to breathe spontaneously throughout the entire ventilatory cycle improving respiratory mechanics and reducing the need for sedation and neuromuscular blockade. However, some authors are concerned that there may be a higher incidence of cyclic alveolar collapse during airway release leading to a greater degree of atelectrauma, as compared with HFOV.346,347 High frequency oscillatory ventilation (HFOV) is being used in pediatrics as a rescue therapy for acute lung injury (ALI) or ARDS. HFOV is a subset of HFV. Use of HFOV was first described by Lunkenheimer in 1972.351 A 1994 publication by Arnold et al.352 is the only multicenter randomized trial of HFOV. This study showed lower use of oxygen supplementation in the HFOV group at 30 days. There have been other pediatric studies showing positive benefit of HFOV such as a single center prospective study by Samransamruajkit et  al.353 and a single center retrospective study by Babbitt et al.354 The conclusion that could be drawn by many studies with HFOV in pediatrics is that for disease processes with significant mortality, rescue therapy with HFOV may be appropriate and may show improved outcomes. In some of the most critically ill patients with a very high mortality such as immune compromised children with ARDS, the response to HFOV has been used as diagnostic criteria to identify survivors from nonsurvivors.347,355 Early use of HFOV has been shown to decrease mortality in patients who have undergone hematopoietic cell transplant who have developed severe pediatric ARDS.356 There is some adult data using HFOV from large randomized trials. The OSCAR trial357 was a negative study and the OSCILLATE Trial357 was stopped early for a potential increase mortality in the HFOV group. It is unclear whether these findings can be translated to pediatric patients. The disease processes and the condition of our patients can be very different as compared with adults. Bateman et al.358 used a propensity score model to reanalyze results from the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) Study.359 Using their adjusted models, they found that early use of HFOV was associated with longer mechanical ventilation. There also was no mortality benefit to the use of HFOV. Given the results of the adult studies as well as those from Bateman et al.,358 it is unclear if the motivation would be present to perform a multicenter HFOV trial in pediatrics. There may continue to be other indications for HFOV in pediatrics, such as air leak syndrome or congenital diaphragmatic hernia. To describe its use, HFV is a type of mechanical ventilation where the RR of the ventilator is much greater than a normal physiologic rate. Maintaining the same minute ventilation these ventilation modes produce tidal volumes that are very small. There are several different methods, but most commonly used in pediatrics is the HFOV. This type of ventilator houses a piston that is attached to semi-rigid connecting tubing which attaches to the ETT. This circuit can be pressurized to a set mean airway pressure (MAP). The piston then oscillates up to 840 times a minute, creating small positive and negative respiratory cycles. The MAP is higher as compared with conventional ventilation, and this prevents atelectasis as well as shear forces from opening and closing alveoli with each respiratory cycle. The FiO2 is set as in a conventional ventilator. The frequency of oscillation of the piston is adjusted to remove carbon dioxide

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SECTION V  •  Pediatric Anesthesia

and can vary between 6 and 14 Hz (Hz = 60 cycles/s). The amplitude of the ventilator is the distance the piston moves with each excursion, and by these excursions small breaths are propelled down the tubing. Several proposed mechanisms for the method of gas transport during HFOV have been proposed but none have been proven. Tidal volumes are dependent on the patient’s compliance, ETT size, device frequency, and device amplitude. Tidal volume is inversely related to cyclic frequency: VCO2 = frequency × VT2. Transitioning from conventional modes of ventilation to HFOV, the initial power setting (ΔP/amplitude) is adjusted to visible chest “wiggle” from the clavicles to the abdomen or pelvis. MAP (mPAW) is initially set approximately 5 cm H2O greater than the last mPAW on conventional ventilation, just prior to the initiation of HFOV. Traditionally, tidal volumes in HFOV are considered to be just above FRC; however, it is difficult to measure actual tidal volumes and provide precise “optimal” lung volumes strategy. Clinically, MAP mPAW is titrated by upward by 1 to 2 cm H2O till oxygenation improves, and inspired oxygen concentrations can be weaned to less toxic levels, below 0.60. While titrating mPAW, it is important to assess for overdistention by following chest radiographs (CXR): overdistention/hyperinflation is determined by greater than nine posterior ribs or flattened hemi-diaphragms on CXR. Initial frequency settings, measured in Hz, can be found in Table 79.7. HFOV is the only mode of ventilation with active expiration. If hypercarbia, despite allowances for permissible hypercapnia, leads to profound respiratory acidosis and patient instability, minute ventilation can be improved by several means during HFOV. First, one of the drawbacks of HFOV is the lack of spontaneous ventilation and adequate airway clearance; therefore, inline suction (without breaking into the circuit causing derecruitment) should be used to ensure adequate airway, ETT patency, and lung recruitment. Second, ΔP should be increased to maximize lung recruitment and increase minute ventilation. Third, frequency (Hz) can be slowly decreased to enhance lung recruitment and increase minute ventilation. Finally, the ETT cuff should be deflated to allow additional escape of CO2around the ETT. Disadvantages of HFOV include no partial ventilatory support leading to increased requirements for sedation and paralysis, cardiopulmonary interactions due higher mPAW and decreased venous return, and loss of alveolar recruitment if circuit detached for suctioning of manual ventilation. High frequency percussive ventilation (HFPV) pneumatically stacks subtidal volume breaths at a set rapid rate superimposed upon conventional cyclic rates. This allows TABLE 79.7  Initial Frequency Settings in High-Frequency Oscillatory Ventilation Patient Weight (kg)

Initial Frequency Setting (Hz)

50

5

for a progressive stepwise inflation of the lung to a set peak pressure while allowing for passive exhalation to a preset lower pressure. HFPV has been well-described in the inhalational injury population for its ability to safely oxygenate and ventilate with continuous pneumatically-powered high frequency percussions to facilitate clearance of airway debris.360-362 These properties may be particularly useful in pediatric patients with acute respiratory failure, by improving oxygenation and ventilation while maintaining lung protective strategies.363 

PEDIATRIC ACUTE RESPIRATORY DISTRESS SYNDROME ARDS is a severe form of ALI that can result from a number of triggers that directly or indirectly injure the lung. The disease results in inflammation of the lungs, edema of the alveoli, and hypoxemic respiratory failure. Prior definitions of pediatric ARDS (PARDS) often were adapted from studies on adult patients and adult consensus conferences. Although PARDS represents a small portion of PICU admissions, it is very clinically important as it carries a very high mortality rate. In turn, PARDS garners a significant amount of attention from PICU researchers and clinicians. Since 2012, PICU intensivists had been using the Berlin definition of ARDS364,365 for management and study enrollment. Finally, in 2015 pediatrics had its own unique definition of ARDS. In 2015 the Pediatric Acute Lung Injury Consensus Conference (PALICC) completed their 2-year process of consensus meetings to provide a new definition of PARDS and guidelines for management.366 The PALICC group included 27 experts from 8 countries. They used peer reviewed data that was specific to pediatrics to form new guidelines. Where data were unavailable specifically for pediatrics, recommendations were adapted from adult or neonatal data as appropriate. In areas where there was no available data, expert opinion formed the basis of their recommendations. Multiple follow-up publications have provided important information in PARDS, including methodology of the group,367 the incidence and epidemiology,368 comorbidities,369 means of ventilator support,370 noninvasive support,371 monitoring,372 use of ECMO,373 and outcomes.374 The group identifies the need for future randomized control trials in PARDS. There are several key aspects to defining PARDS.375 The PALICC definition of PARDS excludes neonates with perinatal-related lung disease, as it is likely a different entity. The lung injury should occur within 7 days of a known clinical insult. The hypoxemic respiratory failure should not be able to be explained by cardiac failure or fluid overload. Chest radiographs typically have new infiltrates consistent with parenchymal lung disease. There are now separate sections for the use of noninvasive and invasive mechanical ventilation. One significant difference in comparison to adult ARDS definitions is that the definition of PARDS for mechanically ventilated patients includes stratification by oxygenation index or oxygen saturation index. Oxygenation index (OI) = [FiO2 × MAP × 100]/PaO2. The oxygen saturation index (OSI) = [FiO2 × MAP × 100]/SpO2. Mild PARDS is 4 ≤ I < 8, as well as 5 ≤ OSI < 7.5. Moderate PARDS is 8 ≤ OI < 16, as well as 7.5 ≤ OSI < 12.3. Severe PARDS is OI ≥ 16, as well as OSI ≥ 12.3. There is additional information for patients

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79 • Pediatric and Neonatal Critical Care

with cyanotic heart disease, chronic lung disease, and left ventricular dysfunction. Future studies will need to address these more difficult aspects of defining PARDS. The management of mechanical ventilation in PARDS currently can be summarized as the use of restrictive tidal volumes, increased use of PEEP, an ongoing relative tolerance of hypoxemia as long as it does not alter systemic oxygen delivery, and a tolerance of relative hypercarbia to reduce trauma from elevated mechanic ventilator pressures. The PALICC group among many others recognizes that there has never been a randomized control trial of tidal volume restriction in PARDS. There are also prior studies that have demonstrated a lower mortality with larger tidal volumes in pediatric patients.376,377 This seems to be a result of the increased use of pressure control ventilation in pediatric patients. An individual patient might be sick enough to be classified as having ARDS, but those with a milder form of the disease have better pulmonary compliance. As pressure is set on the ventilator, larger tidal volumes occur with better compliance. The PALICC guidelines do not make a recommendation as the mode of ventilation. However, the guidelines do recommend targeting the delivered tidal volume to be “in or below the range of physiologic tidal volumes for age/body weight (i.e., 5-8 mL/kg predicted body weight) according to lung pathology and respiratory system compliance.”366 It should be noted that PALICC guidelines do recommend adjusting the tidal volumes to the degree of disease severity. They recommend tidal volumes of 3 to 6 mL/kg predicted body weight for those patients with poor respiratory system compliance. They do believe the larger tidal volumes could be appropriate for patients with better pulmonary compliance. Potentially, one of the more important recommendations from the PALICC group has been the increased application of PEEP. They recommended levels of PEEP of 10 to 15 cm H2O for patients with severe PARDS and identify that levels higher than 15 cmH2O may be needed for some patients. Given concerns for the potential cardiopulmonary interactions, they do recommend following hemodynamics closely. The application of increased PEEP may have significant importance in future PARDS studies. It has recently been shown by Khemani et  al.377 that the use of PEEP settings lower than those recommended by the ARDS Network Protocol is associated with increased mortality in PARDS. Some by extrapolation would consider the use of HFOV the most extreme form of tidal volume restriction. HFOV is able to prevent atelectasis by maintaining a constant airway pressure. Trauma from lung stretch is avoided by delivering tidal volumes that are less than anatomic dead space.378 Unfortunately, there is very little information in pediatric mechanical ventilation with no recent randomized control trials. There have been two recent adult studies, but they did not yield results supportive of HFOV. OSCAR357 was a negative study, and OSCILLATE379 was stopped early for a potential increase in mortality in the HFOV group. Adult practitioners are likely moving away from HFOV and use in pediatrics remains regionalized to a few centers that continue its use. The PALICC guidelines leave HFOV as a potential rescue therapy. There are further adjunctive therapies for PARDS that will require future studies to confirm their potential benefit. This list would include the use of corticosteroids, inhaled

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nitric oxide, ECMO, prone positioning, use of neuromuscular blockade, and the use of exogenous surfactant. There is insufficient data at this time to state these therapies should be routinely used for PARDS. Inhaled NO should be used for patients who have documented pulmonary hypertension or right heart dysfunction. The most recent published pediatric study of inhaled NO shows the possibility for harm.380 The use of extracorporeal life support for PARDS has not been sufficiently studied to indicate it is beneficial. Further, given the complexity of the therapy, future trials may be very difficult, and to what extent ECMO is used for PARDS will vary based upon the individual institution. As patients progress through their disease course and care is no longer increasing, the issue of weaning from mechanical ventilation and timing of extubation must be addressed. Various different strategies have been used to wean off of the ventilator to varying degrees of success. Likely one of the most effective strategies is the daily scheduled use of  spontaneous breathing trials (SBTs) to assess whether a patient is ready for extubation.381,382 Faustino et  al. in 2018 published a secondary analysis of the RESTORE clinical trial.383 Of patients requiring mechanical ventilation for lower respiratory tract disease, they found 43% passed their first extubation readiness. Of the group that passed an extubation readiness test, 66% were extubated within 10 hours. Many PICUs are using protocols to provide daily SBTs. In the right setting, the breathing trial can be performed safely by the respiratory therapy staff without physician input. In the near future, we will see an increase in computerized ventilation protocols driving care in the PICU. Without protocols, there is significant variability in usual care mechanical ventilation strategies,384 and even with protocols, there can be poor adherence to protocols.385 As a group, PICU intensivists would benefit from computer decision support and likely would accept some version of this.386,387 Future studies will be needed to determine if we can find the Goldilocks version of ventilation protocols. We need to provide not so little mechanical ventilation that the patient is struggling to breathe. Yet, we must provide not so much that there is atrophy of the diaphragm.388,389 

PRINCIPLES OF LUNG PROTECTIVE STRATEGIES: LIMITING VENTILATOR ASSOCIATED LUNG INJURY As lung injury progresses, in response to pulmonary or extrapulmonary injury, the lungs can be divided into three hypothetical regions: (1) areas with severe collapse and alveolar flooding “dependent areas”; (2) recruitable areas with alveolar atelectasis “intermediate areas”; and (3) normal lung “nondependent areas” (Fig. 79.4). The goal of mechanical ventilation is to recruit intermediate areas, allowing improved gas exchange, spare normal areas of lung from ventilator associated lung injury (VALI), while giving dependent collapsed regions of lung with alveolar flooding time to recover from the primary process resolves (i.e., pneumonia, sepsis, etc.). Lung recruitment of intermediate areas and prevention of VALI is accomplished by using PEEP and limiting tidal volume and plateau pressures. This can be a complicated task, so let us first look at Fig. 79.5, and try to conceptualize a theoretical pressure-volume curve of the lung. As alveolar airway pressure increases, there is

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SECTION V  •  Pediatric Anesthesia

Lung protective ventilation

“Normal” lung • Nondependent areas

Volume (mL)

Alveoli capable of recruitment • Intermediate areas

Atelectotrauma Optimal Volutrauma

Severe collapse and alveolar flooding • Dependant areas

Fig. 79.4  For the purposes of lung protective ventilator strategies, the lung can be divided into three hypothetical areas.

PEEP Pressure (cmH2O)

Tidal volume

Fig. 79.6  Lung protective ventilation strategy.  PEEP, Positive endexpiratory pressure. ∆V

Alveoli

Volume (mL)

Volume pressure curve

Lung protective ventilation Atelectotrauma Volutrauma

Pressure (cmH2O) Fig. 79.5  Volume pressure curve.

an opening pressure (Pflex) required to overcome airway resistance and alveolar compliance (Compliance = ΔV/ΔP). Pressures below Pflex will lead to alveolar collapse, termed atelectasis. If airway pressure cycles above and below Pflex, alveoli will continually open and collapse, leading to wall shear stress and eventual damage: atelectrauma. Following the hysteresis curve to the upper extent of the inspiratory limb, as pressure increases, there comes a point termed, Pmax, whereby the alveoli start to become overdistended. Above Pmax, shear stress again leads to alveolar damage, this time termed volutrauma. Therefore, in theory, we attempt to keep tidal volumes on the most compliant part of the volume-pressure curve, above Pflex and below Pmax, leading to the idea called “open lung ventilation.” Triggered by the ARDSnet’s initial study, the use of low tidal volumes (6-8 mL/kg) with the addition of PEEP (open lung strategy) may reduce morbidity and mortality in patients with ARDS (Fig. 79.6).390 However, as lung injury to the normal and intermediate areas of the lungs progresses, the volumepressure curve moves to the right as the compliance of the lungs decreases, leaving a smaller therapeutic window requiring an increase in PEEP, resulting in higher MAP to maintain recruitment of areas of normal and recruitable lung (Fig. 79.7). Lung protective strategy attempts to decrease VALI by inhibiting volutrauma, barotrauma, atelectrauma, oxygen toxicity, and biotrauma (Fig. 79.8).      

Low Tidal Volume: Despite using usual control groups in the ARDSnet original study, employing a low tidal volume approach of 6 to 8 mL/kg has become a standard of care. PEEP: The advantages of PEEP as a distending pressure include: increase in FRC, improvement of respiratory

Volume (mL)

∆P

PEEP Pressure (cmH2O) Fig. 79.7  Lung protective ventilation with worsening lung compliance.  PEEP, Positive end-expiratory pressure.

Ventilator Associated Lung Injury (VALI) lung protective ventilation strategy Atelectotrauma Volutrauma

Barotrauma

Oxygen toxicity

VALI

Biotrauma

Fig. 79.8  Tenets of ventilator-associated lung injury.  VALI, Ventilator associated lung injury.

compliance, improvement of ventilation/perfusion mismatch, redistribution of lung water/edema. PEEP ultimately improves arterial oxygenation. The use of low tidal volumes has been consistent across multiple recent trials, but the selection of PEEP in these trials has been highly variable. Recent pediatric studies have shown that setting PEEP lower than the ARDSnet guidelines can result in increased mortality.391 Further, guidelines from

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79 • Pediatric and Neonatal Critical Care

the PALICC recommends increased levels of PEEP.366 It can be difficult to determine the critical opening pressure of alveoli clinically. Therefore, most clinicians initially use a minimal distension strategy by setting PEEP between 5 and 9 cm H2O, as lung injury progresses and hypoxemia worsens, PEEP may be increased to increase mean plateau pressures (keep bacterial), changes in the weather, and strong emotions. Inflammation increases irritability of the airway as well as airway hyper responsiveness. The airway lumen is decreased by spasm of the bronchial muscles, edema, and mucus. Decreases in the airway lumen significantly increase airway resistance. For laminar airflow, airway resistance is related to the third power of the radius, but with turbulent airflow it is related to the fourth power. Due to the smaller lumen of their airways, children experience much greater changes in airway resistance during asthma attacks than adults. Due to resistance in exhalation, an expiratory wheeze is typically noted. Bronchospasm, edema, or mucus plugging

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can lead to complete obstruction of small airways. Hypoxemia occurs as a result of a mismatch in ventilation and perfusion. Airway dead space is increased by obstruction of the airways. To maintain ventilation, the RR is typically increased. In turn, the initial PaCO2 is usually low. Respiratory fatigue or impending failure may be identified by a normal or elevated PaCO2. It should be reinforced early that wheezing is caused more things than just asthma and that asthma can occur without wheezing. Wheezing is the sound that is produced when there is obstruction to airflow. Wheezing can be caused by pneumonia, upper airway obstruction, foreign body aspiration, and CHF. Each would require different therapy. Wheezing in a toddler of a sudden onset should prompt evaluation for foreign body aspiration. The history should be addressed at recent choking or coughing episodes. Even the presence of a history of reactive airways or atopy does not rule out aspiration. A high index of suspicion should be maintained. Intermittently a chest-ray obtained for a child who is wheezing shows cardiomegaly rather than peribronchial cuffing. Asthma is statistically more likely but this can be the presentation of heart failure. In turn, a chest x-ray is warranted for any patient with their first presentation of wheezing patient and certainly for any child who is admitted to the ICU for wheezing. With regard to asthma that occurs without wheezing, the movement of air is required to hear wheezing. It is possible to have such significant airflow restrictions that patients don’t produce audible wheezing. Patients who present with a quiet chest or limited airflow on auscultation require immediate action. Children presenting with an asthma exacerbation may have a few days of URI symptoms followed by increased work of breathing. The patient may have low room air oxygen saturations. The patient’s position of comfort may be sitting up to support their muscles of respiration. Accessory muscle use is noted. There is a prolonged expiratory phase on auscultation. Some children in an effort to increase airway pressure may be breathing out with pursed lips or in smaller children grunting may be noted. The child may not be able to speak in more than one or two word phrases. Therapy should be started immediately first with supplemental oxygen to address hypoxemia. If the child mild respiratory distress, nasal cannula oxygen may be sufficient. If the child has moderate or severe respiratory distress, oxygen should be delivered by either face mask or non-rebreather face mask. Inhaled beta agonists such as albuterol are given to relax bronchial smooth muscles. IV or subcutaneous terbutaline or epinephrine may be required if there is not enough air movement to deliver inhaled medications. Steroids should be given early as the effect will take some time. If there is limited improvement with initial therapy arrangements should be made for ICU admission. Many emergency departments will attempt to obtain arterial blood gases. However, the clinical picture alone may provide enough information to guide therapy.

Asthma Therapy Supplemental Oxygen. Oxygen can be delivered with a standard nasal cannula, but the FiO2 is limited. Standard nasal cannula might provide up to 28% FiO2. Increasing the flow of oxygen with a standard cannula above 4 to 5 LPM

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SECTION V  •  Pediatric Anesthesia

is not usually tolerated. A simple face mask might increase the FiO2 to 50%. A tightly sealed non-rebreather face masks might be able to provide a FiO2 closer to 1. Providing oxygen with a HFHNC may provide nearly complete humidification of the airway gases and the FiO2 also approaches 1. A 2014 study by Rubin et al.440 demonstrated a decrease in effort of breathing in patients receiving HFHNC. The mechanism of its effect is not elucidated. Some clinicians have begun using HFHNC as a mechanism for delivery of beta agonists or other aerosolized medications, but there is not yet data supporting its use.  Inhaled β Agonists. Inhaled β agonists are used to relax bronchial smooth muscles. The most commonly used β agonists is albuterol, which is a racemic mixture of the active R and inactive S enantiomer. Levalbuterol, the active R enantiomer, is available as a separate preparation, but recent studies have not shown it to be more effective441 or have less elevations in HR.442 Albuterol is β2 selective and comes as a metered dose inhaler or solution for nebulization. For initial therapy in the ICU, continuous albuterol is preferred, and the usual dose is 0.15 to 0.5 mg/kg/h or 10 to 20 mg/h. After improvement in air movement with decreased respiratory distress, intermittent doses can be given every 1 to 2 hours. Terbutaline as an inhaled medication is less β2 selective compared with albuterol and therefore is used less commonly. Terbutaline remains as an important IV medication. Tachycardia is commonly associated with albuterol use. At times it is unclear if the elevated HR is related to toxicity of medications or due to ongoing respiratory distress. Arrhythmias may be seen with albuterol use but this is usually just an increased frequency of PVC. Diastolic hypotension is observed with higher doses of albuterol, although this can be related to decreased intravascular volume and increased intrathoracic pressure. Agitation and tremors can be seen with CNS stimulation. Hypokalemia may be noted as the Beta agonists drive potassium into cells. Ipratropium bromide, an inhaled anticholinergic, is sometimes paired with intermittent albuterol doses. Ipratropium bromide has the benefit of promoting bronchodilation without decreasing mucociliary clearance.  Corticosteroids. IV steroids are preferred to oral dosing in the ICU due to the possibility of decreased absorption or delayed onset. Methylprednisolone is used commonly due to its limited mineralocorticoid effects. The initial dose is 2 mg/kg and then 0.5 to 1 mg/kg every 6 hours. There may be regional preference for dexamethasone or hydrocortisone. Steroids are typically given for the duration of the acute asthma phase. If steroids are given for 5 days or less, they are not usually tapered. Systemic steroid use is associated with hyperglycemia, hypertension and occasionally agitation. In the initial ICU care inhaled steroids are of no benefit.  Intravenous Fluids. Children admitted to the ICU with critical asthma will likely be dehydrated from limited oral intake during their illness and increased insensible losses from the higher RR. The patient’s circulating volume should be supported with fluid boluses if needed. However, excessive fluids should be avoided as this could lead to pulmonary edema. Pulmonary edema could worsen both

oxygenation and airway resistance. Fluid boluses may also be needed for children whose respiratory distress progresses require mechanical ventilation. Hypotension often occurs during intubation.  Intravenous and Subcutaneous β Agonists. A significant decrease in air exchange may result in poor delivery of inhaled medications and IV β agonists may be required. Terbutaline is often the first choice of the available beta agonists. Terbutaline is relatively β2 selective as compared with isoproterenol and epinephrine. Terbutaline can be given subcutaneously for children without IV access as a dose of 0.01 mg/kg/dose up to a maximum of 0.3 mg. IV terbutaline is loaded at a dose of 10 μg/kg over 10 to 20 minutes followed by a continuous infusion of terbutaline in a range of 0.1 to 10 μg/kg/min. The infusion can be titrated to effect. Subcutaneous epinephrine may be given for severe asthma exacerbation with limited IV access with a dose of 0.01 mg/ kg of to the 1:1000 solution with a maximum dose of 0.5 mg. Absorption of the drug may be limited by poor perfusion to extremities. IV epinephrine may be an ideal drug for mechanically ventilated patients with hypotension. The use of isoproterenol in critical asthma has decreased over time.  Methylxanthines. There is regional variation in the use of the methylxanthine aminophylline in place of IV terbutaline as a second line drug for critical asthma. Fewer children with asthma are admitted to the ICU with a methylxanthine as a chronic medication. There are improved controller medications including the leukotriene inhibitors so fewer children are receiving oral theophylline. The methylxanthines promote bronchial smooth muscle relaxation, but the exact mechanism of action is not known. IV aminophylline is loaded at a dose of 5 to 7 mg/kg over 30 minutes, followed by a continuous infusion in the range of 0.5 to 0.9 mg/kg/h. If the patient has taken oral theophylline in the past 24 hours, the loading dose is reduced by 50% or the aminophylline dosing is adjusted based on a serum theophylline level. In general, an aminophylline loading dose of 1 mg/kg will raise the serum theophylline level by 2 μg/mL. The target range for serum theophylline in acute asthma is 10 to 20 μg/mL. Theophylline has a very narrow therapeutic window. Theophylline levels above 20 μg/mL are associated with nausea, tachycardia, restlessness, or irritability. Higher theophylline levels have been associated with seizure activity.  Magnesium. Magnesium can be given as an inhaled or IV medication to relax bronchial muscles. Smooth muscle relaxation occurs due to magnesium’s effect as a calcium channel blocker. Results from the 2013 MAGNEsium Trial in Children (MAGNETIC)443 indicate nebulized magnesium may be beneficial in an acute severe asthma exacerbation. There is some evidence that IV magnesium may also be beneficial in severe asthma.444,445 As there is still regional variation to magnesium, at the least a magnesium level should be checked with the initial set of electrolytes and hypomagnesium should be treated. The dose for critical asthma and hypomagnesium can be the same 25 to 45 mg/ kg given over 30 minutes. Magnesium toxicity can include muscle weakness, cardiac arrhythmias, decreased reflexes, and respiratory depression. 

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79 • Pediatric and Neonatal Critical Care

Helium. Mixtures of helium and oxygen (heliox) can be used to improve laminar gas flow. This occurs due to the decreased density of helium as compared with nitrogen (approximately one-seventh). For Helium to be beneficial in small airways, it must occur in a high ration with oxygen. The greatest benefits may be seen with an 80:20 or 70:30 ratio of helium:oxygen. Therefore, hypoxemia and the need for increased supplemental oxygen may limit heliox use. There is data supporting the use of heliox as a method of delivering inhaled β2 agonists.446 As with other advanced therapy, helium may not have a role in routine care, but there may be benefit from its use in severe critical asthma.  Ketamine. Ketamine is a noncompetitive N-methyl-Daspartate (NMDA) receptor antagonist that can produce a state of dissociative anesthesia. An additional effect of ketamine is bronchodilation. It is a useful medication for sedation in the ICU as ketamine has limited effect on the respiratory drive, and in usual doses, hemodynamics are not usually affected. For patients with asthma who are intubated and mechanically ventilated, ketamine may be a good choice for sedation along with a benzodiazepine. Further, there was one pediatric study447 showing an improvement in the PaO2/FiO2 ratio as well as dynamic compliance in mechanically ventilated children with refractory bronchospasm who were receiving a continuous infusion of Ketamine. There has been no study to show whether ketamine used to treat anxiety is beneficial in preventing intubation in patients during an asthma attack. For nonintubated patients, a recent Cochrane Database Review448 did not show significant benefit in severe acute asthma. If a decision is made to use ketamine either for a procedure or a means of sedation, the bolus dose is usually 1 mg/kg, allowing time for effect before repeating. Ketamine is given as a continuous infusion at the dose of 5 to 30 μg/kg/min titrated to effect. One of the additional side effects of ketamine can be dysphoria, and as such it is usually given with a benzodiazepine.  Noninvasive Ventilation. There is very limited evidence that NIV is effective in children with asthma.335 Clinically patients with effective air exchange who fight the mask and positive pressure do not benefit from NIV. Nevertheless, some children with very limited air exchange and fatigue take to NIV easily and appear more comfortable. NIV may allow time for therapies to become effective (steroids) and may prevent intubation. This should not be used when the level of alertness or ability to protect the airway is diminished.  Intubation. By the time patients with asthma require intubation and mechanical, they are hypoxemic, acidotic, fatigued, and have limited reserve. It is suggested that the most experienced person available perform the intubation. Appropriate venous access is required, and fluid boluses may be necessary. Ketamine and a benzodiazepine have been recommended by many. Ketamine may produce increased secretions, so atropine should be considered. Ketamine may produce dysphoria so the benzodiazepine is given for its amnestic effects. The management style in our ICU is to get the patient back to breathing spontaneously or initiating their own breathes as soon as possible

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after intubation. In turn, Rocuronium can be considered as medium short-acting muscle relaxant. Succinylcholine can be used, but the other side effects of this medication, including elevation of potassium, should be considered. A cuffed ETT is recommended, as ventilator settings may require high peak pressures. Immediately after intubation, we typically hand ventilate the patient with a low rate. This is to prevent alveolar overdistension and reduce the risk of pneumothorax. There can be acute decompensation following intubation. Hypovolemia and increased intrathoracic pressures may be an issue. Following the DOPE acronym, one should also look for Displacement or Obstruction of the ETT and rule out Pneumothorax or Equipment failure.  Mechanical Ventilation. There can be controversy regarding the best means to mechanically ventilate patients with asthma. The argument against setting the ventilator in a pressure control mode is that changes in airway resistance that occur with asthma can result in delivery of an inadequate tidal volume. The argument against a the ventilator in a volume control mode is that due to flow patterns of the ventilator the same tidal volume can be delivered with a higher peak pressure as compared with a pressure control mode. As stated before, our management style is to get intubated asthmatics breathing spontaneously as soon as possible. This allows them to set their own breathing rate, and on pressure support and PEEP, they can set their own inspiratory to expiratory ratio. Pressure support has been recommended because it is patient-initiated, even if not patient-limited.449 There may be initial elevations in PaCO2, but if the patient is well oxygenated, the carbon dioxide elevation is usually well tolerated. Historically, clinicians set zero or low PEEP for intubated asthmatics due to the perceived risk of hyperinflation450 and barotrauma. However, since 1988 there have been four adult studies451-454 and one pediatric study277 strongly suggesting the benefits of extrinsic PEEP during mechanical ventilation for intubated asthmatics. These studies demonstrated that extrinsic PEEP, up to a level to matching intrinsic PEEP, improves the triggering sensitivity of the ventilator, diminishes ventilatory work, and reduces mechanical work of breathing for patients spontaneously breathing with assisted ventilation. As the work of breathing is reduced, there is improved patient comfort and potentially a reduced need for sedation. It is felt that matching extrinsic PEEP applied with the ventilator to the intrinsic PEEP developed by the patient with asthma may improve delivery of aerosol therapy via the ETT. Matching PEEP may possibly result in earlier liberation from mechanical ventilation. It should be noted that some clinicians believe that attempts to match PEEP may include the risk that extrinsic PEEP will cause overdistension of the lungs. Overdistension of the lungs may increase the risk of hyperinflation and air leak syndrome.450 Our studies277,287 indicate that spontaneous breathing with pressure support and PEEP lowers WOB. For the individual patient, the level of extrinsic PEEP at which hyperinflation will occur is unknown. Theoretically, for the spontaneously breathing patient, extrinsic PEEP applied to counteract intrinsic PEEP should not cause an increase in end-expiratory lung volume (EELV) until extrinsic PEEP exceeds intrinsic PEEP.455 Further, the EELV may even decrease, leading to decreased dead space

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SECTION V  •  Pediatric Anesthesia

and increased compliance. In our ICU intrinsic, PEEP is measured during a ventilator pause, allowing the patient to exhale completely and measuring the pressure before the next breath. We gradually add extrinsic PEEP with the ventilator and observe RR and clinical work of breathing. We always keep extrinsic PEEP at a level below intrinsic PEEP. We continue to reassess the level of extrinsic and intrinsic PEEP as the patient responds to therapy. Further research is needed to determine the best practice of mechanical ventilation for intubated asthmatics, but this is limited by the small number requiring intubation each year.  Inhalational Anesthetics. One of the properties of inhaled anesthetics is bronchodilation. In turn, inhaled anesthetics have been used as rescue therapy in children with critical asthma who are intubated. We have used isoflurane in our ICU for its reduction in bronchospasm with the added benefit of a decreased sedation requirement. However, inhaled anesthetics are difficult to use in an ICU setting. Modern ICU ventilators are not designed to accept a vaporizer. There is no circle system in ICU ventilators, so there is a tremendous use of anesthetic vapor. There is no primary means of gas scavenging in an ICU ventilator, so significant steps must be taken to contamination of the patient room. There is a case series of six patients reported by Wheeler et  al.456 Dr. J. Tobias has published several articles457-459 detailing the use of inhaled anesthetics in asthma and other clinical conditions. A recent retrospective cohort study by Char et  al.460 in intubated asthmatics did not demonstrate a difference in mortality between centers that did or did not use inhaled anesthetics. There was significantly greater length of mechanical ventilation, greater length of stay, and increased hospital charges in the centers using inhaled anesthetics. The significant

expertise needed to safely deliver inhaled anesthetics may limit its use to a few centers. An anesthetic conserving device (AnaConDa Sedana Medical) is available in the European market but not the United States. The device is a miniature vaporizer and a conserving medium or reflective filter that keeps the inhaled anesthetic on the patient side of the device. This device can be used with a normal ventilator. Finally, as the scientific community learns more about the potential neurotoxicity with inhaled anesthetics, the physician must weigh the risk and benefit profile to long-term inhalational anesthetics for the management of status asthmaticus.  Extra Corporeal Life Support for Status Asthmaticus. ECLS has been used as a rescue therapy in near fatal asthma. As with inhaled anesthetics, the use of ECLS for this indication is likely limited to a small number of centers. One single center study reports35 their use, but the number of patients (13 total) is too small to determine whether this therapy has advantages over mechanical ventilation or conventional therapy. 

Pulmonary Hypertension CENTRAL NERVOUS SYSTEM Systemic illness is a common cause of CNS dysfunction in infants and children. Seizures, head trauma, CNS infections, and hypoxic or metabolic encephalopathy commonly cause acute neurologic dysfunction in the PICU. Assessment of neurologic function depends on an understanding of the age-dependent progression of motor and cognitive skills. Table 79.8 lists the developmental milestones.

TABLE 79.8  Normal Ages for Major Developmental Milestones Age

Motor Function

Language

Adaptive Behavior

4-6 weeks

Lifts head from prone position and turns from side to side

Cries

Smiles

4 months

Shows no head lag when pulled to sitting from supine position; tries to grasp large objects

Utters sounds of pleasure

Smiles, laughs aloud, and shows pleasure from familiar objects or persons

5 months

Grasps voluntarily with both hands; plays with toes

Makes primitive sounds

Smiles at self in mirror (ah, goo)

6 months

Grasps with one hand; rolls prone to supine; sits with support

His increased range of sounds

Expresses displeasure and food preferences

8 months

Sits without support; transfers objects from hand to hand; rolls supine to prone

Combines syllables (baba, dada, mama)

Responds to “No”

10 months

Sits well; crawls; stands holding; finger-thumb apposition in picking up small objects

12 months

Stands holding; walks with support

Says two or three words with meaning

Understands names of objects; shows interest in pictures

15 months

Walks alone

Utters several intelligible words

Requests by pointing; imitates

18 months

Walks up and down stairs holding; removes clothes

Says many intelligible words

Carries out simple commands

2 years

Walks up and down stairs by self; runs

Makes two- or three-word phrases

Engages in organized play; points to some parts of the body

Waves goodbye; plays patty-cake and peek-a-boo

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79 • Pediatric and Neonatal Critical Care

Functional Postnatal Neurologic Development Motor function in the newborn depends on gestational rather than postnatal age. That is, an infant born at 28 weeks’ gestation exhibits motor responses similar to those of a full-term newborn when the former is 3 months old. Although potentially modifiable by cortical influence, most neonatal motor behavior is subcortically controlled, which permits normal motor behavior in newborns who have severe cortical damage. Assessment of intellectual development is difficult in a newborn; initially, it is based on the absence of reflexes and the acquisition of new motor skills. Adaptive or interactive behavior is first seen with accommodation to repeated stimuli and eye contact. The infant’s intellectual development depends on the presence of external stimulation and social interaction, preferably from one or a few individuals. This is why infants and children who require long-term intensive care must have parental input and developmental stimulus.  Assessment of Neurologic Function Clinical examination is the most important tool we have for assessing neurologic function in children. In an awake child, interactions with the examiner and caretakers are sensitive indicators of high or integrative cortical function. When the child’s cognitive function is depressed from disease or drugs, examination of the general level of activity and peripheral and brainstem reflexes becomes an important, albeit crude, measure of CNS function. A detailed examination includes an evaluation of the level of consciousness and alertness in the context of sedative medications. The Glasgow Coma Scale (GCS) is a commonly accepted tool to evaluate the level of function of neurologically impaired

patients (Table 79.9); however, it was not developed for this purpose, and extensive research needs to continue on directed scales and noninvasive means to improve assessment consciousness in the critically ill child.461 Painful stimulation can stimulate both decorticate or decerebrate posturing and likely indicates significant CNS malfunction and should trigger further investigation. Decerebrate posturing is an extension at the elbows with the arms and hands pronated, whereas decorticate posturing of the upper extremities is flexion at the elbows with the hands clenched. These responses to painful stimuli or no response at all should (in combination with attempts to elicit a cough, gag, or ability to handle oral secretions) make the practitioner question whether the patient can protect their airway. Pupillary reflex is a well preserved function, and therefore unreactive pupils are very concerning. Large reactive pupils may be caused by tricyclic antidepressant ingestion, atropine administration, or a symptom of pharmacologic withdrawal. Small reactive pupils may indicate damage at the level of the pons, but usually indicate the presence of opioids or barbiturates. Fundoscopic exam is important to assess for signs of increased ICP or retinal hemorrhage; however, the bedside practitioner may have difficulty with these assessments, and it may require an ophthalmologist consultation. 

Laboratory Assessment of Neurologic Function The EEG is used to diagnose seizures and isoelectric brain death and to monitor the effects of barbiturates administered to induce coma. In addition, continuous EEG monitoring is often used to detect nonconvulsive seizure activity in critically ill children.226,462,463 This is a resource-intense monitoring system that has yet to show that it improves

TABLE 79.9  Glasgow Coma Scale for Infants and Children Activity

Adult/Child Response

Infant Response

Eye opening (E)

Spontaneous

Spontaneous

4

To verbal stimuli

To verbal stimuli

3

To pain

To pain

2

None

None

1

Oriented, appropriate

Coos and babbles

5

Confused conversation

Irritable cries

4

Inappropriate words

Cries to pain

3

Incomprehensible words

Moans to pain

2

None

None

1

Obeys verbal command

Normal movement

6

Localizes stimulus

Withdraws upon touch

5

Withdraws from noxious stimulus

Withdraws upon pain

4

Decorticate flexion

Decorticate flexion

3

Decerebrate extension

Decerebrate extension

2

None (flaccid)

None (flaccid)

1

Best verbal response (V)

Best motor response (M)

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Score

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outcomes; however, its use continues to grow in neonatal and pediatric critical care, and further study is needed for this promising noninvasive tool. CT allows rapid detection of CNS lesions, the extent of structural injury, and noninvasive assessment of ICP. Cranial ultrasound is a bedside technique used to assess ventricular size and intracranial anatomy in infants with nonfused cranial sutures. MRI permits intraorbital and ocular injuries and brainstem and spinal cord lesions to be examined; it is also good for defining soft tissue abnormalities.464 MRI’s major drawback is the length of time required for each examination and the relative inaccessibility of the patient while in the scanner. Maintaining body temperature can also be a problem in small children during MRI scanning because the room must be cold. It may be difficult to safely perform MRI in patients who have significant cardiorespiratory compromise because many of the pumps and ventilators cannot enter the scanner. Doppler ultrasound allows bedside assessment of CBF velocity in the ICU. Although it does not directly measure CBF, Doppler ultrasound is a useful bedside guide to therapy. CBF scans are the “gold standard” and are usually required to diagnose brain death during barbiturate coma. ICP can be monitored by inserting a catheter into a lateral ventricle or by inserting a subarachnoid screw or transducer into the epidural space or cerebral parenchyma. The ventricular catheter provides an accurate waveform and permits withdrawal of cerebrospinal fluid (CSF) to reduce ICP. The other devices used to measure ICP provide less consistent pressure waves and do not permit removal of CSF. 

Traumatic Brain Injury Despite advances in resuscitation care, morbidity following pediatric TBI remains high. TBI is composed of two components, an initial primary injury due to direct mechanical deformation of brain parenchyma, and a subsequent secondary injury that may develop over hours to days. Secondary injury may be the result of multiple mechanisms including ischemia, excitotoxicity, metabolic failure and eventual apoptosis, cerebral swelling, axonal injury, and inflammation and regeneration.465 For improvements in outcome to be achieved in the pediatric critical care setting, secondary brain injury must be prevented or minimized. Conventional wisdom about TBI has dictated that ischemia plays a major role in secondary brain injury. While reversal of ischemia is crucial, simply delivering oxygen to injured areas of the brain does not abate the onslaught of secondary injury cascades destroying vulnerable areas of brain following TBI. Recent evidence suggests that secondary injury persists despite adequate oxygen delivery to brain tissue due to persistent metabolic crisis.466,467 Furthermore, hyperoxia is not effective in completely reversing metabolic crisis and may lead to persistent secondary injury due to superoxide and free radical generation. There is widespread heterogeneity of metabolism following TBI, with some regional areas of increased glucose and oxygen utilization (likely due to electrical instability); however, in large regions of the brain, oxidative metabolism is reduced to a critical threshold with critically low rates of CMRO2.468 This coupled with ongoing low CBF following TBI places viable brain tissue at risk.468,469 How the neurovascular

bundle regulates the delivery of blood flow to regions gripped in metabolic crisis in ongoing secondary crisis and determining how to manipulate CBF remains an important avenue of study in the immature brain. 

Cerebral Perfusion Pressure and Cerebral Blood Flow In children, developing effective treatments for TBI is complicated by the rapid changing responses of the immature brain to each type of brain injury during development from infancy through childhood.470,471 Therefore, evaluation of therapies for children with brain injury must utilize immature animal models as a translational pathway to human trials in children. It must be understood that much of the research in this field that drives clinical guidelines and recommendations are born from adult clinical studies and adult aged small animal research. How this evidence translates to the child provides some direction but should catalyze further research focusing on the immature brain. This is especially true when the practitioner must indirectly target metabolic delivery in the face of secondary brain injury by attempting to modulate CBF and predict regulation or lack of regulation in the neurovascular bundle. Even in the healthy brain, CVR regulation is complex and poorly understood.472-474 To add to this layer of complexity, CVR is likely heterogenous following brain injury dependent on the mechanisms of injury, age, and even gender. Optimal global CBF is an elusive clinical target, with a lower inflection point associated with ischemic injury and an upper inflection point associated with hyperemia increasing cerebral blood volume and ICP. In early posttraumatic brain injury, cerebral hypoperfusion may greatly contribute to secondary brain injury, ultimately increasing morbidity and mortality.469,475 In adults, areas of contusions have low CBF similar to the ischemic penumbral zones surrounding areas of acute ischemic stroke.476,477 Low CBF states have been demonstrated in children by xenon CT scans following TBI within 24 hours of the initial injury, but by 48 hours these patients had normal or supernormal blood flows.475 Furthermore, CBF in pediatric patients as a target for neuro-resuscitation is a theoretical point of manipulation due to limited options of continuous measurement in the clinical setting. Therefore, CPP (mean arterial blood pressure [MAP] minus ICP) is a commonly used surrogate. When cerebral autoregulation is impaired, CBF and the metabolic needs of the injured brain may depend on maintaining adequate CPP. The difficulty comes in identifying the term adequate. Currently, pediatric CPP thresholds (40-60 mm Hg) have been extrapolated from adult experimental and clinical TBI and stroke studies.476,478 However, recently it has been reported in adults that ischemia following TBI may occur at much higher levels of CBF compared with stroke.476 Chambers et al, have published much needed age-specific pediatric thresholds for critical CPP, below which cerebral ischemia occurs with unfavorable neurologic outcomes and increased mortality.479-481 These studies identified inadequate CPP levels but did not identify an “optimal treatment” CPP, and therefore assumed that these CPP levels were equivalent to brain injury insult thresholds.

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79 • Pediatric and Neonatal Critical Care

It is not clear if a CPP of 40 mm Hg is a minimal threshold and/or that an optimal CPP to prevent brain injury may be higher.482 Using currently accepted pediatric CPP guidelines (CPP >40 mm Hg) may not ensure adequate oxygen delivery to brain tissue.483,484 This raises the question: is a CPP greater than 40 mm Hg in the pediatric TBI patient high enough? Mild induced hypertension after ischemic stroke has shown promise in animal models but remains controversial in the clinical setting.485,486 Adult TBI studies have observed an increased risk of adult RDS associated with targeting a CPP greater than 70 mm Hg, but it is unclear how applicable this is to pediatric neurocritical care.487,488 A retrospective study of 146 pediatric TBI patients observed a strong association of poor outcome at discharge with hypotension within the first 6 hours of injury.489 The window for treatment of hypoperfusion appears to be early after pediatric TBI, and may be of relatively short duration in children. We believe that early aggressive intervention of blood pressure support especially during early critical periods, such as initial resuscitation of a multitrauma patient, intubation, placement of support lines and neuromonitoring devices is critical to neuro-resuscitation. Guidelines released in 2012, based on Class III evidence for pediatric traumatic brain injury, suggest that a minimum CPP of 40 mm Hg should be maintained and that 50 mm Hg for a minimum CPP in older children may be required.490 However, data in our laboratory in large animal models of TBI may support the use of higher CPP support (>70 mm Hg) in severe TBI.491 Targeting CPP often requires vasopressor support. While central venous access should not delay administration of vasopressor support, it is important to understand the risks of extravasation of these infusions and have qualified individuals place central venous access as soon as possible to mitigate these risks. Initial stabilization of the pediatric TBI patient may occur in limited resource environments where complex invasive intracranial monitoring may not be available. Early stabilization of cerebrovascular hemodynamics with phenylephrine and targeting a higher MAP or CPP may reduce brain injury and improve long-term outcomes. A common first-line vasopressor to improve MAP in pediatric brain injury is phenylephrine. Phenylephrine is an α adrenergic agonist that may have little or no effect on cerebral vasculature resistance.492-495 Another vasoactive medication gaining favor is NE. NE primarily targets alpha-receptors for peripheral vasoconstriction, but has additional effects on β-receptors increasing inotropy. There are several published reports now in adults that show the rising use of NE as a preferred vasoactive medication and may provide more predictable CPP augmentation when compared with dopamine.496-498 Prathep et al. have reported that adults with isolated traumatic brain injury and cardiac dysfunction have a higher incidence of in-hospital mortality.499 Further research is critical to determine the degree of cardiovascular compromise following TBI in children and which vasopressor should be considered a first-line agent in pediatric brain injury; this currently should be determined by local experience and comfort of use. We believe that the next generation of treatments will build upon the tenets of ischemic neuro-resusciation and combine early directed metabolic neuroresuscitation.500 

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Respiratory Management in the Brain Injured Child Airway Management. The comatose and brain-injured patient is at severe risk for respiratory failure due to loss of airway protective reflexes and impaired central regulation of respiratory function. In addition, progression of ALI and ARDS can be exacerbated by concomitant injuries (pulmonary contusions, aspiration, left ventricular dysfunction or failure, and inflammation due to systemic inflammation due to trauma or infection) and treatments to improve cerebral perfusion (crystalloid administration, hyperchloremic metabolic acidosis, hypernatremia, and vasopressor therapy). It is critical that the physician caring for these patients have a neuroprotective plan in place for induction and intubation, as well as adequate training and skill to obtain an artificial airway. In addition, the physician needs to be adept at ongoing neuro-resuscitation in the face of progressive lung disease and hemodynamic instability from SIRS and rising MAPs impeding cardiac preload. The initial step in treating the head-injured pediatric patient is always to promote adequate oxygenation and ventilation, and to prevent or treat hypotension thereby limiting ischemia. Criteria for tracheal intubation include hypoxemia not resolved with supplemental oxygen, apnea, hypercarbia (PaCO2 > 45 mm Hg), GCS ≤8, an incremental decrease in GCS greater than 3 independent of the initial GCS (combined with clinical correlation, anisocoria greater than 1 mm, cervical spine injury compromising ventilation, loss of pharyngeal reflex, and any clinical evidence of a herniation pattern or Cushing triad).501  Induction and Intubation. Patients with neurologic injury are at a high risk for aspiration during induction of anesthesia, due to loss of airway protective reflexes. In addition, there is a heightened risk of cervical spine injury due to trauma and most patients will be in a cervical collar requiring manual in-line stabilization. The goal of intubation in the neurologically impaired patients should be (1) rapid sequence from induction to placement of an ETT to reduce the risk of pulmonary aspiration; (2) blunt nociceptive reflexes that may further elevate ICP or cerebral hypertension that may exacerbate intracranial hemorrhage or facilitate herniation; (3) maintaining adequate, age-appropriate CPP; and (4) limiting ischemia by maximizing adequate oxygen delivery and maintaining PaCO2 in a normal range to ensure appropriate CBF.502 It should be assumed that all patients are at risk for a full stomach and cervical spine injury, so intubation should be performed utilizing a neuroprotective, rapid-sequence induction whenever possible. Supplemental oxygen (100%) should be delivered by face mask to allow nitrogen washout from the patient’s FRC to allow sufficient oxygenation prior to tracheal intubation attempts. To avoid risk of aspiration bag-valve-mask (BVM) ventilation should not be done, unless the patient has signs and symptoms of impending herniation or life threatening desaturation events. Outside of impending herniation, if BVM ventilation is conducted it is imperative to not over-ventilate the patient, decreasing PaCO2 and thereby increasing cerebral vascular resistance, resulting in decreased CBF and metabolic delivery in a brain-injured patient. A separate health care professional’s sole responsibility is to maintain the child’s neck in a neutral position by

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mild axial traction during airway maneuvers to prevent or perpetuate cervical spinal injury. Cricoid pressure should be done by a third individual only if the individual is appropriately trained in the technique and it should be abandoned if it hinders a rapid intubation attempt. Orotracheal intubation by direct laryngoscopy should be performed, and nasotracheal intubation should be avoided due to potential for direct intracranial damage in a patient with a basilar skull fracture. Because tracheal intubation is a noxious stimulus and can increase ICP, appropriate sedative and analgesic medications should be administered during rapid-sequence induction. The hemodynamic and neurologic status of the patient dictates the choice of agents. Patients usually receive lidocaine (1-1.5 mg/kg) intravenously before intubation to help blunt the rise in ICP that occurs during direct laryngoscopy.73 For the hemodynamically unstable patient, the combination of lidocaine, etomidate (0.2-0.6 mg/kg), and neuromuscular blockade with rocuronium (1 mg/kg) or succinylcholine (1 mg/kg) IV is a popular choice. The authors believe that succinylcholine may still be an option for rapid sequence intubation (RSI) in children who may be a difficult airway due to its rapid recovery, as opposed to the non-depolarizing intermediate neuromuscular blockade of rocuronium. There are several choices for induction agents in the critically ill child with acute brain injury. In the following sections, we will discuss the pros and cons of each induction agent. It still remains unclear if any of these agents have particular advantages or disadvantages for patients with brain injury, all have been implicated in animal studies as neuroprotectants and neurotoxins. But what is clear is that they are essential to the care of these patients and practitioners should stay current with literature and consider the pharmacodynamics of each drug.  Etomidate. Etomidate is a short-acting IV drug that produces sedation, anxiolysis, and amnesia. Side effects include respiratory depression, hypotension, myoclonus, and adrenal suppression; and it should not be used in children with suspected adrenal insufficiency and sepsis.503 Etomidate has the benefits of decreasing ICP by reductions in CBF and CMRO2 and has the advantage of producing less cardiovascular depression than barbiturates or propofol, preserving CPP.504,505 These neuroprotective qualities are counterbalanced by its ability to increase cerebral vascular resistance by a greater magnitude than its reduction of CMRO2 resulting in an increased metabolic deficit.506,507 The increased metabolic deficit has the potential expand the ischemic core and penumbra in brain injured tissue. This increase in cerebrovascular tone is thought to be attributed to etomidate’s inhibition of NO synthase.508 Particular attention should also be paid to the rapid recovery of etomidate, once the airway is secured etomidate’s effects on consciousness dissipates quickly, principally due to the redistribution of the drug from the brain to inactive tissue sites. Recovery of consciousness can be between 5 and 15 minutes, and if rocuronium (paralyzed for approximately 45 minutes) is used in combination for RSI, the patient will need ongoing sedation while paralyzed. The addition of a short-acting opioid such as fentanyl may be necessary, especially if the

patient has concomitant injuries, such as bone fractures. An alternative is the combination of lidocaine, fentanyl (1-4 μg/kg), and rocuronium. In the hemodynamically stable patient, either of the provided combinations with fastacting benzodiazepine midazolam (0.05-0.2 mg/kg) can be added. In addition, the short-acting narcotic fentanyl, when used with lidocaine, can decrease the catecholamine release associated with direct laryngoscopy.509  Ketamine. Ketamine is a phencyclidine derivative typically formulated as a mixture of two enantiomers in a hydrochloride salt form. It possess of low pH of around 4, which can produce pain at the injection site when administered intramuscularly or intravenously. Ketamine is a NMDA antagonist, which produces increases in CBF and CMRO2.510,511 Early studies in patients with obstructed CSF pathways reported ketamine administration increase ICP with reductions in CPP.512,513 More recent studies in adult patients with severe head injury have demonstrated improvements in CPP and minimal increases in ICP with ketamine.514-516 One recent report of 30 intubated pediatric head injury patients observed that single doses of ketamine lowered ICP without producing decreases in blood pressure or CPP.517 It is still unclear what ketamine’s effect is on neurologic outcome in these patients or in patients where ventilation is not being tightly controlled. However, we believe that ketamine can be used in the brain injured patient, especially in multitrauma patients and if etomidate is not indicated.  Propofol. Propofol is a short-acting sedative-hypnotic IV agent that can be used to provide moderate or deep sedation. Propofol can induce a deep state of sedation rapidly, provide a short duration of effect, and have a pleasant recovery phase. Propofol is a very popular agent for sedating pediatric patients with neurologic conditions for noninvasive diagnostic imaging, such as a CT scan or MRI. Due to the fast onset and recovery following administration, repeated neurologic examinations are easy to assess such as a child with sickle cell disease who comes in with altered mental status due to a stroke. Propofol also has anticonvulsant properties and reduces ICP, which can be advantageous in sedating a patient with epilepsy or a patient with concerns for obstructive hydrocephalus due to a malfunctioning ventriculoperitoneal shunt to obtain diagnostic neuroradiologic imaging.518 While there have been cases of propofol providing adequate sedation and successfully treating intracranial hypertension,518,519 several pediatric traumatic brain injury case reports have reported metabolic acidosis and death in patients on prolonged (24 hours) continuous infusion of propofol.520-524 Furthermore, a rare but potentially fatal “propofol infusion syndrome,” associated with lactic acidosis, hyperlipidemia, and multiorgan system failure, was first described in pediatric patients who received prolonged (24 hours) continuous infusion and at higher dosages (>4.5 mg/ kg/h).525 Current guidelines suggest, that in the care of pediatric traumatic brain-injured patients, “continuous infusion of propofol is not recommended.”526 Adverse effects of propofol include pain at the injection site, apnea or respiratory depression, hypotension, and bradycardia,

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79 • Pediatric and Neonatal Critical Care

which can be detrimental in a patient at risk for brain ischemia. If used particular attention should be paid to the decrease in mean arterial blood pressure with the administration of propofol. Crystalloid bolus and vasopressor usage will likely be needed to counter act the effects of propofol to maintain proper CPP and avoid ischemic insult. Propofol does not provide any analgesia.  Dexmedetomidine. Dexmedetomidine, a centrally acting α2-adrenergic agonist, is a recently FDA-approved agent used for short-term (100 kg) identifies adults who are at increased risk for oxygen desaturation when breathing room air on transport to the PACU.7 Hypoventilation alone may cause hypoxemia even in healthy patients who undergo minor procedures. 

Upper Airway Obstruction LOSS OF PHARYNGEAL MUSCLE TONE The most frequent cause of airway obstruction in the immediate postoperative period is the loss of pharyngeal muscle tone in a sedated or obtunded patient. The persistent effects of inhaled and intravenous anesthetics, neuromuscular blocking drugs, and opioids all contribute to the loss of pharyngeal tone in the PACU patient. In an awake patient, opening of the upper airway is facilitated by the contraction of the pharyngeal muscles at the same time that negative inspiratory pressure is generated by the diaphragm. As a result, the tongue and soft palate are pulled forward, tenting the airway open during inspiration. This pharyngeal muscle activity is depressed during sleep, and the resulting decrease in tone can promote airway obstruction. A vicious cycle then ensues wherein the collapse of compliant pharyngeal tissue during inspiration produces a reflex compensatory increase in respiratory effort and negative inspiratory pressure that promotes further airway obstruction.8 The effort to breathe against an obstructed airway is characterized by a paradoxical breathing pattern consisting of retraction of the sternal notch and exaggerated abdominal muscle activity. Collapse of the chest wall and protrusion of the abdomen with inspiratory effort produces a rocking motion that becomes more prominent with increasing airway obstruction. Obstruction secondary to loss of pharyngeal tone can be relieved by simply opening the airway with the “jaw thrust maneuver” or continuous positive airway pressure (CPAP) applied via a facemask (or both). Support of the airway is needed until the patient has adequately recovered from the effects of drugs administered during anesthesia. In selected patients, placement of an oral or nasal airway, laryngeal mask airway, or endotracheal tube may be required. 

RESIDUAL NEUROMUSCULAR BLOCKADE Postoperative residual neuromuscular blockade is unfortunately very common (Box 80.2). The literature reports incidences between 20% and 40%9 and a recent study even found that 56% of patients had residual neuromuscular blockade upon arrival in the PACU.10 When evaluating upper airway obstruction in the PACU, the possibility of residual neuromuscular blockade should be considered in any patient who received neuromuscular blocking drugs during anesthesia.11,12 Residual neuromuscular blockade

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BOX 80.2  Factors Contributing to Prolonged Nondepolarizing Neuromuscular Blockade Drugs Inhaled anesthetic drugs Local anesthetics (lidocaine) Cardiac antiarrhythmics (procainamide) Antibiotics (polymyxins, aminoglycosides, lincosamines [clindamycin], metronidazole [Flagyl], tetracyclines) Corticosteroid agents Calcium channel blockers Dantrolene  Metabolic and Physiologic States Hypermagnesemia Hypocalcemia Hypothermia Respiratory acidosis Hepatic or renal failure Myasthenia syndromes Excessive dose of succinylcholine Reduced plasma cholinesterase activity Decreased levels □ Extremes of age (newborn, old age) □ Disease states (hepatic disease, uremia, malnutrition, plasmapheresis) □ Hormonal changes □ Pregnancy □ Contraceptives □ Glucocorticoids Inhibited activity □ Irreversible (echothiophate) □ Reversible (edrophonium, neostigmine, pyridostigmine) Genetic variant (atypical plasma cholinesterase)

may not be evident on arrival in the PACU because the diaphragm recovers from neuromuscular blockade before the pharyngeal muscles do. With an endotracheal tube in place, end-tidal carbon dioxide concentrations and tidal volumes may indicate adequate ventilation while the ability to maintain a patent upper airway and clear upper airway secretions remains compromised. The stimulation associated with tracheal extubation, followed by the activity of patient transfer to the gurney and subsequent encouragement to breathe deeply may keep the airway open during transport to the PACU. Only after the patient is calmly resting in the PACU does upper airway obstruction become evident. Even patients treated with intermediate- and short-acting neuromuscular blocking drugs may manifest residual paralysis in the PACU despite what was deemed clinically adequate pharmacologic reversal in the operating room. Measurement of the train-of-four (TOF) ratio is a subjective assessment that is often misleading when done by touch or observation alone. A decline in this ratio may not be appreciated until it reaches a value less than 0.4 to 0.5, whereas significant signs and symptoms of clinical weakness persist to a ratio of 0.7.13 Pharyngeal function is not restored to normal until an adductor pollicis TOF ratio is greater than 0.9.14 In the anesthetized patient, a quantitative TOF measurement showing a TOF ratio ≥0.9 is the most reliable

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SECTION VI  •  Postoperative Care

indicator of adequate reversal of drug-induced neuromuscular blockade.13,15 Qualitative TOF measurement and 5-second sustained tetanus at 50 Hz are insensitive and will not allow detection of fade above an average TOF ratio of 0.31 ± 0.15; 5-second sustained tetanus at 100 Hz is unreliable.16 In an awake patient, clinical assessment of reversal of neuromuscular blockade is preferred to the application of painful TOF or tetanic stimulation. Clinical evaluation includes grip strength, tongue protrusion, the ability to lift the legs off the bed, and the ability to lift the head off the bed for a full 5 seconds. Of these maneuvers, the 5-second sustained head lift has been considered to be the standard, reflecting not only generalized motor strength but, more importantly, the patient’s ability to maintain and protect the airway. However, studies have shown that the 5-second head lift is remarkably insensitive and should not routinely be used to assess recovery from neuromuscular blockade. The ability to strongly oppose the incisor teeth against a tongue depressor is a more reliable indicator of pharyngeal muscle tone. This maneuver correlates with an average TOF ratio of 0.85 as opposed to 0.60 for the sustained head lift.13 In a year-long study of 7459 PACU patients who had received general anesthesia, Murphy et al. reported critical respiratory events (CREs) in 61 of them. These events occurred within the first 15 minutes of PACU admission, at which time a TOF ratio was measured. When compared with matched controls, these patients had a significantly lower TOF ratio (0.62 [+0.20]) compared to controls 0.98 [+0.07]).17 In a recent study, Bulka and associates were able to demonstrate that patients who had received neuromuscular blocking drugs, but did not receive reversal agents, had a 2.26 times higher risk of developing postoperative pneumonia compared to those who did receive reversal agents.18 When a PACU patient demonstrates signs and/or symptoms of muscular weakness in the form of respiratory distress and/or agitation, one must suspect that there could be a residual neuromuscular blockade and prompt review of possible etiologic factors is indicated (see Box 80.2). Common factors include respiratory acidosis and hypothermia, alone or in combination. Upper airway obstruction as a result of the residual depressant effects of volatile anesthetics or opioids (or both) may result in progressive respiratory acidosis after the patient is admitted to the PACU and external stimulation is minimized. Simple measures such as warming the patient, airway support, and correction of electrolyte abnormalities can facilitate recovery from neuromuscular blockade. The approval of sugammadex in the United States by the FDA in December 2015 may have a major impact on residual paralysis in patients who were paralyzed with aminosteroid neuromuscular blocking drugs (sugammadex does not work with benzylisoquinolinium neuromuscular blocking drugs). While reversal with neostigmine requires a baseline twitch response, and the duration until the patient has a TOF ratio of ≥0.9 is highly variable, sugammadex can be administered at any depth of neuromuscular blockade and most commonly produces full recovery within several minutes after administration. In a recent study, reversal with sugammadex resulted in a return of TOF ratio to greater than 0.9 within 5 minutes in 85% of patients with no twitches on TOF stimulation.19 It is anticipated that the increased availability and use of

sugammadex, as an alternative to neostigmine, will result in a decreased incidence of residual neuromuscular blockade in the PACU. 

LARYNGOSPASM Laryngospasm refers to a sudden spasm of the vocal cords that completely occludes the laryngeal opening via forceful tonic contractions of the laryngeal muscles and descent of the epiglottis over the laryngeal inlet. It typically occurs in the transitional period when the extubated patient is emerging from general anesthesia yet not fully awake. Although laryngospasm is most likely to occur in the operating room at the time of tracheal extubation, patients who arrive in the PACU asleep after general anesthesia are also at risk for laryngospasm upon awakening, which is often triggered by airway irritants, such as secretions or blood. Treatment of laryngospasm involves removal of the stimulus (suctioning of secretions, blood) and the application of a jaw thrust maneuver with CPAP (up to 40 cm water [H2O]) is often sufficient stimulation to break the laryngospasm. However, if jaw thrust maneuver and CPAP fail, then immediate skeletal muscle relaxation can be achieved with succinylcholine (0.1-1.0 mg/kg intravenously [IV] or 4 mg/kg intramuscularly [IM]). If these maneuvers fail, one should proceed with a full dose of an induction agent and intubating dose of a muscle relaxant to enable the practitioner to perform an emergent tracheal intubation; attempting to pass a tracheal tube forcibly through a glottis that is closed because of laryngospasm is not acceptable. 

EDEMA OR HEMATOMA Airway edema is a possible surgical complication in patients undergoing prolonged procedures in the prone or Trendelenburg position, procedures involving the airway and neck (including thyroidectomy,20 carotid endarterectomy,21 and cervical spine procedures22), as well as those in which the patient receives a large volume resuscitation. Although facial and scleral edema is an important physical sign that can alert the clinician to the presence of airway edema, visible external signs may not accompany significant edema of pharyngeal tissue (see also Chapter 44). Patients who have had a difficult intraoperative intubation and/or airway instrumentation may also have increased airway edema from direct injury. If tracheal extubation is to be attempted in these patients in the PACU, then evaluation of airway patency must precede removal of the endotracheal tube. The patient’s ability to breathe around the endotracheal tube can be evaluated by suctioning the oral pharynx and deflating the endotracheal tube cuff. With occlusion of the proximal end of the endotracheal tube, the patient is then asked to breathe around the tube. Good air movement suggests that the patient’s airway will remain patent after tracheal extubation. An alternative method involves measuring the intrathoracic pressure required to produce a leak around the endotracheal tube with the cuff deflated. This method was originally used to evaluate pediatric patients with croup before extubation.23-25 When used in patients with general oropharyngeal edema, the safe pressure threshold can be difficult to identify. Lastly,

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80 • The Postanesthesia Care Unit

when ventilating patients in the volume control mode, one can measure the exhaled tidal volume before and after cuff deflation. Patients who require reintubation generally have a smaller leak (i.e., less percentage difference between exhaled volume before and after cuff deflation) than those who do not. A difference greater than 15.5% is the advocated cutoff value for extubation of the trachea.26 The presence of a cuff leak demonstrates the likelihood of successful extubation, not a guarantee, just as a failed cuff leak does not rule out a successful extubation.27 The cuff leak test does not and should never take the place of sound clinical judgment, as it is neither sensitive nor specific; it may be used as an adjunct to aid in providing another layer of guidance. In order to facilitate the reduction of airway edema, one may sit the patient upright to ensure adequate venous drainage, and consider administering a diuretic and intravenous dexamethasone (4-8 mg every 6 hours for 24 hours), which may help decrease airway swelling. External airway compression is most often caused by hematomas following thyroid, parathyroid, or carotid surgical procedures. Patients may complain of pain and/or pressure, dysphagia, and can demonstrate signs of respiratory distress as the pressure from the expanding hematoma within the tissue can disrupt both venous and lymphatic drainage, both of which can further exacerbate airway swelling. Mask ventilation may not be possible in a patient with severe upper airway obstruction resulting from edema or hematoma. In the case of a hematoma, an attempt can be made to decompress the airway by releasing the clips or sutures on the wound and evacuating the hematoma. This maneuver is recommended as a temporizing measure, but it will not effectively decompress the airway if a significant amount of fluid or blood (or both) has infiltrated the tissue planes of the pharyngeal wall. If emergency tracheal intubation is required, then ready access to difficult airway equipment and surgical backup to perform an emergency tracheostomy are crucial, as one should assume increased difficulty secondary to laryngeal and airway edema, possible tracheal deviation, and a compressed tracheal lumen. If the patient is able to move adequate air via spontaneous ventilation, then an awake technique is often preferred as visualization of the cords by direct laryngoscopy may not be possible. 

OBSTRUCTIVE SLEEP APNEA Obstructive sleep apnea (OSA) syndrome is an often overlooked cause of airway obstruction in the PACU, given that most patients are actually not obese and the vast majority of patients are undiagnosed at the time of surgery.28,29 It is well known that patients with OSA are at an increased risk of suffering from cardiopulmonary complications as compared to the general population not affected by OSA syndrome. Patients with OSA are particularly prone to airway obstruction and should not be extubated until they are fully awake and following commands.30,31 Any redundant compliant pharyngeal tissue in these patients not only increases the incidence of airway obstruction, but can also increase the difficulty of intubation by direct laryngoscopy.32,33 Once in the PACU, a patient with OSA whose trachea has been extubated is exquisitely sensitive to

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opioids and, when possible, continuous regional anesthesia techniques should be used to provide postoperative analgesia.34,35 Other opioid-sparing techniques should be utilized, such as scheduled acetaminophen, and use of nonsteroidal antiinflammatory drugs (NSAIDs) when not contraindicated. One may also employ the use of ketamine, dexmedetomidine, and clonidine, all of which can also decrease postoperative opioid requirements. Interestingly, benzodiazepines can have a greater effect on pharyngeal muscle tone than opioids, and the use of benzodiazepines in the perioperative setting can significantly contribute to airway obstruction in the PACU.8,36 Another strategy to employ when caring for a patient with OSA is to position them in either an upright (seated, reverse Trendelenburg) or semi-upright position whenever possible, as the supine position is known to worsen OSA. In addition, the use of goal-directed fluid strategies should be utilized with consideration of lower salt-containing substances, as these patients are more prone to fluid shifts, which can worsen airway edema. When caring for a patient with OSA, plans should be made preoperatively to provide CPAP in the immediate postoperative period. Patients should be asked to bring their own CPAP machines with them on the day of surgery to enable the equipment to be set up before the patient’s arrival in the PACU. Patients who do not routinely use CPAP at home or who do not have their machines with them may require additional attention from the respiratory therapist to ensure proper fit of the CPAP delivery device (mask or nasal airways) and to determine the amount of positive pressure needed to prevent upper airway obstruction.37,38 In patients with OSA who are morbidly obese, immediately applying CPAP postextubation in the operating room rather than waiting to apply positive pressure in the PACU may offer additional benefits. In patients undergoing laparoscopic bariatric surgery, Neligan and colleagues compared the application of 10 cm H2O CPAP immediately postextubation to instituting the same CPAP 30 minutes later in the PACU. When compared with matched controls, patients who received immediate CPAP demonstrated improved spirometric lung function (i.e., functional residual capacity [FRC], peak expiratory flow [PEF], and forced expiratory volume [FEV]) at 1 hour and 24 hours postoperatively.38 Two large cohort studies demonstrated that patients with OSA who are not treated with positive airway pressure (PAP) preoperatively are at increased risk for cardiopulmonary complications after general and vascular surgery and that PAP therapy was associated with a reduction in postoperative cardiovascular complications. If the patient can tolerate PAP, and their surgical procedure is not a contraindication to its application, patients with OSA should use a PAP device postoperatively. 

Management of Upper Airway Obstruction An obstructed upper airway requires immediate attention. Efforts to open the airway by noninvasive measures should be attempted before reintubation of the trachea. Jaw thrust

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SECTION VI  •  Postoperative Care

with CPAP (5-15 cm H2O) is often enough to tent the upper airway open in patients with decreased pharyngeal muscle tone. If CPAP is not effective, an oral, nasal, or laryngeal mask airway can be inserted rapidly. After successfully opening the upper airway and ensuring adequate ventilation, the cause of the upper airway obstruction should be identified and treated. In adults the sedating effects of opioids and benzodiazepines can be reversed with persistent stimulation or small, titrated doses of naloxone (0.3-0.5 μg/ kg IV) or flumazenil (0.2 mg IV to maximum dose of 1 mg), respectively. Residual effects of neuromuscular blocking drugs can be reversed pharmacologically or by correcting contributing factors such as hypothermia. 

Differential Diagnosis of Arterial Hypoxemia in the Postanesthesia Care Unit

BOX 80.3  Factors Contributing to Postoperative Arterial Hypoxemia Right-to-left intrapulmonary shunt (atelectasis) Mismatching of ventilation to perfusion (decreased functional residual capacity) Congestive heart failure Pulmonary edema (fluid overload, postobstructive edema) Alveolar hypoventilation (residual effects of anesthetics and/or neuromuscular blocking drugs) Diffusion hypoxia (unlikely if receiving supplemental oxygen) Inhalation of gastric contents (aspiration) Pulmonary embolus Pneumothorax Increased oxygen consumption (shivering) Sepsis Transfusion-related lung injury Adult respiratory distress syndrome Advanced age Obesity

Atelectasis and alveolar hypoventilation are the most common causes of transient postoperative arterial hypoxemia in the immediate postoperative period.39 Clinical correlation should guide the workup of a postoperative patient who remains persistently hypoxic.40 Review of the patient’s history, operative course, and clinical signs and symptoms will direct the workup to rule in possible causes (Box 80.3).

ALVEOLAR HYPOVENTILATION

FiO2 (PB

PaCO2 PAO2

40 mm Hg 21(760 47)

PaCO2 PAO2

80 mm Hg 21(760 47)

PAO2 Paco2 FiO2 PB PH2O RQ

alveolar oxygen pressure partial pressure of CO2 in arterial blood fraction of inspired oxygen barometric pressure vapor pressure of water respiratory quotient

PH2O)

RQ

40 0.8

150

50

100 mm Hg

80 0.8

150

100

50 mm Hg

Fig. 80.2 Hypoventilation as a cause of arterial hypoxemia. (From Nicholau D. Postanesthesia recovery. In: Miller RD, Pardo MC Jr, eds. Basics of Anesthesia. 7th ed. Philadelphia: Elsevier; 2018.)

250

200 PCO2 (mm Hg)

Review of the alveolar gas equation demonstrates that hypoventilation alone is sufficient to cause arterial hypoxemia in a patient breathing room air (Fig. 80.2). At sea level, a normocapnic patient breathing room air will have an alveolar oxygen pressure (PAO2) of 100 mm Hg. Thus, a healthy patient without a significant alveolar-arterial gradient will have a Pao2 near 100 mm Hg. In the same patient, an increase in Paco2 from 40 to 80 mm Hg (alveolar hypoventilation) results in a Pao2 of 50 mm Hg. Hence, even a patient with normal lungs will become hypoxic if allowed to significantly hypoventilate while breathing room air. Normally, minute ventilation increases linearly by approximately 2 L/min for every 1-mm Hg increase in Paco2. In the immediate postoperative period, the residual effects of inhaled anesthetics, opioids, and sedative-hypnotics can significantly depress this ventilatory response to carbon dioxide. In addition to depressed respiratory drive, the differential diagnosis of postoperative hypoventilation includes generalized weakness due to residual neuromuscular blockade or underlying neuromuscular disease. The presence of restrictive pulmonary conditions, such as preexisting chest wall deformity, postoperative abdominal binding, or abdominal distention, can also contribute to inadequate ventilation. Arterial hypoxemia secondary to hypercapnia can be reversed by the administration of supplemental oxygen (Fig. 80.3)41 or by normalizing the patient’s Paco2 by external stimulation of the patient to wakefulness, pharmacologic reversal of opioid or benzodiazepine effect, or controlled mechanical ventilation of the patient’s lungs. 

PaCO2

PAO2

45% 40%

150

35% 30%

100

25% 21%

50

0 0

1

2

3

4

Alveolar ventilation (L-min–1) Fig. 80.3  Alveolar partial pressure of carbon dioxide (Pco2) as a function of alveolar ventilation at rest. The percentages indicate the inspired oxygen concentration required to restore alveolar partial pressure of oxygen (Po2) to normal. (Adapted from Nunn JF. Nunn’s Applied Respiratory Physiology. 6th ed. Philadelphia: Butterworth-Heinemann; 2005, with permission.)

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80 • The Postanesthesia Care Unit

DECREASED ALVEOLAR OXYGEN PRESSURE Diffusion hypoxia refers to the rapid diffusion of nitrous oxide into alveoli at the end of a nitrous oxide anesthetic. Nitrous oxide dilutes the alveolar gas and produces a transient decrease in Pao2 and Paco2. In a patient breathing room air, the resulting decrease in Pao2 can produce arterial hypoxemia while decreased Paco2 can depress the respiratory drive. In the absence of supplemental oxygen administration, diffusion hypoxia can persist for 5 to 10 minutes after discontinuation of a nitrous oxide anesthetic; therefore, it may contribute to arterial hypoxemia in the initial moments in the PACU. 

VENTILATION-PERFUSION MISMATCH AND SHUNT Hypoxic pulmonary vasoconstriction refers to the attempt of normal lungs to optimally match ventilation and perfusion. This response constricts vessels in poorly ventilated regions of the lung and directs pulmonary blood flow to well-ventilated alveoli. In the PACU, the residual effects of inhaled anesthetics and vasodilators such as nitroprusside and dobutamine used to treat systemic hypertension or improve hemodynamics will blunt hypoxic pulmonary vasoconstriction and contribute to arterial hypoxemia. Unlike a mismatch, a true shunt will not respond to supplemental oxygen. Causes of postoperative pulmonary shunt include atelectasis, pulmonary edema, gastric aspiration, pulmonary emboli, and pneumonia. Of these, atelectasis is probably the most common cause of pulmonary shunting in the immediate postoperative period. Mobilization of the patient to the sitting position, incentive spirometry, and PAP by facemask can be effective in treating atelectasis. 

INCREASED VENOUS ADMIXTURE Increased venous admixture typically refers to low cardiac output states. It is due to the mixing of desaturated venous blood with oxygenated arterial blood. Normally, only 2% to 5% of cardiac output is shunted through the lungs, and this shunted blood with a normal mixed venous saturation has a minimal effect on Pao2. In low cardiac output states, blood returns to the heart severely desaturated. Additionally, the shunt fraction increases significantly in conditions that impede alveolar oxygenation, such as pulmonary edema and atelectasis. Under these conditions, mixing of desaturated shunted blood with saturated arterialized blood decreases Pao2. 

DECREASED DIFFUSION CAPACITY A decreased diffusion capacity may reflect the presence of underlying lung disease such as emphysema, interstitial lung disease, pulmonary fibrosis, or primary pulmonary hypertension. In this regard, the differential diagnosis of arterial hypoxemia in the PACU must include the contribution of any preexisting pulmonary condition.

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Finally, keep in mind that inadequate oxygen delivery may result from an unrecognized disconnection of the oxygen source or empty oxygen tank. 

Pulmonary Edema Pulmonary edema in the immediate postoperative period is often cardiogenic in nature, secondary to intravascular volume overload or congestive heart failure. Other causes of noncardiogenic pulmonary edema, namely postobstructive pulmonary edema (secondary to airway obstruction), sepsis, or transfusion (transfusion-related acute lung injury [TRALI]), may occur less frequently, but they must not be overlooked as a potential cause of pulmonary edema in the postoperative period.

POSTOBSTRUCTIVE PULMONARY EDEMA Postobstructive pulmonary edema (also referred to as negative pressure pulmonary edema, NPPE) is a rare, but significant consequence of laryngospasm and other upper airway obstruction that may follow tracheal extubation at the conclusion of anesthesia and surgery. Laryngospasm is likely the most common cause of postobstructive pulmonary edema in the PACU, but postobstructive pulmonary edema may result from any condition that occludes the upper airway.42-45 The etiology of NPPE is multifactorial, but is clearly correlated with the generation of exaggerated negative intrathoracic pressure attributable to forced inspiration against a closed glottis. The resulting negative intrathoracic pressure augments blood flow to the right side of the heart, which in turn dilates and increases hydrostatic pressure gradient across the pulmonary vascular bed, promoting the movement of fluid into the interstitial and alveolar spaces from the pulmonary capillaries. Negative inspiratory pressure will also increase left ventricular afterload, thus decreasing the ejection fraction, which heightens left ventricular end diastolic pressure, left atrial pressure, and pulmonary venous pressure. This chain of events further escalates the development of pulmonary edema via increase of pulmonary hydrostatic pressures. Patients who are muscularly healthy are at increased risk of postobstructive pulmonary edema secondary to their ability to generate significant inspiratory force. The resulting arterial hypoxemia develops relatively quickly (usually observed within 90 minutes of the upper airway obstruction), and is accompanied by dyspnea, pink frothy sputum, and bilateral fluffy infiltrates on the chest radiograph. Treatment is generally supportive and includes supplemental oxygen, diuresis, and, in severe cases, initiation of positive-pressure ventilation. The general consensus of postoperative monitoring in these patients ranges anywhere from 2 to 12 hours. Resolution of NPPE typically occurs within 12 to 48 hours when recognized and treated immediately; however, if diagnosis and resulting therapy is delayed, mortality rates can reach 40%. Although it is quite uncommon, pulmonary hemorrhage and hemoptysis have been observed. 

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TRANSFUSION-RELATED ACUTE LUNG INJURY The differential diagnosis of pulmonary edema in the PACU should include transfusion-related lung injury in any patient who intraoperatively received blood products.46-48 Transfusion-related lung injury is typically exhibited within 2 to 4 hours after the transfusion of plasma-containing blood products, including packed red blood cells, whole blood, fresh frozen plasma, or platelets. TRALI occurs when recipient neutrophils become activated by constituents of the donor blood products. These neutrophils then release inflammatory mediators which initiate the cascade of pulmonary edema and resulting lung injury via increasing the permeability of the pulmonary vasculature. Given that presenting symptoms (sudden onset of hypoxemic respiratory failure) can appear up to 6 hours after the conclusion of the transfusion, the syndrome may develop during the patient’s stay in the PACU. The resulting noncardiogenic pulmonary edema is often associated with fever, pulmonary infiltrates on chest radiograph (without signs of left heart failure), cyanosis, and systemic hypotension. If a complete blood cell count is obtained with the onset of symptoms, then documenting an acute drop in the white blood cell count (leukopenia) is possible, reflecting the sequestration of granulocytes within the lung and exudative fluid.49,50 Treatment is supportive and includes supplemental oxygen and diuresis. It is estimated that up to 80% of patients will recover within 48 to 96 hours. Mechanical ventilation may be needed to support hypoxemia and respiratory failure. Vasopressors may be required to treat refractory hypotension.51,52 In past years, the lack of specific diagnostic criteria has resulted in the underdiagnosing and underreporting of this syndrome. Recently, a group of transfusion experts in the American-European Consensus Conference developed and implemented diagnostic criteria that have raised the awareness of the syndrome (Box 80.4).51,53-56 

TRANSFUSION-ASSOCIATED CIRCULATORY OVERLOAD (TACO) TACO may be difficult to distinguish from TRALI, however TACO should be highly considered in patients who have diminished cardiac function at baseline, renal insufficiency, and in surgical procedures where there is both rapid and large-volume fluid and blood product administration.57 Patients with TACO are essentially unable to manage the rate and/or volume of product received secondary to their underlying comorbidities, and tend to develop symptoms of respiratory distress, hypoxemia, and signs of left and/or right heart failure within 2 to 6 hours of the transfusion. TACO is commonly associated with physical manifestations of fluid overload and these patients frequently are hypertensive during the onset of dyspnea. The chest radiograph may demonstrate findings of preexisting cardiac disease and a possible cardiogenic component, such as cardiomegaly and pleural effusions. Elevated levels of BNP are suggestive of TACO. TACO and TRALI may indeed coexist. Treatment is mainly supportive and should focus on treatment of supplemental oxygen for hypoxemia and diuresis for acute volume overload. Positive pressure ventilation can be employed as well. 

BOX 80.4  Criteria for the Diagnosis of Transfusion-Related Acute Lung Injury: the American-European Consensus Conference Recommendations . Acute lung injury evidenced by: 1 a. Acute onset of signs and symptoms b. Hypoxemia: i. PaO2/FiO2 40%).135 Interventions were both pharmacologic and technique related. Pharmacologic intervention included droperidol, 1.25 mg; dexamethasone, 4 mg; or ondansetron, 4 mg. Anesthetic intervention included propofol in lieu of volatile anesthetic, nitrogen in lieu of nitrous oxide, or remifentanil in lieu of fentanyl. More than 4000 patients were assigned to 1 of 64 possible combinations. The study found that each of the three antiemetics reduced the relative risk of PONV to the same degree (26%). Together, propofol (19% decrease) and nitrogen (12% decrease) reduced the relative risk of PONV to a similar degree. Although prophylactic measures to prevent PONV are more effective than rescue measures, a subset of patients will require treatment in the PACU even after appropriate prophylactic treatment. There is no convincing evidence that any of the serotonin receptor antagonists commonly prescribed at this time are more effective than any others. Box 80.9 lists the different classes of antiemetic medications commonly prescribed for prophylaxis as well as treatment of PONV in the PACU. If an adequate dose of antiemetic given at the appropriate time is ineffective, simply giving more of the same class of drug in the PACU is unlikely to produce any significant benefit. Therefore, it is not recommended to redose any medication of the same class within 6 hours after the initial dose. Specific antiemetic medications such as scopolamine, dexamethasone, and aprepitant should not be redosed at all.136 The likelihood of a patient experiencing PONV depends on several risk factors and increases with the number of those factors that the patient possesses. Apfel et al. identified female gender, non-smoker, history of PONV/motion

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BOX 80.9  Commonly Used Antiemetics (Adult Doses) Anticholinergics Scopolamine (1.5 mg) transdermal patch to a hairless area behind the ear before surgery (remove 24 h postoperatively)  NK-1 receptor antagonist Aprepitant (40 mg per os within 3 h prior to anesthesia)  Corticosteroids Dexamethasone (4 mg IV after induction of anesthesia)  Antihistamines Hydroxyzine (12.5-25 mg IM) Diphenhydramine (25-50 mg IV)  Phenothiazines Promethazine (12.5-25 mg IM) Prochlorperazine (5-10 mg IV)  Butyrophenones Droperidol (0.625-1.25 mg IV); monitor the ECG for prolongation of the QT interval for 2-3 h after administration; preoperative 12-lead ECG recommended Haloperidol (0.5-40% of the preanesthetic level

0

ACTIVITY LEVEL (ABLE TO AMBULATE AT PREOPERATIVE LEVEL) Steady gait without dizziness or meets the 2 preanesthetic level Requires assistance

1

Unable to ambulate

0

NAUSEA AND VOMITING None to minimal

2

Moderate

1

Severe (continues after repeated treatment)

0

PAIN (MINIMAL TO NO PAIN, CONTROLLABLE WITH ORAL ANALGESICS; LOCATION, TYPE, AND INTENSITY CONSISTENT WITH ANTICIPATED POSTOPERATIVE DISCOMFORT) Acceptability: Yes

2

No

1

SURGICAL BLEEDING (CONSISTENT WITH THAT EXPECTED FOR THE SURGICAL PROCEDURE) Minimal (does not require dressing change) 2 Moderate (up to two dressing changes required)

1

Severe (more than three dressing changes required)

0

*Patients achieving a score of at least 9 are acceptable for discharge. Modified from Marshall SI, Chang F. Discharge criteria and complications after ambulatory surgery. Anesth Analg. 1999;88:508–517.

surgery setting, postoperative pain is the most significant cause of delayed discharge and unplanned hospital admission. In an effort to improve patient satisfaction and timely discharge, Chung and associates identified a subset of high-risk patients who are likely to benefit from intense prophylactic analgesic therapy. This study of 10,008 consecutive ambulatory surgical patients found that the incidence and intensity of postoperative pain increased with increasing BMI and duration of anesthesia. Orthopedic and urologic procedures were the most significant surgical factors.175 PACU Standards of Care require that a physician accept responsibility for the discharge of patients from the unit (Standard V).1 This is the case even when the decision to discharge the patient is made at the bedside by the PACU nurse in accordance with hospital-sanctioned discharge criteria or scoring systems. If discharge criteria are to be used, they must first be approved by the department of anesthesia and the hospital medical staff. A responsible physician’s name must be noted on the record. 

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TABLE 80.5  Infectious Agent Precautions Droplet Precautions

Airborne Precautions

Neisseria meningitides (meningitis)

Tuberculosis (TB)

Group A Streptococcus

Varicella virus (chickenpox)

Rubella (German measles)

Variola virus (smallpox)

Mumps virus

Influenza A

Corynebacterium diphtheria (pharyngeal diphtheria)

Hemorrhagic Fever viruses (Ebola, Marburg, Lassa)

Bordetella pertussis (whooping cough)

Rubeola virus (measles)

Yersinia pestis (pneumonic plague)

SARS

TABLE 80.6  Massachusetts General Hospital’s Indications for Admission to the Intensive Care Unit After Transcatheter Aortic Valve Implantation Preoperative

Intraoperative

Transapical approach Transaortic approach Need for preoperative hemodynamic support Emergency case Pulmonary artery catheter needed postoperative Preoperative significant delirium Significant pulmonary hypertension High-grade coronary artery disease

Expected postoperative intubation Unexpected placement of a PA line Hemodynamic instability Conditions requiring close monitoring (pericardial fluid, aortic injury) Ischemia Significant arrhythmia Suspected complete heart block without adequate safe pacing

PA, Pulmonary artery.

respiratory, alimentary, genital, or urinary tracts are entered under controlled conditions without unusual contamination). As expected, compliance was best in patients with contaminated or known infected wounds. There are three primary modes of transmission of infectious agents: contact (direct or indirect), droplet, and airborne. The most common way pathogens are transmitted is via contact. In direct contact, organisms are transmitted directly from one person to another usually via blood or bodily fluids. Contact Plus (IE: C difficile infections) requires the healthcare worker to both wash their hands and use ABHR. Droplet transmission occurs when the source coughs or sneezes and usually requires relatively close contact for the other person to become infected as droplets (large particle, >5 mm) do not remain suspended in the air for greater than three feet. Airborne transmission occurs when small particle droplets (6.5 hours), high EBL (>45% of estimated blood volume), and lower percent colloid administration.208,209 If POVL is suspected, immediate ophthalmologic consultation should be sought. However, the long-term outcome of this complication is unfortunately usually poor.210 

Future Considerations INTENSIVE CARE In recent years, the demand for ICU beds has increased significantly within the United States and Europe. Because the PACU possesses the equipment and expertise to monitor, ventilate, and resuscitate patients recovering from general anesthesia, it has become the logical choice to provide care for critically ill patients for whom ICU beds are not available.211 Although it is now common to care for critically ill patients in the PACU, the maintenance of quality patient care continues to challenge hospital administrators and staff.212 One obstacle to efficient ICU care in the PACU is the diversity of physician coverage required. Whereas the proximity of the operating room and the patient population recovering from anesthesia dictate that an anesthesiologist be the responsible physician for the majority of patients in the unit, nonsurgical ICU patients often require physician coverage by specialists who are unfamiliar with the unit and whose practices are located in distant areas of the hospital. As a result, PACU nurses must identify and contact physicians with whom they rarely interact. Physician coverage (who will be primarily responsible for patient care—internist, anesthesiologist, or surgeon), privacy for family visitation (lack of space in a traditionally open unit), infection control (the proximity of patient beds and rapid turnover of patients), and nursing competencies (ongoing ICU training of staff) are some of the challenges facing the PACU today.213 In a study of 400 ICU overflow patients admitted to the PACU in the United Kingdom, Ziser and colleagues identified insufficient medical and nursing coverage, inadequate communications, and visiting facilities for patient’s families as the most significant problems facing the unit. The ICU patients in this study were on average 53 years of age with a mean length of stay of 12.9 hours. Seventy percent were mechanically ventilated,

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80 • The Postanesthesia Care Unit

77.8% required invasive monitoring, and 4.5% died in the PACU while awaiting placement in the ICU. The busiest hours of admission were 1 am to 11 am.214 In an effort to ensure the quality of patient care in the PACU, the professional societies responsible for the delivery of care in the unit have collaborated to develop standards for the care of ICU overflow patients. The “Joint Position Statement on ICU Overflow Patients” issued in 2000 is the result of this collaboration. It specifically requires that PACU staffing meet the nursing staffing ratios and competencies required in the critical care units.215 The Joint Position Statement reproduced here recommends that the following criteria be met:   

It must be recognized that the primary responsibility for Phase 1 PACU is to provide the optimal standard of care to the postanesthesia patient and to effectively maintain the surgery schedule. □  Appropriate staffing requirements should be met to maintain safe, competent nursing care of the postanesthesia patient as well as the ICU patient. Staffing criteria for the ICU patient should be consistent with ICU guidelines and based on individual acuity and needs. □  Phase 1 PACUs are by their nature critical care units and as such should meet the competencies required for the care of the critically ill patient. These competencies should include, but are not limited to, ventilator management, hemodynamic monitoring, and medication administration, as appropriate to their patient population. □  Management should develop and implement a comprehensive resource utilization plan with ongoing assessment that supports the staffing needs for both the PACU and ICU patients when the need for overflow admission arises. □  Management should have a multidisciplinary plan to address appropriate utilization of ICU beds. Admission and discharge criteria should be utilized to evaluate the necessity for critical care and to determine the priority of admission.    In addition to increasing the acuity of patient care in the PACU, the shortage of ICU beds has encouraged the deescalation of care in selected patient populations. Postoperative patients who were historically admitted directly to the ICU from the operating room for intensive or specialized monitoring have had successful recovery by routine postoperative care in the PACU. Examples include postoperative craniotomy,216 liver transplantation,217,218 and cardiac surgery patients. The neurosurgical group at the University of Florida has shown that uncomplicated craniotomy patients can be safely cared for in the PACU at a significant savings of hospital-days and cost without increased morbidity or mortality.187 Likewise, the trend to early extubation of liver transplant patients in the operating room has led to the successful uncomplicated recovery of these patients in the PACU. Finally, in an effort to protect ICU bed availability and reduce the number of cardiac surgery cancellations, a group in Melbourne established a cardiac surgery recovery unit within the PACU.219 Each of these examples requires adequate space and specialized nursing skills to be successful.  □ 

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OUTPATIENT PROCEDURES Finally, the PACU has responded to the economic restrictions that currently limit hospital resources by accommodating the performance of simple outpatient procedures (see Chapter 72).220 The PACU is uniquely equipped to care for patients who are undergoing noninvasive and minimally invasive procedures such as electroconvulsive therapy,221,222 cardioversion,223 epidural blood patch,220 and liver biopsy.220 Ambulatory patients undergoing such procedures can be admitted directly to the PACU for the procedure and discharged to home after a brief recovery period. In order to do so, the PACU must be appropriately staffed and scheduled so as to not interfere with routine operating room scheduling and postoperative recovery. Electroconvulsive therapy is somewhat unique in that it requires general anesthesia that is delivered by an anesthesia care practitioner. Typically these are short procedures that can be scheduled before the routine operating room cases. One successful electroconvulsive therapy program schedules the procedure at 5:30 am with nurse-to-patient ratio of 2:1 and estimated PACU length of stay of 2 hours.222 

Summary The PACU is more than a postanesthesia observation unit. It is unique in its ability to support the care of patients of all ages and in every stage of illness. Since its inception more than 50 years ago, the PACU has proved to be an exceptionally adaptable unit that is equipped to meet the demands of an evolving healthcare system.

Acknowledgment The editors and publisher would like to thank Drs. Daniel Sessler, Theodora Katherine Nicholau, and Christian C. Apfel for their contributions in the prior edition of this work. Their chapters have served as the foundation for the current chapter. Complete references available online at expertconsult.com.

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References 2613.e5 205. Lichter JR, Marr LB, Schilling DE, et  al. A Department-of-Anesthesiology-based management protocol for perioperative corneal abrasions. Clinical Ophthalmology. 2015;9:1689–1695. 206. Epstein NE. Perioperative visual loss following prone spinal surgery: a review. Surg Neurol Int. 2016;7(suppl 13):S347–S360. 207. Rubin DS, Parakati I, Lee LA, Moss HE, Joslin CE, Roth S. Perioperative visual loss in spine fusion surgery: ischemic optic neuropathy in the United States from 1999 to 2011 in the nationwide inpatient sample. Anesthesiology. 2016;125:457–464. 208. American Society of Anesthesiologists Task Force on Perioperative Visual Loss. Practice advisory for perioperative visual loss associated with spine surgery: an updated report by the American Society of Anesthesiologists task force on perioperative visual loss. Anesthesiology. 2012;116:274. 209.  Visual Loss Study Group. Risk factors associated with ischemic optic neuropathy after spinal fusion surgery. Anesthesiology. 2012;116:15. 210. Myers MA, Hamilton SR, Bogosian AJ, et  al. Visual loss as a complication of spine surgery. a review of 37 cases. Spine. 1997;22: 1325–1329. 211. Schweizer A, et  al. Opening of a new postanesthesia care unit: impact on critical care utilization and complications following major vascular and thoracic surgery. J Clin Anesth. 2002;14(7): 486–493. 212. Weissman C. The enhanced postoperative care system. J Clin Anesth. 2005;17(4):314–322. 213. Lindsay M. Is the postanesthesia care unit becoming an intensive care unit? J Perianesth Nurs. 1999;14(2):73–77.

214. Ziser A, et al. The postanaesthesia care unit as a temporary admission location due to intensive care and ward overflow. Br J Anaesth. 2002;88(4):577–579. 215. A Joint Position paper on ICU Overflow Patients. Developed by the American Society of PeriAnesthesia Nursing, American Association of Critical Care Nurses. American Society of Anesthesiologists: Anesthesia Care Team Committee and Committee on Critical Care Medicine and Trauma Medicine; 2000. 216. Beauregard CL, Friedman WA. Routine use of postoperative ICU care for elective craniotomy: a cost-benefit analysis. Surg Neurol. 2003;60(6):483–489. discussion 489. 217. Mandell MS, et  al. Reduced use of intensive care after liver transplantation: influence of early extubation. Liver Transpl. 2002;8(8): 676–681. 218. Mandell MS, et al. Reduced use of intensive care after liver transplantation: patient attributes that determine early transfer to surgical wards. Liver Transpl. 2002;8(8):682–687. 219. Heland M, Retsas A. Establishing a cardiac surgery recovery unit within the post anaesthesia care unit. Collegian. 1999;6(3): 10–13. 220. Saastamoinen P, Piispa M, Niskanen MM. Use of postanesthesia care unit for purposes other than postanesthesia observation. J Perianesth Nurs. 2007;22(2):102–107. 221. Petty DS. ECT in the PACU? It’s possible. Nurs Manage. 2000;31(11):42–44. 222. Irvin SM. Treatment of depression with outpatient electroconvulsive therapy. Aorn J. 1997;65(3):573–578. 581-2. 223. Walker JR. Anesthesia for cardioversion. J Perianesth Nurs. 1999;14(1):35–38.

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81

Acute Postoperative Pain ROBERT W. HURLEY, NABIL M. ELKASSABANY, and CHRISTOPHER L. WU

KEY POINTS

□

□

□

□

□

□

□

□

T he process of nociception is a dynamic process (i.e., neuroplasticity) with multiple points of modulation. Persistent noxious input may result in relatively rapid neuronal sensitization and possibly persistent pain. Postoperative pain, especially when poorly controlled, results in harmful acute effects (i.e., adverse physiologic responses) and chronic effects (i.e., delayed long-term recovery and chronic pain). By preventing central sensitization, preventative analgesia may reduce acute and chronic pain. Although studies overwhelmingly support the concept of preemptive analgesia, the evidence from clinical trials is equivocal, mostly because of methodological issues. Multimodal analgesia entails use of multiple classes of analgesic drugs (acetaminophen, gabapentinoids, nonsteroidal antiinflammatory drugs [NSAIDs], ketamine, and others) to act on different receptors along the pain pathway. Different drugs act synergistically to enhance analgesia and reduce side effects resulting from use of an individual class of drugs. Use of multimodal analgesia is recommended whenever feasible. By allowing individual titration of analgesic drugs, use of patient-controlled analgesia (oral, subcutaneous, iontophoretic, intravenous, paravertebral, or epidural) may provide several advantages over traditional provider-administered analgesia (e.g., intramuscular or intermittent intravenous injections) in the management of postoperative pain. The incidence of respiratory depression from opioids is not significantly different among the various routes of administration (i.e., oral, intravenous vs. intramuscular vs. subcutaneous vs. neuraxial). Appropriate monitoring of patients receiving opioid analgesics is essential to detect those with opioid-related side effects, such as respiratory depression. When compared with systemic opioids, perioperative epidural analgesia may confer several advantages, including a facilitated return of gastrointestinal function and decrease in the incidence of pulmonary complications, coagulation-related adverse events and cardiovascular events, especially in higher-risk patients or procedures. However, the risks and benefits of epidural analgesia should be evaluated for each patient, and appropriate monitoring protocols should be used during postoperative epidural analgesia. Epidural analgesia is not a generic entity because different catheter locations (catheter-incision congruent vs. catheter-incision incongruent), durations of postoperative analgesia, and analgesic regimens (local anesthetics vs. opioids) may differentially affect perioperative morbidity. Postoperative pain management should be tailored to the needs of special populations (e.g., opioid-tolerant, pediatric, and obese patients, as well as those with obstructive sleep apnea) who may have different anatomic, physiologic, pharmacologic, or psychosocial issues.

Fundamental Considerations A revolution in the management of acute postoperative pain has occurred during the past four decades. Widespread recognition of the undertreatment of acute pain by clinicians, economists, and health policy experts has led to the development of a national clinical practice guideline for management of acute pain by the Agency for Healthcare Quality and Research (formerly the Agency for Health Care Policy and Research) of the U.S. Department of Health and Human Services.1 This landmark document includes acknowledgment of the historical inadequacies in perioperative pain management, importance of good pain control, need for accountability for adequate provision of perioperative analgesia by health care institutions,

and a statement on the need for involvement of specialists in appropriate cases. In addition, several professional societies including American Society of Anesthesiologists (ASA),2 The Joint Commission,3 American Society of Regional Anesthesia and Pain Medicine, and American Pain Society4 have developed clinical practice guidelines for acute pain management or provided new pain management standards. With their knowledge of and familiarity with pharmacology, various regional anesthetic techniques, and the neurobiology of nociception, anesthesiologists are prominently associated with the clinical and research advances in acute postoperative pain management. Anesthesiologists developed the concepts of acute pain services (APS) (inpatient pain services), application of evidence-based practice to acute postoperative pain, and

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81 • Acute Postoperative Pain

creation of innovative approaches to acute pain medicine (APM), all of which are a natural extension of the anesthesiologist’s role as a “perioperative physician,” consultant, and therapist throughout the institution, in addition to being a highly skilled expert in the operating room. Provision of effective analgesia for surgical and other medical patients is an important component of this multidimensional role. An area that is often challenging in the acute perioperative pain services (PPS) is the management of patients with acute surgical pain in addition to a baseline chronic pain. These patients are often not well served by the arbitrary distinction of “acute” versus “chronic” pain services in hospitals. Anesthesiologists are well trained to manage acute pain in the patient with concomitant chronic pain as a result of the strength of chronic pain curricula in current anesthesiology training programs. Although this chapter focuses on the patient who has acute perioperative pain, acute management of chronic pain in the hospitalized setting is discussed in Chapter 51, “Management of the Patient with Chronic Pain.”

PAIN PATHWAYS AND THE NEUROBIOLOGY OF NOCICEPTION Surgery produces tissue injury with consequent release of histamine and inflammatory mediators such as peptides (e.g., bradykinin), lipids (e.g., prostaglandins), neurotransmitters (e.g., serotonin), and neurotrophins (e.g., nerve growth factor).5 Release of inflammatory mediators activates peripheral nociceptors, which initiate transduction and transmission of nociceptive information to the central nervous system (CNS) and the process of neurogenic inflammation in which release of neurotransmitters (e.g., substance P and calcitonin gene-related peptide) in the periphery induces vasodilatation and plasma extravasation.5 Noxious stimuli are transduced by peripheral nociceptors and transmitted by A-delta and C nerve fibers from peripheral visceral and somatic sites to the dorsal horn of the spinal cord, where integration of peripheral nociceptive and descending modulatory input (i.e., serotonin, norepinephrine, γ-aminobutyric acid, enkephalin) occurs. Further transmission of nociceptive information is determined by complex modulating influences in the spinal cord. Some impulses pass to the ventral and ventrolateral horns to initiate segmental (spinal) reflex responses, which may be associated with increased skeletal muscle tone, inhibition of phrenic nerve function, or even decreased gastrointestinal motility. Others are transmitted to higher centers through the spinothalamic and spinoreticular tracts, where they induce supra-segmental and cortical responses to ultimately produce the perception of and affective component of pain. Continuous release of inflammatory mediators in the periphery sensitizes functional nociceptors and activates dormant ones. Sensitization of peripheral nociceptors may occur and is marked by a decreased threshold for activation, increased rate of discharge with activation, and increased rate of basal (spontaneous) discharge. Intense noxious input from the periphery may also result in central sensitization (“persistent postinjury changes in the CNS that result in pain hypersensitivity”)6 and hyperexcitability (“exaggerated and prolonged responsiveness of neurons to normal afferent input after tissue damage”).6 Such noxious

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input may lead to functional changes in the dorsal horn of the spinal cord and other consequences that may later cause postoperative pain to be perceived as more painful than it would otherwise have been. The neural circuitry in the dorsal horn is extremely complex, and we are just beginning to elucidate the specific role of the various neurotransmitters and receptors in the process of nociception.5 However, it seems that certain receptors (e.g., N-methylD-aspartate [NMDA]) may be especially important for the development of chronic pain after an acute injury, although other neurotransmitters or second messenger effectors (e.g., substance P, protein kinase C) may also play important roles in spinal cord sensitization and chronic pain. Our understanding of the neurobiology of nociception has progressed from the hard-wired system proposed by Descartes in the 17th century to the current view of neuroplasticity in which dynamic integration and modulation of nociceptive transmission take place at several levels. There still are many gaps in our knowledge of the specific roles of various receptors, neurotransmitters, and molecular structures in the process of nociception. An understanding of the neurobiology of nociception is important for appreciating the transition from acute to chronic pain. The traditional dichotomy between acute and chronic pain is arbitrary because acute pain may quickly transition into chronic pain.7 Noxious stimuli can produce expression of new genes (which are the basis for neuronal sensitization) in the dorsal horn of the spinal cord within 1 hour and these changes are sufficient to alter behavior within the same timeframe.8 Also, the intensity of acute postoperative pain is a significant predictor of chronic postoperative pain.9 Control of perioperative pain (e.g., preventive analgesia) and the manner in which it is implemented (e.g., multimodal perioperative pain management) may be important in facilitating short- and long-term patient convalescence after surgery. 

ACUTE AND CHRONIC EFFECTS OF POSTOPERATIVE PAIN Uncontrolled postoperative pain may produce a range of detrimental acute and chronic effects. The attenuation of perioperative pathophysiology that occurs during surgery through reduction of nociceptive input to the CNS and optimization of perioperative analgesia may decrease complications and facilitate recovery during the immediate postoperative period10 and after discharge from the hospital.

Acute Effects The perioperative period has a variety of pathophysiologic responses that may be initiated or maintained by nociceptive input. At one time, these responses may have had a beneficial teleological purpose; however, the same response to the iatrogenic nature of modern-day surgery may be harmful. Uncontrolled perioperative pain may enhance some of these perioperative pathophysiologies and increase patient morbidity and mortality. Attenuation of postoperative pain, especially with certain types of analgesic regimens, may decrease perioperative morbidity and mortality. Transmission of nociceptive stimuli from the periphery to the CNS results in the neuroendocrine stress response,

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SECTION VI  •  Postoperative Care

a combination of local inflammatory substances (e.g., cytokines, prostaglandins, leukotrienes, tumor necrosis factor-α) and systemic mediators of the neuroendocrine response. The dominant neuroendocrine responses to pain involve hypothalamic-pituitary-adrenocortical and sympathoadrenal interactions. Suprasegmental reflex responses to pain result in increased sympathetic tone, increased catecholamine and catabolic hormone secretion (e.g., cortisol, adrenocorticotropic hormone, antidiuretic hormone, glucagon, aldosterone, renin, angiotensin II), and decreased secretion of anabolic hormones.11 The effects include sodium and water retention and increased levels of blood glucose, free fatty acids, ketone bodies, and lactate. A hypermetabolic, catabolic state occurs as metabolism and oxygen consumption are increased and metabolic substrates are mobilized from storage depots.11 The extent of the stress response is influenced by many factors, including the type of anesthesia and intensity of the surgical injury, with the extent of the stress response being proportional to the degree of surgical trauma.12 The negative nitrogen balance and protein catabolism may impede convalescence; however, attenuation of the stress response and postoperative pain may facilitate and accelerate the patient’s recovery postoperatively. The neuroendocrine stress response may enhance detrimental physiologic effects in other areas of the body. The stress response is likely a factor in the postoperative development of hypercoagulability. Enhancement of coagulation (i.e., decreased levels of natural anticoagulants and increased levels of procoagulants), inhibition of fibrinolysis, and increased platelet reactivity and plasma viscosity may enhance the incidence of postoperative hypercoagulable-related events such as deep venous thrombosis, vascular graft failure, and myocardial ischemia.13 The stress response may also enhance postoperative immunosuppression, the extent of which correlates with the severity of surgical injury.7 Hyperglycemia from the stress response may contribute to poor wound healing and depression of immune function. Uncontrolled postoperative pain may activate the sympathetic nervous system and thereby contribute to morbidity or mortality. Sympathetic activation may increase myocardial oxygen consumption, which may be important in the development of myocardial ischemia and infarction,13 and may decrease myocardial oxygen supply through coronary vasoconstriction and attenuation of local metabolic coronary vasodilation.14 Activation of the sympathetic nervous system may also delay return of postoperative gastrointestinal motility, which may develop into paralytic ileus. Although postoperative ileus is the result of a combination of inhibitory input from central and local factors,13,14 an increase in sympathetic efferent activity, such as from uncontrolled pain, may decrease gastrointestinal activity and delay return of gastrointestinal function. Nociceptors are activated after surgical trauma and may initiate several detrimental spinal reflex arcs. Postoperative respiratory function is markedly decreased, especially after upper abdominal and thoracic surgery. Spinal reflex inhibition of phrenic nerve activity is an important component of this decreased postoperative pulmonary function.13 However, patients with poor postoperative pain control may breathe less deeply, have an inadequate cough, and

be more susceptible to the development of postoperative pulmonary complications.14 Activation of nociceptors may also initiate spinal reflex inhibition of gastrointestinal tract function and delay return of gastrointestinal motility.13 Many detrimental postoperative pathophysiologic effects can occur in the perioperative period and can activate nociceptors and the stress response. Uncontrolled pain may activate the sympathetic nervous system, which can cause a variety of potentially harmful physiologic responses that may adversely increase morbidity and mortality. Nociceptor activation may also result in several detrimental inhibitory spinal reflexes. Control of the pathophysiologic processes associated with acute postoperative pain may attenuate the stress response, sympathetic outflow, and inhibitory spinal reflexes and contribute to improvements in morbidity, mortality, and patient-reported outcomes (e.g., health-related quality of life [HRQL], patient satisfaction).13 

Chronic Effects Chronic persistent postsurgical pain (CPSP) is a largely unrecognized problem that may occur in 10% to 65% of postoperative patients (depending on the type of surgery), with 2% to 10% of these patients experiencing severe CPSP.15 Poorly controlled acute postoperative pain is an important predictive factor in the development of CPSP.9,16 The transition from acute to chronic pain occurs very quickly, and long-term behavioral and neurobiologic changes occur much sooner than was previously thought.7 CPSP is relatively common after procedures such as limb amputation (30%-83%), thoracotomy (22%-67%), sternotomy (27%), breast surgery (11%-57%), and gallbladder surgery (up to 56%).9 Although the severity of acute postoperative pain may be an important predictor in the development of CPSP,9 a causal relationship has not been definitively established, and other factors (e.g., area of postoperative hyperalgesia) may be more important in predicting the development of CPSP.17 One such factor may be the severity of the patient’s preoperative pain. Patients with more intense levels of preoperative pain may also develop a degree of CNS sensitization predisposing them to the increased likelihood of higher postoperative pain and the subsequent development of chronic pain.17 Thus, it is important that APS clinicians understand chronic pain conditions and involve themselves in the patient’s preoperative care. The increased involvement of the APM team in preoperative anesthesia clinics or services can positively attenuate the incidence and severity of postoperative pain. Control of acute postoperative pain may improve longterm recovery or patient-reported outcomes (e.g., quality of life). Patients whose pain is controlled in the early postoperative period (especially with the use of continuous epidural or peripheral catheter techniques) may be able to actively participate in postoperative rehabilitation, which may improve short- and long-term recovery after surgery.18 Optimizing treatment of acute postoperative pain can improve HRQL.19 Postoperative chronic pain that develops as a result of poor postoperative pain control may interfere with patients’ activities of daily living.  Preventive Analgesia The older terminology of “preemptive” analgesia referred to an analgesic intervention that preceded a surgical injury

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81 • Acute Postoperative Pain

and was more effective in relieving acute postoperative pain than the same treatment following surgery. The precise definition of preemptive analgesia is one of the major controversies in this area of medicine and contributes to the question of whether preemptive analgesia is clinically relevant. Definitions of preemptive analgesia include what is administered before the surgical incision, what prevents the establishment of central sensitization resulting from incisional injury only (i.e., intraoperative period), what prevents central sensitization resulting from incisional and inflammatory injury (i.e., intraoperative and postoperative periods), or the entire perioperative period encompassing preoperative interventions, intraoperative analgesia, and postoperative pain management (i.e., preventive analgesia).6 The first two definitions are relatively narrow and may contribute to the lack of a detectable effect of preemptive analgesia in clinical trials. The rationale for preemptive analgesia was based on the inhibition of the development of central sensitization. Effectively, noxious input initiated by surgical procedures induced a state of CNS hyperactivity that accentuates pain. Although a very popular and discussed theory, a single analgesic treatment (either peripheral or neuraxial) before the incision does not reduce postoperative pain behaviors beyond the expected duration of the analgesic effect.20 When the block of nociceptive afferents diminishes, the surgical injury is able to reinitiate central sensitization. Clinical trials have been negative.21 For these reasons, this terminology has fallen out of favor. As stated previously, intense noxious input (e.g., postoperative pain from the periphery) can change the CNS (i.e., central sensitization) to induce “pain hypersensitivity” and hyperexcitability (i.e., exaggerated and prolonged responsiveness of neurons to normal afferent input after tissue damage). Preventive analgesia is aimed at inhibiting the development of this type of chronic pain. This definition broadly includes any regimen given at any time during the perioperative period that controls pain-induced sensitization. Central sensitization and hyperexcitability can develop after the surgical incision in a patient who has no history of preoperative pain. In contrast, some patients may already have existing acute or chronic pain and developed central sensitization prior to the surgical incision. These patients with preexisting pain may have even more intense pain in the postoperative period. This augmentation of preexisting pain can occur in the acutely hospitalized and even in those patients in subacute or chronic outpatient settings. Preventing the establishment of altered central processing by analgesic treatment may result in short-term (e.g., reduction in postoperative pain and accelerated recovery) and longterm (e.g., reduction in chronic pain and improvement in HRQL19 benefits during a patient’s convalescence). Unfortunately, many clinical studies (e.g., trials) lack clarity of study design and clear terminology of preemptive versus preventative analgesia.21,22 Timing of the intervention may not be as clinically important as other aspects of preventive analgesia (i.e., intensity and duration of the intervention). An intervention administered before the surgical incision is not preventative if it is incomplete or insufficient such that central sensitization is not prevented. Incisional and inflammatory injuries are important in initiating and maintaining central

2617

sensitization. Confining the definition of preventative analgesia to only the intraoperative (incisional) period is not relevant or appropriate because the inflammatory response lasts well into the postoperative period and continues to maintain central sensitization. Maximal clinical benefit is observed when there is complete multi-segmental blockade of noxious stimuli with extension of this into the postoperative period. Preventing central sensitization with intensive multimodal analgesic interventions21 could theoretically reduce the intensity or even eliminate acute postoperative pain/hyperalgesia and chronic pain after surgery.9 

Multimodal Approach to Perioperative Recovery/ Enhanced Recovery after Surgery The analgesic benefits of controlling postoperative pain are generally maximized when a multimodal strategy to facilitate the patient’s convalescence is implemented. Yet, postoperative pain treatment may not provide major improvements in some outcomes because it is unlikely that a unimodal intervention can be effective in addressing a complex problem such as perioperative outcomes.10,23 The complex nature of nociception and mixed mechanisms of generating surgical pain are also responsible for failure of unimodal analgesia to adequately address postoperative pain.10,23 Principles of a multimodal analgesia include using multiple strategies and drug classes to manage patient expectation and control postoperative pain to allow early mobilization, enteral nutrition, and to attenuate the perioperative stress response.10 These strategies include: patient education, local anesthetic-based techniques (local infiltration, peripheral nerve blocks, and neuraxial analgesia),10 and a combination of analgesic drugs that act via different mechanisms on different receptors within the pain transmission pathway to provide synergistic effect, superior analgesia, and physiologic benefits. A multimodal approach to perioperative recovery to control postoperative pathophysiology and facilitate rehabilitation is an integral part of almost all enhanced recovery after surgery (ERAS) pathways and will result in accelerated recovery and decreased length of hospitalization.24 One of the key components of a multimodal analgesic regimen within any ERAS pathway is the minimization of opioid use and side effects from opioids by utilizing nonopioid analgesics and techniques.25 Patients undergoing major abdominal or thoracic procedures and who participate in a multimodal strategy have a reduction in hormonal and metabolic stress, preservation of total-body protein, shorter times to tracheal extubation, lower pain scores, earlier return of bowel function, and earlier fulfillment of intensive care unit discharge criteria when compared to patients receiving traditional pain management.24 ERAS pathways integrate the most recent evidence from surgery, anesthesiology, nociceptive neurobiology, and pain treatment, and transforms traditional care programs into effective postoperative rehabilitation pathways.24 This approach will decrease perioperative morbidity, costs of care, decrease the length of hospital stay, and improve patient satisfaction without compromising safety.26,27 ERAS pathways are more common in adult surgical patients, although there is increasing interest in utilizing ERAS in pediatric patients.26 Widespread implementation of these programs requires

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SECTION VI  •  Postoperative Care

multidisciplinary collaboration, change in the traditional principles of postoperative care, additional resources, and expansion of the traditional APS, which may be limited in the current economic climate.28 

Treatment Methods Many options are available for the treatment of postoperative pain, including systemic (i.e., opioid and non-opioid) analgesics and regional (i.e., neuraxial and peripheral) analgesic techniques. By considering patients’ preferences and making an individualized assessment of the risks and benefits of each treatment modality, the clinician can optimize the postoperative analgesic regimen for each patient. Essential aspects of postoperative monitoring of patients receiving various postoperative analgesic treatment methods are listed in Box 81.1.29 

BOX 81.1  Monitoring and Documentation of Postoperative Analgesia Analgesic Medication* Medication, concentration, and dose of drug Settings of PCA device: demand dose, lockout interval, continuous basal infusion Amount of drug administered (including number of unsuccessful and successful doses) Limits set (e.g., 1- and 4-h limits on dose administered) Supplemental or breakthrough analgesics  Routine Monitoring Vital signs: temperature, heart rate, blood pressure, respiratory rate, average pain score Pain score at rest and with activity, pain relief  Side Effects

Systemic Analgesic Techniques OPIOIDS Advantages and Characteristics Opioid analgesics are one of the cornerstone options for the treatment of postoperative pain. They generally exert their analgesic effects through μ-receptors in the CNS, although opioids may also act at peripheral opioid receptors. A theoretical advantage of opioid analgesics is that there is no analgesic ceiling. Realistically, the analgesic efficacy of opioids is typically limited by the development of tolerance or opioid-related side effects such as nausea, vomiting, sedation, or respiratory depression. Opioids may be administered by the subcutaneous, transcutaneous, transmucosal, or intramuscular route, but the most common routes of postoperative systemic opioid analgesic administration are oral and intravenous (IV). Opioids may also be administered at specific anatomic sites such as the intrathecal or epidural space (see later sections, “Single-Dose Neuraxial Opioids” and “Continuous Epidural Analgesia”). There is wide intersubject and intrasubject variability in the relationship of opioid dose, serum concentration, and analgesic response in the treatment of postoperative pain. Serum drug concentrations may exhibit wider variability with certain routes of administration (e.g., intramuscular) than with others (e.g., IV). In general, opioids are administered parenterally (intravenously or intramuscularly) for the treatment of moderate to severe postoperative pain, in part because these routes provide a more rapid and reliable onset of analgesic action than the oral route does. Parenteral opioid administration may be necessary in patients who are unable to tolerate oral intake postoperatively. The transition from parenteral to oral administration of opioids usually occurs after the patient resumes oral intake and postoperative pain has been stabilized with parenteral opioids.  Intravenous Patient-Controlled Analgesia Various factors, including the aforementioned broad interpatient and intrapatient variability in analgesic needs, variability in serum drug levels (especially with intramuscular injection), and administrative delays, may contribute to inadequate postoperative analgesia. A traditional prescribed as-needed

Cardiovascular: hypotension, bradycardia, or tachycardia Respiratory status: respiratory rate, level of sedation Nausea and vomiting, pruritus, urinary retention  Neurologic Examination Assessment of motor block or function and sensory level Evidence of epidural hematoma  Instructions Provided Treatment of side effects Concurrent use of other CNS depressants Parameters for triggering notification of the covering physician Provision of contact information (24 hr/7 day per week) if problems occur Emergency analgesic treatment if the PCA device fails *Postoperative analgesia includes systemic opioids and regional analgesic techniques. This list incorporates some of the important elements of preprinted orders, documentation, and intravenous PCA and epidural analgesia daily care described in the ASA Practice Guidelines for Acute Pain Management.29 CNS, Central nervous system; PCA, patient-controlled analgesia.

(PRN) analgesic regimen probably cannot compensate for these limitations. By circumventing some of these issues, IV patient-controlled analgesia (PCA) optimizes delivery of analgesic opioids and minimizes the effects of pharmacokinetic and pharmacodynamic variability in individual patients. IV PCA is based on the premise that a negative-feedback loop exists; when pain is experienced, analgesic medication is selfadministered, and when pain is reduced, there are no further demands. When the negative-feedback loop is violated, excessive sedation or respiratory depression may occur. Although some equipment-related malfunctions can occur, the PCA device itself is relatively free of problems, and most problems related to PCA use result from user or operator error.30 A PCA device can be programmed for several variables, including the demand (bolus) dose, lockout interval, and background infusion (Table 81.1). An optimal demand or bolus dose is integral to the efficacy of IV PCA because an insufficient demand dose may result in inadequate analgesia, whereas an excessive demand dose may result in a higher incidence of undesirable side effects such as respiratory depression.31 Although the optimal demand dose is uncertain, the data available suggest that the optimal

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81 • Acute Postoperative Pain

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TABLE 81.1  Intravenous Patient-Controlled Analgesia Regimens Drug Concentration

Size of Bolus*

Lockout Interval (min)

Continuous Infusion

Adult

0.5-2.5 mg

5-10

—

Pediatric

0.01-0.03 mg/kg (max, 0.15 mg/kg/h)

5-10

0.01-0.03 mg/kg/h

AGONISTS Morphine (1 mg/mL)

Fentanyl (0.01 mg/mL) Adult

10-20 μg

4-10

—

Pediatric

0.5-1 μg/kg (max, 4 μg/kg/h)

5-10

0.5-1 μχg/kg/h

0.05-0.25 mg

5-10

—

Hydromorphone (0.2 mg/mL) Adult

0.003-0.005 mg/kg (max, 0.02 mg/kg/h)

5-10

0.003-0.005 mg/kg/h

Alfentanil (0.1 mg/mL)

Pediatric

0.1-0.2 mg

5-8

—

Methadone (1 mg/mL)

0.5-2.5 mg

8-20

—

Oxymorphone (0.25 mg/mL)

0.2-0.4 mg

8-10

—

Sufentanil (0.002 mg/mL)

2-5 μg

4-10

—

AGONIST-ANTAGONISTS Buprenorphine (0.03 mg/mL)

0.03-0.1 mg

8-20

—

Nalbuphine (1 mg/mL)

1-5 mg

5-15

—

Pentazocine (10 mg/mL)

5-30 mg

5-15

—

*All doses are for adult patients unless noted otherwise. Units vary across agents for size of the bolus (mg vs. mg/kg vs. mcg vs. μg/kg) and continuous infusion (mg/kg/h vs. μχg/kg/h). The anesthesiologist should proceed with titrated intravenous loading doses if necessary to establish initial analgesia. Individual patient requirements vary widely, with smaller doses typically given to elderly or compromised patients. Continuous infusions are not initially recommended for opioid-naïve adult patients.

demand dose is 1 mg for morphine and 40 μg for fentanyl in opioid-naïve patients; however, the actual dose for fentanyl (10-20 μg) is often less in clinical practice.30 The lockout interval may also affect the analgesic efficacy of IV PCA. A lockout interval that is too long may result in inadequate analgesia and decrease the effectiveness of IV PCA. A lockout interval that is too short allows the patient to self-administer another demand dose before feeling the full analgesic effect of the previous dose and thus may contribute to an increase in medication-related side effects. In essence, the lockout interval is a safety feature of IV PCA, and although the optimal lockout interval is unknown, most intervals range from 5 to 10 minutes, depending on the medication in the PCA pump; varying the interval within this range appears to have no effect on analgesia or side effects.30 Most PCA devices allow administration of a continuous or background infusion in addition to the demand dose. Initially, routine use of a background infusion predicted certain advantages, including improved analgesia, especially during sleep; however, analgesic benefits of a background infusion have not been successful in opioid-naïve patients. A background infusion only increases the analgesic dosage used and the incidence of adverse respiratory events in the postoperative period, especially in adult subjects. Furthermore, use of a nighttime background infusion does not improve postoperative sleep patterns, analgesia, or recovery profiles.32 Although routine use of continuous or background infusion as part of IV PCA in adult opioid-naïve

patients is not recommended, a background infusion in opioid-tolerant or pediatric patients may be effective (see later sections, “Opioid-Tolerant Patients” and “Pediatric Patients”) (also see Chapter 24). When compared with traditional PRN analgesic regimens, IV PCA provides superior postoperative analgesia and improves patient satisfaction, but the presence of economic benefits is not clear.33 A metaanalysis revealed that IV PCA (vs. as-needed opioids) provides significantly better analgesia and patient satisfaction; however, these patients used more opioids and had a more frequent incidence of pruritus than those treated with PRN opioids, but there was no difference in the incidence of adverse events.33 With regard to economic outcomes, whether IV PCA is less expensive than traditional PRN intramuscular opioid administration is not clear because the calculations of cost are complex. IV PCA may provide advantages when assessing other patient-related outcomes such as patient satisfaction; these outcomes have become more important as healthcare organizations use them as a measure of quality and a tool for marketing purposes. Patients usually prefer IV PCA over intravenously, intramuscularly, or subcutaneously administered PRN opioids. Greater patient satisfaction with IV PCA may be the result of superior analgesia and perceived control over the administration of analgesic medications and avoidance of disclosing pain or securing analgesic medication from nurses; however, the reasons for patient satisfaction are complex and many factors may contribute to or predict satisfaction with IV PCA. Although IV PCA use

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SECTION VI  •  Postoperative Care

overall creates better satisfaction, the proper assessment of patient satisfaction can be complex.34 The incidence of opioid-related adverse events from IV PCA is not different from that of PRN opioids administered intravenously, intramuscularly, or subcutaneously. The rate of respiratory depression associated with IV PCA is infrequent (approximately 1.5%) and is not more frequent than that with PRN systemic or neuraxial opioids.35 Factors that may influence the frequency and intensity of respiratory depression with IV PCA include use of a background infusion, advanced age, concomitant administration of sedative or hypnotic drugs, and coexisting pulmonary disease such as obstructive sleep apnea (OSA).36 IV PCA-related respiratory depression may also be caused by errors in programming or administration (i.e., operator error).37 

NON-OPIOIDS Nonsteroidal Antiinflammatory Agents Nonsteroidal antiinflammatory drugs (NSAIDs) consist of a diverse group of analgesic compounds with different pharmacokinetic properties. The primary mechanism by which NSAIDs exert their analgesic effect is through inhibition of cyclooxygenase (COX) and synthesis of prostaglandins, which are important mediators of peripheral sensitization and hyperalgesia. In addition to being peripherally acting analgesics, NSAIDs can also exert their analgesic effects through inhibition of spinal COX.38 The discovery of at least two COX isoforms (i.e., COX-1 is constitutive and COX-2 is inducible) with different functions (i.e., COX-1 participates in platelet aggregation, hemostasis, and gastric mucosal protection, whereas COX-2 participates in pain, inflammation, and fever) has led to the development of selective COX-2 inhibitors that differ from traditional NSAIDs, which block both COX-1 and COX-2.39 The discovery of a COX-3 variant may represent a primary central mechanism by which acetaminophen and other antipyretics decrease pain and fever; however, the precise relationship between COX-3 and acetaminophen is still uncertain.40 NSAIDs given alone generally provide effective analgesia for mild to moderate pain. NSAIDs are also traditionally considered a useful adjunct to opioids for the treatment of moderate to severe pain. Yet, some quantitative, systematic reviews suggest that NSAIDs, alone or in combination with opioids, may be more beneficial than previously thought (Table 81.2 and Fig. 81.1). NSAIDs may be administered orally or parenterally and are particularly useful as components of a multimodal analgesic regimen by producing analgesia through a different mechanism from that of opioids or local anesthetics. Several meta-analyses have examined the analgesic efficacy of NSAIDs (including COX-2 inhibitors) and acetaminophen when added to IV PCA with opioids. Surprisingly and importantly, NSAIDs41,42 resulted in a statistically significant (but probably not clinically meaningful) reduction in pain scores.43,44 Although all regimens significantly decreased morphine consumption, only NSAIDs reduced risk for the opioid-related side effects of nausea, vomiting, and sedation. Perioperative use of NSAIDs has several side effects, including decreased hemostasis, renal dysfunction, and gastrointestinal hemorrhage. Inhibition of COX and the formation of prostaglandins cause many of the side effects,

TABLE 81.2  Relative Efficacy of Single-Dose Analgesics in Providing Greater than 50% Relief of Moderate to Severe Postoperative Pain Drug*

†

Mean NNT

95% CI

Acetaminophen (1000 mg PO) 3.8

3.4-4.4

Aspirin (600-650 mg PO)

4.4

4.0-4.9

Aspirin (1000 mg PO)

4.0

3.2-5.4

Diclofenac (50 mg PO)

2.3

2.0-2.7

Diclofenac (100 mg PO)

1.9

1.6-2.2

Ibuprofen (600 mg PO)

2.4

1.9-3.3

Ketorolac (10 mg PO)

2.6

2.3-3.1

Ketorolac (30 mg IM)

3.4

2.5-4.9

Naproxen (550 mg PO)

2.7

2.3-3.3

Celebrex (200 mg PO)

3.5

2.9-4.4

Celebrex (400mg PO)

2.1

1.8-2.5

Tramadol (100 mg PO)

4.8

3.8-6.1

Gabapentin (600 mg PO)

11

6.0-35

Codeine (60 mg) + acetamino- 4.2 phen (600-650 mg PO)

3.4-5.3

Oxycodone (5 mg) + acetaminophen (325 mg PO)

2.5

2.0-3.2

Codeine (60 mg PO)

16.7

11.0-48.0

Morphine (10 mg IM)

2.9

2.6-3.6

Oxycodone (15 mg PO)

2.4

1.5-4.9

*Data obtained in part and modified from Bandolier with permission. http:// www.bandolier.org.uk/booth/painpag/Acutrev/Analgesics/lftab.html. †NNT in this case refers to the number of patients who must be treated to obtain greater than 50% relief of moderate to severe postoperative pain. NNT conveys statistical and clinical significance, is useful in comparing the efficacy of different interventions, and summarizes treatment effects in a clinically relevant manner. A lower mean NNT implies greater analgesic efficacy in this example. CI, confidence interval; IM, intramuscular; NNT, number needed to treat; PO, oral route.

which mediate many diverse processes throughout the body. Decreased hemostasis from NSAID use is from platelet dysfunction and inhibition of thromboxane A2 (generated by COX-1), an important mediator of platelet aggregation and vasoconstriction. Evidence of the effect of NSAIDs on perioperative bleeding is equivocal; a surveillance study of perioperative ketorolac administration did not demonstrate a significant increase in operative site bleeding. Whether NSAIDs may also have a deleterious effect on bone healing and osteogenesis is controversial. Although NSAIDs have been used following acetabular/hip fractures and hip replacement surgery to reduce heterotopic ossification, the short-term effect of NSAIDs on other skeletal tissues is less clear.45 Two recent systematic reviews indicated that when examining the highest-quality studies, there was no increased risk of nonunion with NSAID exposure. Certainly, a short-term NSAID regimen can be used for treatment of post-fracture pain without significantly increasing the risk of disrupted healing.46 A brief (90%, PEEP >15 cm H O, prone ventilation 2 2 □ Refractory hypercarbia (e.g., PaCO > 80) with acidosis 2 □ Injurious ventilating pressures (e.g., plateau pressures >30 mm Hg) with lung-protective tidal volumes Common clinical conditions □ Severe pneumonia (viral or bacterial) □ Aspiration pneumonitis □ ARDS from any cause □ Pulmonary contusion □ Status asthmaticus □ Severe air leak syndrome □ Inhalation injury □ Airway obstruction (e.g., mediastinal mass) □ Pre and post lung transplant

From ELSO website, www.ELSO.org

ECMO for Respiratory Failure (VV ECMO) In contrast to the ECMO experience in neonatal and pediatric respiratory failure as previously described, demonstration of benefit in adults took much longer, delayed in part due to the publication of a trial in 1979 by Zapol and associates12 in 90 adult patients with respiratory failure. This trial had many limitations, including the use of VA rather than VV ECMO, patient selection, anticoagulation technique and bleeding complications, and the use of standard ventilation at the time—relatively high-tidal volume and low positive end-expiratory pressure (PEEP). Poor outcomes deterred adult use of ECMO for more than 20 years. From 2001 to 2006 a large, ambitious British trial, the CESAR trial, was performed to evaluate VV ECMO for respiratory failure in adults.13 This study was performed during the H1N1 influenza pandemic, and involved transferring patients with severe respiratory failure to a central expert ECMO center, where they were randomly assigned to ECMO or standard therapy. Despite some methodological and statistical limitations, the results supported the use of ECMO performed in a specialized center to improve survival: 63% versus 43% survival with ECMO versus standard treatment. At the same time, another report (case series) of VV ECMO in adults with severe acute respiratory distress syndrome (ARDS) due to H1N1 was reported from Australia and New Zealand (ANZ ECMO).14 This study found a 79% survival at 30 days in patients who received ECMO. Recently a large multicenter trial of VV ECMO in adults with severe ARDS, the EOLIA trial, was published in 2018,15 with the authors concluding no difference in mortality between ECMO and conventional therapy at 60 days: 35% versus 46% (P = .09), with 28% of the control group crossing over to ECMO after randomization and a 57% mortality in this crossover group. Editorial comments on this study have challenged this conclusion, maintaining that it supports the use of early ECMO in adults with severe ARDS.16,17 The ELSO database reports survival to discharge

with ECMO for adult respiratory failure as 60% with this percentage being relatively stable over 15 years.18

INDICATIONS FOR VV ECMO IN RESPIRATORY FAILURE Box 85.1 lists common indications for VV ECMO in respiratory failure. As VV ECMO supports only respiratory function, if the patient has right- or left-sided cardiac failure then another configuration of support must be used. The most common indication is ARDS, most commonly due to viral or bacterial infection. As indicated previously, the most studied population is patients with H1N1 viral pneumonia. A commonly used assessment for the severity of ARDS is the Murray score, which is based on four standard criteria: PaO2/FiO2 gradient for oxygen, degree of PEEP, number of quadrants affected as shown on the chest radiograph, and lung compliance.19 In 2012, the Berlin criteria were published, where the severity of ARDS is rated as mild, moderate, or severe based on the PaO2/ FiO2 gradient for oxygen if other criteria are present.20 In general, patients with severe ARDS (PaO2/FiO2 gradient of < 100 mm Hg with PEEP > 5) are potential candidates for ECMO as the mortality without ECMO is approximately 40%.20 As described later in the section on the ethics of ECMO, there are studies that evaluate the likelihood of survival at the time ECMO is being considered; this can help guide decision making. It should also be mentioned that from the CESAR trial described earlier,13 if a patient being considered for VV ECMO is not at an ECMO center or one with expertise in management of ARDS, transfer to such a facility is likely to provide a better outcome even in the absence of ECMO. While not formally studied, many reports indicate that outcomes are better with earlier institution of ECMO, probably at least in part because this permits the use of lung protective ventilation when respiration is supported by ECMO.21 ECMO for lung transplantation is discussed in the next section. 

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85  •  Extracorporeal Membrane Oxygenation and Cardiac Devices

BOX 85.2  Indications for VA ECMO □ □ □ □

Cardiogenic shock □ Hypotension/poor tissue perfusion despite maximum ­medical therapy +/− balloon pump Combined cardiorespiratory failure □ Cardiogenic shock with pulmonary edema and hypoxemia Urgent ECMO for respiratory failure □ As temporizing measure before institution of VV ECMO Common clinical conditions □ Refractory cardiogenic shock (any cause) □ Failure to separate from cardiopulmonary bypass □ Bridge to durable ventricular assist device or transplant □ Intraoperative lung transplant □ Unstable arrhythmias □ Anaphylaxis □ Massive pulmonary embolus □ Cardiac arrest without return of spontaneous circulation

VA ECMO, venoarterial extracorporeal membrane oxygenation; VV ECMO, venovenous extracorporeal membrane oxygenation.

CONTRAINDICATIONS TO VV ECMO In keeping with ELSO guidelines18 there are no absolute contraindications for VV ECMO in adults Box 85.2. There are, however, conditions known to be associated with a poor ­outcome, despite ECMO; these should always be considered before initiating ECMO assistance. These conditions include: injurious mechanical ventilation for 7 days or longer, major pharmacologic immunosuppression, and intracranial hemorrhage that is recent or expanding. Specific patient conditions should also be considered. Although no specific age is a contraindication, increased age is considered to increase the risk.18 A body mass index (BMI) of more than 40 to 45 may be associated with technical difficulties and the risk of not being able to achieve an adequate blood flow. VV ECMO is a bridge to either recovery or lung transplant; if neither of these outcomes appears at all likely then its initiation is not advisable. 

Extracorporeal Membrane Oxygenation for Patients Awaiting and Undergoing Lung Transplantation The history of ECMO for severe respiratory failure as described previously refers mostly to patients with acute or acute on chronic disease where recovery could be anticipated. Another population is patients with end-stage chronic lung disease awaiting lung transplantation. These patients often have a slow (in years) deterioration in function and an increased need for oxygen support, with the final stage being an acute deterioration where standard therapy with mechanical ventilation ultimately fails. Institution of ECMO to prolong survival until transplant, use of ECMO during transplant surgery, and extension or initiation of ECMO postoperatively for primary graft dysfunction (PGD) or other indications have all become common applications for this advanced therapy. As recently as 2010 there was concern that the use of ECMO resulted in a reduced long-term survival from lung transplantation,22 but this is no longer the case in 2018. Case reports, single

2697

center reports, and surveys have documented that the use of pretransplant ECMO, sometimes for months, was followed by successful transplant and good long-term outcomes.23,24 Raleigh and associates compared 10 studies on the use of preoperative ECMO for lung transplant patients and found similar outcomes to the patients who did not need ECMO25 and Loor and associates described factors that contributed to posttransplant survival in this population.26 Intraoperative use of ECMO during the procedure has also been shown to reduce the inflammatory response and leads to less PGD when compared to CPB and leads to improved short-term and longer-term outcomes1,26,27 even when compared to no use of either CPB or ECMO intraoperatively.28 While preoperative ECMO may be VV, VA, or VPA, intraoperatively VA ECMO is usually used due to surgical manipulation of the heart with its attendant hemodynamic compromise as well as the need for one-lung ventilation in patients with end-stage pulmonary disease and elevated pulmonary vascular pressures. Postoperatively, ECMO support may be needed to support the new lungs in the face of PGD, the right heart, the left heart, or any combination of these. Postoperative ECMO support is also associated with excellent outcomes.28 

ECMO for Circulatory Failure (VA ECMO) VA ECMO can be used to support the heart and lungs temporarily in a patient with poor cardiac function who undergoes an invasive cardiology procedure, to continue postoperative cardiopulmonary support in a cardiac surgery patient who fails to separate from CPB, and in a patient with refractory cardiac failure with or without associated respiratory failure. These conditions may occur due to an acute recoverable illness (e.g., myocarditis) or may be in the setting of acute on chronic heart failure in patients being evaluated for longterm advanced therapies such as a durable ventricular assist device or cardiac transplant. Urgent use of ECMO in the acute setting of in-hospital cardiac arrest (ECPR) is also practiced in some centers. Finally, as VA ECMO can be instituted at the bedside without imaging, it may be the preferred technique for emergent cannulation in any form of respiratory or cardiac failure, with elective conversion to another form (e.g., VV ECMO) once the patient has stabilized. The historical perspective for use of VA ECMO for cardiac or combined cardiorespiratory support in adults is illustrated in the 2016 report from the ELSO registry.29 Adult cardiac ECMO was in its infancy in 1990 with little increase in use until 2006 when its use began to increase exponentially; there were more than 2000 adult cardiac ECMO runs reported to ELSO in 2015, comprising an ever-increasing proportion of all ECMO runs (Fig. 85.2). This exponential increase was likely fueled by consistent success in the neonatal and pediatric populations; improvements in the ECMO circuits, pumps, and oxygenators; and the success and experience with VV ECMO for adult respiratory failure. Overall survival in adults who receive ECMO for cardiac indications is approximately 40% with a slight increasing trend over the last 10 years.29

INDICATIONS FOR VA ECMO For periprocedural support of the heart only, short-term devices such as a percutaneous left ventricular assist device

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2698

SECTION VII  •  Critical Care Medicine

ELSO REGISTRY INTERNATIONAL REPORT 2016 100% 90% 80% 70% 60% 50% 40% 30% 20% 10%

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

199

199

199

199

199

199

199

199

199

199

200

200

200

200

200

200

200

200

200

200

201

201

201

201

201

201

0%

Neonatal Respiratory Adult Cardiac

Pediatric Respiratory Pediatric Cardiac

Adult Respiratory Neonatal Cardiac

Fig. 85.2  Distribution of trends in extracorporeal membrane oxygenation (ECMO) utilization (data from the ELSO registry) by patient age and indication (pulmonary or cardiac) between 1990 and 2016. In the early years the majority of ECMO was neonatal respiratory, whereas in recent years it is more adult respiratory and cardiac. (From Thiagarajan RR, Barbaro RP, Rycus PT, et al. Extracorporeal Life Support Organization Registry International Report 2016. ASAIO J. 2017;63(1):60–67.)

(LVAD, e.g., Impella or TandemHeart) are one type of support; the other is short-term ECMO, usually peripheral (femoral) VA ECMO. Recent reviews of temporary circulatory support devices in cardiology compare and summarize risks, benefits, and outcomes with the different approaches in different settings.30,31 Use of VA ECMO provides support for both the right and left heart, whereas short-term LVADs support only one ventricle. Surgeons are much more likely to use VA ECMO in the setting of postcardiotomy failure, partly due to familiarity with surgical cannulation (or the presence of central cannulae), but also due to the support this provides for both ventricles and the lungs. Reviews of postcardiotomy ECMO suggest approximately 30% survival to hospital discharge.32,33 For support of the patient with refractory end-stage cardiac failure who may be a potential candidate for durable LVAD or transplant, or who has already been evaluated for such advanced therapy, there are advantages and disadvantages to both the short-term LVAD (Impella or TandemHeart) and ECMO. Such patients always need left ventricular support but if right heart function and pulmonary function are adequate a short-term percutaneous LVAD might be appropriate. As discussed later, a significant advantage of these devices over VA ECMO is decompression of the left ventricle, which is not a feature of VA ECMO. If placed via the axillary/subclavian artery, the patient can be at least somewhat mobile with such a device. If, however the right heart, or lungs, or both, needs support, then VA ECMO is most appropriate. Another issue is urgency or acuity: peripheral VA ECMO can be initiated at the bedside without imaging more rapidly than a temporary assist device. The main problem if this support is needed for days or weeks is the femoral cannulae prevent mobilization. A recent systematic review (publications between 2006 and 2016) of

short-term mechanical circulatory support as a bridge to durable LVAD or transplant (or recovery) documented a wide range in the number of days of support (individual study means of up to 47 days) and an overall 45% to 66% of patients surviving to discharge.34 In this report where the support was via central ECMO (see later), a higher proportion of patients went on to receive durable LVAD or transplant and survived to discharge than those who received peripheral ECMO. For acute recoverable myocardial illness such as myocarditis, survival is approximately 67% with VA ECMO.35 This is a better outcome than for other cardiac indications, likely reflective of the younger age of such patients and possibly because in this setting ECMO is usually instituted before cardiogenic shock or arrest. In the 2016 ELSO report, use of ECMO in the setting of cardiopulmonary resuscitation (CPR) or extracorporeal cardiopulmonary resuscitation (ECPR) in adults comprises approximately 15% of all adult ECMO.29 Sixty-six percent of all centers reporting to the registry indicate some use in this setting. While referrals for ECMO for respiratory and cardiac failure are often relatively acute and urgent, in the setting of bedside CPR, ECMO needs to be instituted very rapidly; time from starting CPR to ECMO initiation is an important determinant of good outcome.36,37 This limits its use to institutions able to support a team that is ready for such rapid activation. Survival to discharge is, not surprisingly, the lowest of all ECMO applications in both adults (29%) and pediatrics (41%).29 The quality of evidence in published studies comparing ECLS to standard CPR is low, with a great deal of heterogeneity.37 Indications for VA ECMO are summarized in Box 85.2. According to the 2013 ELSO guidelines18 the most common indication for VA ECMO in adult cardiac

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85  •  Extracorporeal Membrane Oxygenation and Cardiac Devices

failure is the presence of cardiogenic shock with end organ hypoperfusion despite the use of dual inotropes and significant vasopressor requirement. This includes cardiogenic shock with or without myocardial infarction, fulminant myocarditis, peripartum cardiomyopathy, decompensated chronic heart failure, right heart failure, medication or toxic drug overdose, and postcardiotomy shock. 

CONTRAINDICATIONS TO VA ECMO Absolute contraindications to VA ECMO include acute intracranial hemorrhage or massive stroke, active bleeding, and severe aortic insufficiency. Relative contraindications (variable by center) may include contraindication for anticoagulation, advanced age, obesity, active cancer, suicide attempt, chronic hemodialysis, end-stage liver disease, aortic dissection, and lack of social support. As is the case for VV ECMO, if neither recovery nor candidacy for durable therapy (LVAD or transplant) are likely, VA ECMO should not be initiated. 

The Ethics of Extracorporeal Membrane Oxygenation The initiation of any form of ECMO is lifesaving when the heart, or lungs, or both are failing despite maximum medical therapies. It is a very invasive and labor-intensive therapy, with associated severe complications, and may confine a patient to an ICU for days, weeks, or even months. As the practice has evolved over time, many groups have tried to address issues of patient appropriateness, possible exclusion criteria, and prognosis before initiating the therapy. An essential consideration is that ECMO is a “bridge” to something else and cannot be viewed as a long-term solution; Box 85.3 lists the uses of ECMO as a “bridging” therapy to a variety of possible scenarios. The following discussion addresses only the individual patient ethical dilemmas, and not the overriding issue of the use of a limited availability, expensive, and labor-intensive therapy with its cost:benefit implications, and overall implications for health care systems. When an otherwise relatively young and healthy patient develops an acute severe illness resulting in acute cardiac failure and shock (e.g., viral cardiomyopathy) or acute refractory lung failure (e.g., viral pneumonia), the decision to initiate lifesaving extracorporeal support as a “bridge to recovery” seems relatively straightforward. Similarly, a patient with end-stage disease of any kind who already has a “do not resuscitate” status would likely not be a candidate for ECMO if the heart suddenly failed. Unfortunately, the clinical spectrum of potential candidates runs as a continuum between these two examples. From the patient and family, through all levels of caregivers and decision makers, tools to help assess the likelihood of successful outcome with this advanced therapy are needed. The ELSO registry database has been used to study the likelihood of survival prior to ECMO initiation, both in respiratory failure (Table 85.2)38 and cardiac failure (Table 85.3).39 There are many common elements in these

2699

BOX 85.3  Extracorporeal Membrane Oxygenation as “Bridge” Therapy Bridge to Decision Bridge to Recovery Bridge to Advanced ­Durable Therapy “Bridge to Nowhere”

Urgent initiation before the ability to assess likelihood of recovery or ­candidacy for advanced therapy Initiation for organ failure that is believed to be potentially recoverable Initiation after acceptance for eligibility for device (e.g., VAD) or transplant Bridge to decision which is likely to be non-recovery and non-eligibility for advanced therapy

VAD, Ventricular assist device.

publications, including the duration and degree of respiratory support, age, other organ function, and acidosis. While these publications can be used as a general guide and can be quoted to referring physicians and families, they have to be placed in clinical context; decision making for life-sustaining treatment must be patient-specific. Courtwright and associates40 make a point of the need to emphasize to the patient’s family the “bridging” nature of ECMO therapy, and that a destination must be formulated at the outset or early on. Because of the need for anticoagulation and the risk for bleeding or thrombosis, patients who are not candidates for anticoagulation (e.g., intracranial hemorrhage) are generally not candidates for ECMO, even though more experience is accumulating with reduced or even no anticoagulation with the use of anticoagulant bonded cannulae, tubing, pump heads, and oxygenators. Patients with underlying severe disease who are not expected to survive more than some predetermined period (i.e., 6 months or a year) independent of the need for ECMO are unlikely to be considered as candidates. Rather than have a single physician or surgeon determine whether ECMO should be initiated in a given patient, especially when a request comes from an outside hospital, many institutions make this a shared decision by a small committee (i.e., 3 individuals) who are all familiar with and participate in ECMO management.41 Overall survival for adult respiratory and cardiac ECMO is approximately 60% and 40%, respectively. Although this is certainly a major advance for diseases that were previously not survivable, the other side of this coin is that mortality remains at 40% and 60%. It makes good sense to engage palliative care and/or an ethics committee and other counselling services, where available and appropriate, at the outset for this therapy.40,41 When ECMO is being considered but there is uncertainty about the likelihood of recovery or candidacy for advanced durable therapy, discussions with family and caregivers should be similar to those made regarding “do not resuscitate,” assessing the values and goals of the patient.42 Counselling for ICU caregivers as well as family, including postmortem “debriefings,” can be very valuable to help staff deal with end-of-life issues. There are few settings where withdrawal of therapy can so immediately result in death, where patients have intact neurologic function but are on the “bridge to nowhere”; it can be extremely troubling to all involved when ECMO is stopped. 

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SECTION VII  •  Critical Care Medicine

TABLE 85.2  The “RESP” Score for Pre-ECMO Prediction of Survival at 30 Days After Initiation of VV ECMO for Respiratory Failure Score

PARAMETER AGE, YEARS 18-49

0

50-59

−2

≥60

−3

Immunocompromised status*

−2

MECHANICAL VENTILATION PRIOR TO INITIATION OF ECMO 7 days

0

ACUTE RESPIRATORY DIAGNOSIS GROUP (SELECT ONLY ONE) Viral pneumonia

3

Bacterial pneumonia

3

Asthma

11

Trauma and burn

3

Aspiration pneumonitis

5

Other acute respiratory diagnoses

1

Nonrespiratory and chronic respiratory diagnoses

0

Central nervous system dysfunction†

−7

Acute associated (nonpulmonary)

infection‡

−3

Neuromuscular blockade agents before ECMO

1

Nitric oxide use before ECMO

−1

Bicarbonate infusion before ECMO

−2

Cardiac arrest before ECMO

−2

PaCO2, mm Hg 70 UI/L. †CNS dysfunction combined neurotrauma, stroke, encephalopathy, cerebral embolism, as well as seizure and epileptic syndromes. ‡Renal dysfunction is defined as acute renal insufficiency (e.g., creatinine > 1.5 mg/dL) with or without RRT. §Chronic kidney disease is defined as either kidney damage or glomerular filtration rate < 60 mL/min/1.73 m2 for ≥ 3 months. ¶Worse value within 6 hours prior to ECMO cannulation. VA ECMO, Venoarterial extracorporeal membrane oxygenation; VF, ventricular fibrillation; VT, ventricular tachycardia. From Schmidt M, Burrell A, Roberts L, et al. Predicting survival after ECMO for refractory cardiogenic shock: the survival after veno-arterial-ECMO (SAVE)-score. Eur Heart J. 2015;36(33):2246–2256.

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2702

SECTION VII  •  Critical Care Medicine

The Mechanics of Extracorporeal Membrane Oxygenation THE PUMP The delivery of ECMO includes a centrifugal pump in series with a membrane oxygenator connected by tubing to an inflow and an outflow cannula from the pump to the patient. Convention is to describe the cannulae in relation to the pump: the inflow cannula aspirates venous blood from the patient and the outflow cannula carries arterialized blood from the pump to the patient. Figs. 85.3 and 85.4 illustrate two common ECMO pumps in use today. Fig. 85.3 shows the Maquet Cardiohelp device (Getinge Group, Wayne, NJ) where the pump head and oxygenator are combined into one disposable unit. Fig. 85.4 shows the Thoratec CentriMag pump where the pump head and oxygenator can be disposed separately. Both pumps work in a similar manner with a magnetically driven rotor. Note, the only variable that is adjustable on the pump is the number of revolutions per minute (RPM); the flow generated at a given RPM is dependent on filling (preload) and impedance to ejection (afterload).43 In the human heart, it has been argued that venous return is the single most important factor in maintaining adequate cardiac output.44 In a similar way, the most important determinants of flow for a centrifugal pump fed from the patient’s central veins and right atrium are the volume status of the venous circulation and internal diameter of the cannula. Also important in VA ECMO is the mean systemic pressure, as the flow from the pump will be reduced by hypertension. While the centrifugal pumps used in ECMO are relatively nontraumatic to red blood cells, there is hemolysis especially at high RPM

settings. In order to maximize flow at a low RPM, thereby reducing hemolysis, the goal is to maintain adequate preload and decrease afterload. Use of the largest possible arterial or outflow cannula will also reduce hemolysis but this need must be balanced with the patient’s vessel size. What is less clear physiologically is how much ECMO flow is necessary for adequate tissue perfusion. This is a complex question and the answer can vary depending on the current physiologic state of the patient (e.g., native cardiac function, hyperthermia, hypothermia, sepsis, ischemia).45 Most centers have settled on a “normal cardiac output” ECMO flow of 2.2 to 2.4 L/min/m2 as an initial goal, but this may not be possible in a large patient due to cannula size. Using markers of end-organ perfusion (mental status changes, lactate, mixed venous oxygen saturation, liver function

Fig. 85.3  The Maquet “Cardiohelp” system showing the pump, the combined pump head/oxygenator, and an arterial and venous cannula. (Courtesy MAQUET Cardiovascular, LLC, Wayne, NJ.)

Fig. 85.4  The Thoratec “CentriMag” pump (top left) with cart/control panel (top right), pump head (center) and oxygenator (bottom left). (Courtesy Thoratec Switzerland GmbH, Zürich, Switzerland.)

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85  •  Extracorporeal Membrane Oxygenation and Cardiac Devices

tests, creatinine), the flow goal can be changed as is feasible and necessary.46 A very important feature of ECMO is that the flow is not necessarily replacing the patient’s own cardiac output, either on the right side or the left. With VV ECMO, the circuit may oxygenate only a fraction of the total venous return so that there will still be significant shunt of poorly oxygenated blood through the lungs. With VA ECMO in severe cardiac failure, the circuit may supply the majority of blood flow but as cardiac function improves, native flow may become a significant proportion of total flow. In this case, similar to VV ECMO, the native blood flow through the lungs will dilute the gas exchange benefit provided by the VA ECMO. The effects of continuous flow rather than physiologic pulsatile flow on the vasculature and organ systems have been studied for short-term CPB runs and long-term durable LVADs, but not well for moderate duration (e.g., days to weeks) as seen in ECMO patients. Changes with durable LVADs include increased aortic valve regurgitation (if it is not opening), histological alterations in the aorta making it stiffer, gastrointestinal mucosal changes associated with increased bleeding and arteriovenous malformations, and acquired von Willebrand disease.47 Despite this, continuous flow nonpulsatile pumps have replaced pulsatile pumps in all settings of extracorporeal support because of their simplicity, durability, and the reduced trauma to formed elements of the blood; while still being investigated, pulsatile modifications or replacements are not on the clinical horizon. Hemolysis and issues related to coagulation top the list of things to follow closely while on a continuous flow circuit.48 Lactate dehydrogenase, haptoglobin, bilirubin, and free hemoglobin all remain important laboratory parameters to follow while on ECMO as a way to assess for hemolysis.49 

THE OXYGENATOR The membrane oxygenator is constructed to separate gas flow around microtubules of membrane through which the blood is passed, with additional circuitry permitting heat exchange. Traditionally “flow” refers to the flow of blood through the ECMO circuit, and the amount of air-oxygen mixture run through the oxygenator is the “sweep.” Oxygenation of the blood is determined by the FiO2 of the sweep gas mixture, and carbon dioxide removal is determined by the liters per minute of sweep, which is commonly in the range of 1 to 5 L/min depending in part on the patient’s metabolic state, size, native lung function, and ventilator settings. Oxygen transfer is very effective at normal blood flows, with post-oxygenator blood samples usually showing a partial pressure of oxygen (pO2) of more than 300 mm Hg when the sweep is 100% oxygen. As mentioned before, the patient’s blood gas values will be the result of a combination of the ECMO blood flow with its carbon dioxide and oxygen content, and the patient’s native circulation and gas exchange. Figs. 85.3 and 85.4 show the membrane oxygenator most widely used in North America, the Quadrox made by Getinge (the oxygenator and pump head are one unit with Maquet). With time (days to weeks) the oxygenator becomes less efficient at gas exchange due to build-up of fibrin and micro- or macrothrombi. Need for an increase in FiO2 or sweep should prompt an evaluation of

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the pressure drop across the membrane and drawing of a post-oxygenator blood gas. 

PULSATILITY WITH VA ECMO Pulsatility is a term used when describing the arterial waveform both in patients on ECMO and in those with durable LVADs. In the latter case, pulsatility with the cardiac cycle may be related both to LV ejection (i.e., independent of the LVAD) and to the increased filling of the ventricular assist device due to left ventricular contractility. Pulsatility can be detected in this latter case even without aortic valve opening. With VA ECMO the blood filling the ECMO circuit comes from the venous side so any pulsatility is due entirely to left ventricular ejection. When VA ECMO is initiated for cardiac decompensation, there is often very little pulsatility, but as the left ventricle recovers there is gradual recovery of a normal arterial waveform as native left ventricular ejection increases. With VV ECMO, there is normal filling of the left ventricle and arterial pulsatility is not affected. 

FLOW AND GAS EXCHANGE PHYSIOLOGY WITH VV ECMO When VV ECMO is instituted using two separate cannulae as shown in Fig. 85.5, there are two main limitations to its effectiveness. The first limitation is that the patient’s native cardiac output may be equal to or even greater than the ECMO flow, which is functionally a large shunt through the lungs. This may lead to inadequate oxygenation despite what appears to be appropriate pump and oxygenator function. The second limitation, due to proximity of the cannulae in the right atrium, is recirculation where some portion of the oxygenated blood being pumped into the patient is aspirated back into the inflow cannula rather than going through the tricuspid valve. This will also result in poor gas exchange.50,51 Use of the Avalon dual-lumen cannula (Figs. 85.6 and 85.7), where blood is aspirated from superior vena cava and inferior vena cava ports on one lumen and returned through a port positioned (using transesophageal echocardiography [TEE] guidance) such that it flows into the tricuspid valve, is less likely to cause recirculation. The improvement in gas exchange with VV ECMO may result in at least partial relief of pulmonary hypertension, possibly avoiding the need for right ventricular assist (i.e., V-PA or VA ECMO). If oxygenation is not adequately improved due to problems with recirculation or native cardiac output, either additional pulmonary measures such as increasing PEEP and/or prone positioning, or transfusing to a higher hemoglobin can improve oxygen delivery. Addition of a second ECMO circuit is also a possibility. 

FLOW AND GAS EXCHANGE PHYSIOLOGY WITH VA ECMO Peripheral VA ECMO usually is performed with a venous cannula advanced from the femoral vein into the right atrium, and a femoral arterial cannula that ends in the internal iliac artery (Fig. 85.8). Physiology of this arterial flow is complex in that it competes with native left ventricular ejection and also poses an afterload stress to the failing left ventricle.52,53 A principle of treating the failing heart is

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SECTION VII  •  Critical Care Medicine

VV-ECMO (1) Femoral vein

Internal jugular vein Returning oxygenated blood

Right atrium

De-oxygenated blood

Oxygenator

Pump

O2 In

CO2 Out

Fig. 85.5  Traditional venovenous extracorporeal membrane oxygenation (VV ECMO) circuit with inflow cannula in right femoral vein and outflow cannula in right internal jugular vein.

Fig. 85.6 Venovenous extracorporeal membrane oxygenation cannulation with the Avalon cannula, Maquet Inc.  The dual-lumen catheter is placed in the right internal jugular vein, with venous blood drawn from the superior and inferior vena cavae (blue arrow) into the extracorporeal membrane oxygenation circuit where it is oxygenated and pumped back into the right atrium directed toward the tricuspid valve (red arrow). (Courtesy MAQUET Cardiovascular, LLC, Wayne, NJ.)

to reduce wall stress and myocardial oxygen consumption and decrease pulmonary pressures; this is violated with VA ECMO. As discussed, it may be necessary to decompress the left ventricle with either an Impella or a surgically placed left ventricular vent if it is not possible to adequately improve left ventricular function with inotropes or to keep systemic pressures low. Competition with left ventricular ejection

means that the ECMO flow from the iliac artery may not reach the aortic arch, leaving the coronary and cerebral vessels hypoxic if there is poor native lung function. The place in the aorta where the ECMO flow meets the native flow (from the left ventricle-aortic valve) is sometimes called the “mixing cloud”; ideally this is as close to the heart as possible. For this reason the right radial artery, reflecting aortic blood flow closest to the heart and to the brain, rather than the left is the sampling site of choice.54 The phenomenon of poorly oxygenated cerebral and upper body oxygenation but good oxygenation in the lower body is called the “harlequin syndrome” (after an autonomic condition associated with asymmetric upper body sweating and flushing). Solutions to this problem include central cannulation (requiring sternotomy/thoracotomy) where the arterial cannula is in the ascending aorta, or addition of a second cannula in the right atrium to which part of the ECMO outflow is diverted, or VAV ECMO.55 This runs the risk of recirculation at the atrium, as well as too high a flow diverted away from the aorta and systemic circulation due to the low resistance of the pulmonary circulation. Partial clamping of this cannula to increase resistance will help drive blood to the systemic cannula. 

EXTRACORPOREAL MEMBRANE OXYGENATION FOR THE FAILING RIGHT HEART Clinical circumstances where only the right heart needs mechanical assist are less common than when the left ventricle or both ventricles are failing. Pulmonary hypertension with right ventricular failure in the pre-lung transplant

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85  •  Extracorporeal Membrane Oxygenation and Cardiac Devices

2705

VV-ECMO (2)

Returning oxygenated blood

De-oxygenated blood

Oxygenator

Pump

O2 In

CO2 Out

Fig. 85.7  Venovenous extracorporeal membrane oxygenation (VV ECMO) circuit using the Avalon cannula (Maquet Inc.).

Femoral vein

Right atrium

Internal iliac artery Femoral artery

Fig. 85.8  Venoarterial extracorporeal membrane oxygenation circuit with femoral cannulation.  The venous cannula (dark blue) is advanced to the junction of the inferior vena cava and right atrium, then attached to the pump inflow side of the circuit; the arterial cannula (red) is advanced to the iliac artery and attached to the oxygenator/pump outflow side of the circuit. Graft to pulmonary artery

Right atrium

V-PA ECMO

Returning oxygenated blood Superior vena cava

De-oxygenated blood

Oxygenator

Pump

O2 In

CO2 Out

Fig. 85.9 Venous-pulmonary artery extracorporeal membrane oxygenation circuit showing the venous cannula placed through the internal jugular vein to the right atrium, and the arterial cannula placed in a graft which is sewn to the pulmonary artery.

patient, or immediately post-durable LVAD placement where there is right ventricular failure are two examples. It is possible to support the right ventricle alone with V-PA ECMO where the venous cannula is in the right atrium and the “arterial” (outflow) cannula is surgically placed in the pulmonary artery via a graft (Fig. 85.9). If the lungs are intact, then an oxygenator may not be needed and support of the right ventricle can be accomplished by percutaneous devices (TandemHeart or Impella) or with the surgically placed ECMO, or, more correctly, right ventricular assist device (RVAD) circuit without an oxygenator. If there is also respiratory failure, then an oxygenator can be added to the circuit to provide true ECMO. This latter combination for right ventricular failure after LVAD provides a flexible means for managing the RV, lungs, and LV relatively independently.56 

Vascular Access for Extracorporeal Membrane Oxygenation Vascular cannulation location and technique vary depending on the type of support needed, the patient’s age, size, and clinical situation, and the need for imaging. Actual placement techniques include percutaneous vessel puncture (Seldinger technique) followed by guidewire, serial dilators, then finally the cannula. Alternatively, surgical cutdown and direct exposure can be used for peripheral vessels. Finally, surgical access to the right atrium, pulmonary artery, and ascending aorta requires sternotomy/thoracotomy. For percutaneous access there can be little doubt that ultrasound is a very valuable aid. Although there is little science to support this contention specifically for ECMO, in other settings there is compelling evidence.57,58 In order to verify placement of the venous cannula appropriately in the right atrium or at the junctions of the superior and inferior vena cavae with the right atrium, TEE is very helpful; similarly during placement of guidewires in peripheral vessels the use of TEE to verify wires in the aorta

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SECTION VII  •  Critical Care Medicine

or the right atrium is also very helpful. Finally, radiographic imaging may be used for guiding the wire used for right internal jugular (RIJ) vein placement with a dual-lumen catheter (AVALON) (see later), followed by TEE imaging to verify correct cannula placement. Vascular cannulation, especially arterial, requires heparinization during cannula placement and generally also requires two operators, for either percutaneous access (one person to handle guidewire, dilators, and intermittent vascular occlusion) or for cutdown (surgical assistance in addition to handling wire and dilators).

CANNULATION FOR VV ECMO In the original descriptions of VV ECMO in adults, two cannulae were used: one usually inserted in the right femoral vein and advanced to the junction between the inferior vena cava and the right atrium, and the other inserted in the RIJ vein and advanced through the superior vena cava into the right atrium (see Fig. 85.5). The largest possible cannulae are used to maximize flow (see later). When the cannulation of the IJV is technically not possible, an alternative configuration of VV ECMO support involves bilateral femoral cannulation. The tip of the drainage venous cannula is placed in the inferior vena cava while the tip of the outflow cannula is positioned into the right atrium. Either two-cannula technique presents a major drawback in terms of recirculation, where some portion of the oxygenated blood returned to the right atrium is reaspirated back into the inflow cannula. The Avalon ELITE is a dual-lumen cannula used in contemporary VV ECMO and many centers insert this catheter as the first choice if possible. With this cannula designed for RIJ placement, one lumen is used for inflow to the ECMO circuit; this lumen is designed to reside such that ports for aspiration of blood are in both the superior and vena cavae but not the right atrium. The second lumen where the pump outflow is directed is designed to be positioned in the right atrium aimed at the tricuspid valve (see Fig. 85.6). By use of inflow ports in the vena cavae and outflow in the right atrium directed at the tricuspid valve, blood recirculation is minimized. Use of echocardiography to place the cannula is important to be sure the inflow and outflow ports are in the correct position. TEE is especially useful in identifying the direction of the outflow jet of blood toward the tricuspid valve. In addition to the advantage of a single vascular access and minimal recirculation, the Avalon ELITE catheter improves patient comfort and facilitates mobilization and rehabilitation. It may also decrease the infectious risk associated with groin cannulation. The main limitation of this cannula is the maximum internal diameter achievable for pump inflow, as this is the main determinant of the flow rate. 

CANNULATION FOR VA ECMO The objective of VA ECMO is to provide oxygenated blood into systemic circulation so cannulation of a large artery for the outflow cannula is required. The femoral arteries are usually the first choice, and only in particular conditions (e.g., burns, open wounds, significant peripheral vascular disease) is the subclavian or axillary artery used. Vascular

From ECMO

To iliac artery/aorta

To leg

Fig. 85.10  Illustration of a “distal perfusion cannula” in the femoral artery.  The extracorporeal membrane oxygenation (ECMO) arterial cannula is placed in the artery and advanced to the internal iliac artery; the distal perfusion cannula is placed distal to the arterial ECMO cannula, aiming down the leg to provide additional perfusion.

cannulation for peripheral VA ECMO is therefore most commonly done using a venous cannula in the femoral vein advanced to the inferior vena cava/right atrium junction, and an arterial cannula entering the femoral artery with the tip residing in the common iliac artery (Fig. 85.8). As in VV ECMO, the maximum flow achievable is mostly determined by the internal diameter and length of the venous cannula. Placement of the femoral arterial cannula, as with the venous cannula, can be done using the Seldinger technique and serial dilators, or surgical cutdown. Imaging is not required; the venous cannula is placed by the inserter estimating the position of the inferior vena cava/ right atrium junction, with possible adjustment in position if needed at a later time. Surgical cutdown is required for accessing the subclavian or axillary artery. In an attempt to reduce the incidence of distal limb ischemia in the cannulated leg, small catheters (commonly referred to as distal perfusion catheters) can be placed distal to the ECMO arterial cannula, aiming down the leg (Fig. 85.10). Different parts of the distal limb arterial tree can be used as cannulation sites; the femoral artery is most often used but the superficial femoral artery or posterior tibial artery have also been described. Another possible approach to limit distal limb ischemia is to sew a synthetic graft on the femoral artery, and place the cannula in the graft rather than the vessel itself. This approach is always used for subclavian/axillary cannulation. In some centers the femoral artery and vein on the same side are cannulated; in others one cannula is placed in each extremity in order to avoid both reduced arterial perfusion and increased venous obstruction to the same extremity. The subclavian/axillary artery cannulation for VA ECMO has both advantages and drawbacks when compared to the femoral site. The subclavian artery is rarely affected by atherosclerotic lesions compared to the femoral artery; the

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85  •  Extracorporeal Membrane Oxygenation and Cardiac Devices

presence of a rich collateral flow may reduce the risk of distal extremity ischemia, bacterial contamination is less likely in this anatomic region, and it provides a systemic antegrade perfusion into the distal aortic arch (more proximal than the common iliac). The drawbacks include a potentially challenging surgical dissection in obese patients or in the presence of chest wall edema; the vessel is smaller than the femoral artery, and the limited reports for its use suggest an increased risk of hyperperfusion (rather than hypoperfusion) to the extremity.59 It is not used in acute emergent cannulations (e.g., unstable cardiogenic shock or cardiac arrest) as it is time-consuming. With axillary artery cannulation, the venous cannula is usually placed in the RIJ to obtain the potential benefit of patient mobility. Direct cardiac and aortic cannulation for VA ECMO is usually used for patients who cannot come off CPB in the operating room, using the CPB cannulas (central ECMO). The short, large-bore venous cannula permits excellent venous drainage. As oxygenated blood is returned to the ascending aorta, there is less concern for upper body hypoxemia. Other circumstances where central VA ECMO may be used include failure to obtain adequate flow from peripheral cannulation due to vessel size or disease, inadequate improvement in oxygenation (usually upper body), or vascular complications from peripheral VA ECMO. Central cannulation may also facilitate mobilization (e.g., out of bed) provided there is chest wall stability. 

CANNULATION FOR VPA ECMO Where there is right ventricular dysfunction or failure but intact left ventricular function, it would be ideal to avoid peripheral arterial cannulation (i.e., VA ECMO). If the lungs function adequately, a temporary RVAD could be used (e.g., Impella). If lung assist in addition to right ventricular assist is needed, then two options are (1) VPA ECMO using a graft placed surgically on the pulmonary artery for outflow and either a femoral or RIJ venous cannula, or (2) use of a Protek Duo (Cardiac Assist, Inc., Pittsburgh, PA) dual-lumen cannula similar to the Avalon but designed to have the tip reside in the pulmonary artery rather than the inferior vena cava. This cannula is placed via the RIJ with inflow ports in the right atrium and outflow ports in the pulmonary artery. It can provide both oxygenation and cardiac output for the pulmonary circulation but not require a systemic (arterial) cannula. Although there is less experience with the Protek Duo dual-lumen cannula than with the Avalon, it appears to be promising.60 

ALTERNATIVE CANNULATION STRATEGIES The cannulation strategy may not be fixed for the duration of the ECMO support; patient physiology or clinical condition and needs may change over time and modifications in ECMO configuration may occasionally be necessary. Conversion from the initial ECMO strategy to a different modality should always be strongly considered if the patient’s perfusion is inadequate, other goals of therapy are not being met, or if complications are arising as a result of the cannulation strategy, for example upper extremity hypoxemia with femoral VA ECMO61 or left ventricle distension with VAECMO.

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Conversion from VV to VA or from VA to VV ECMO, or the use of “hybrid” modes, may be desirable or necessary. Patients on VV ECMO can have hemodynamic deterioration (secondary to right, left, or bi‐ventricular failure) and require cardiocirculatory support. This can be achieved by the addition of an arterial perfusion cannula to the circuit. This ECMO configuration (also known as veno‐arterial‐ venous [VAV] ECMO) provides circulatory support through an arterial cannula introduced via the femoral or subclavian artery and is referred to as a hybrid approach.62 In situations where femoral VA ECMO does not provide sufficient oxygenated blood to the upper body (harlequin syndrome or north/south syndrome), an extra outflow cannula can be introduced to the right atrium via the RIJ, directing oxygenated blood into the pulmonary circulation (VAV ECMO hybrid approach).63 Alternatively, the femoral arterial cannula can be converted to a central (proximal aortic) position, requiring sternotomy or thoracotomy. When there is left ventricular distension with VA ECMO that cannot be overcome with inotropic drugs, then surgical placement of a left-sided inflow vent (usually in the left atrium or pulmonary vein) or insertion of an Impella may be necessary. Placement of additional cannulae of any kind must be approached with caution and the cannula flow monitored. Bleeding and clotting complications are compounded by use of additional cannulae. 

Monitoring on Extracorporeal Membrane Oxygenation PUMP PRESSURES AND FLOWS Understanding pressures and flows in the circuit is key to the management of an ECMO patient. The Maquet Cardiohelp device has built-in pressure transducers such that it measures the incoming pressure to the pump (the venous pressure), the pressure after the pump but before the oxygenator, and finally the pressure after the oxygenator (the outflow pressure). It also has a flow probe on the outflow cannula and a monitoring probe for air on the inflow cannula. In order to generate flow, the pump creates a negative pressure on the venous side, and this pressure is displayed on the console. As this pressure becomes more negative, concern arises regarding the volume status of the patient, or a cannula issue (e.g., obstruction, position). For the same flow a smaller cannula will require a greater negative pressure. Greater negative pressures usually precede the phenomenon of venous line “chatter” where flow is intermittently reduced or stopped when the inflow ports (in the superior vena cava and/or right atrium) are sucked against the venous wall due to inadequate volume status of the patient. The pressure change across the oxygenator is used to indicate the possibility of obstruction due to accumulation of fibrin or clot. Outflow cannula pressure, also displayed, can be elevated by cannula obstruction or high arterial pressure in the patient. Smaller cannulae require higher pressures to generate flow than larger ones. The Maquet Cardiohelp device also has a sampling port on the outflow cannula (post oxygenator) to allow blood gas analysis in the assessment of membrane function; declining pO2 or rising carbon dioxide partial pressure (pCO2) indicate a need

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SECTION VII  •  Critical Care Medicine

to change the oxygenator. There is no venous side sampling port; this may be useful on VV ECMO when there is suspicion of recirculation as described previously, but an access point pre-pump is a potential source for air entrainment. Flow probes can be applied to the branches of outflow cannulae connected to the circuit if these are employed. For example, a probe can be attached to the distal perfusion cannula used in peripheral VA ECMO or to the left ventricular vent in the centrally cannulated patient. A flow that drops abruptly may indicate occlusion of the line possibly from fibrin/thrombus formation. 

INTRAVASCULAR PRESSURES The arterial catheter offering both continuous blood pressure monitoring and sampling for blood gas analysis is an essential monitor in this patient population. As previously mentioned, all current forms of mechanical circulatory support (except intraaortic balloon pumps) provide continuous flow. In the patient on VA ECMO, the arterial line provides real-time information regarding the relative contribution of the native heart (pulsatile) versus the ECMO pump (nonpulsatile). Blood pressure cuffs (manual or automatic) are not able to provide this type of continuous monitoring and in the absence of pulsatility may not be able to measure the pressure at all. In the VA ECMO patient, the location of the arterial catheter is also important as mentioned; blood gas samples from left upper extremity catheters may not reflect the blood perfusing the coronaries and the brain, depending on the location of the “mixing cloud.” A central venous catheter provides access to administer vasoactive and inotropic drugs, and while the presence of a large cannula near or in the right atrium from which the ECMO pump is aspirating blood likely affects the pressure measurement, it can be a useful trend to monitor especially during weaning of flow. Although use of the pulmonary artery catheter in settings other than severe heart failure or cardiac surgery has greatly declined, it provides very useful information in the patient on VA ECMO. As discussed previously, a problem with VA ECMO is left ventricular distension due to the afterload stress; elevated or rising pulmonary artery pressure can be the first indication of this phenomenon, preceding pulmonary edema or even pulmonary hemorrhage. A rising mean pulmonary artery pressure may initiate a discussion regarding treatment with inotropic medications or placement of an Impella device, and be used to monitor the effectiveness of such treatment. During weaning trials when the ECMO pump flow is progressively reduced, the pulmonary artery catheter provides pressures on both sides of the heart and information about biventricular function. 

TISSUE OXIMETRY Tissue oximetry has been used for many years in the cardiac operating room to assess the adequacy of cerebral perfusion. Some ECMO centers are now using this technology to assess both cerebral oxygenation (in the sedated patient) as well as distal extremity perfusion where there is vessel cannulation.64 Tissue oximetry applied to the lower extremities may alert the provider of a mismatch between the cannulated extremity and the one that is not. This information, along

with clinical assessment (physical state of the extremity and pulses) and flow probes applied to the circuit can be used to guide intentional changes in flow or cannula reposition/ relocation. Decreasing the cannulated extremity perfusion can sometimes be necessary if there is edema or compartment syndrome. 

Anticoagulation There is continuous contact between the foreign surfaces of the circuit and the patient’s blood while on ECMO. Foreign surfaces are intrinsically thrombogenic, placing the circuit components at an increased risk for thrombosis and the patient at risk for embolic complications as well as reduced pump effectiveness. Both Maquet and Thoratec (Thoratec Corp., Pleasanton, CA) have tried to at least partly address this issue by coating the blood-contacting surfaces of the circuit components with proprietary heparin or heparin-albumin bonding processes. In some instances it is possible to run ECMO without anticoagulation at all or using low levels of anticoagulation, but this is not well studied.65,66 The membrane oxygenator and distal perfusion tubing used in femoral arterial cannulation are commonly reported sites for clot formation. In order to prevent thrombosis, the standard practice in North America is to administer antithrombotic therapy to a target below the levels used for CPB. The goal is to maintain the circuit with minimal thrombotic risk to the circuit and minimal hemorrhagic risk to the patient.67 Anticoagulation targets may be altered by the absence of circuit coating, the flow rate (higher target for lower flows), and patient-specific factors such as thrombocytopenia or other coagulation disorders. Unfractionated heparin (UFH) is the most commonly used anticoagulant for ECMO. Heparin works via antithrombin 3 (AT3); the heparin-AT3 complex then inhibits thrombin and factor Xa.68 Patients usually receive an initial UFH bolus of 50 to 100 units/kg at the time of cannulation. Dosing of UFH and measured anticoagulation status are institution specific. Problems with the use of UFH include its relative unpredictable bioavailability, the necessity for maintaining AT3 levels, and the occurrence of heparininduced thrombocytopenia with thrombosis (HITT).67,69 If the AT3 concentration in plasma is low, coagulation can occur even when large doses of heparin are given. The level of AT3 should be monitored, especially if there is an increasing need for heparin dose to achieve the desired anticoagulation. A low AT3 level can be treated by giving fresh frozen plasma or recombinant AT3. 

Therapeutic Monitoring of Unfractionated Heparin (Table 85.4) ACTIVATED CLOTTING TIME The activated clotting time (ACT) remains the most commonly utilized test for ECMO to guide UFH dosage, partly due to its being a point-of-care (POC) whole-blood test that

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85  •  Extracorporeal Membrane Oxygenation and Cardiac Devices

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TABLE 85.4  Anticoagulation Strategies Drug

Pro

Absolute/Relative Contraindications

No anticoagulation

Avoids anticoagulation in high-risk patients (hemorrhagic CVA, postoperative bleeding, etc.)

High risk for thrombus/embolism/short circuit life span

Unfractionated heparin

Most frequently used

HITT

Low-molecular-weight heparin

Infrequently used

Very dependent on renal function and patient weight, HITT

Argatroban

No concern for HITT

Hepatically cleared

Bivalirudin

No concern for HITT, short half-life

Renally cleared

Heparin bonded circuits

Decreases fibrin coating of circuits

HITT

HITT, Heparin-induced thrombocytopenia and thrombosis.

provides immediate results.70 Results of the ACT may be affected by factors other than UFH including anemia, hypofibrinogenemia, thrombocytopenia and coagulation factor deficiencies, hypothermia, and hemodilution. The UFH infusion is titrated to maintain the ACT at institution-specific levels, usually 1.5 times normal (180-220 s).18 

ACTIVATED PARTIAL THROMBOPLASTIN TIME The activated partial thromboplastin time (aPTT) is a laboratory standardized test used in adults where moderate doses of UFH are administered, and many adult ECMO programs use the aPTT instead of the ACT. The aPTT appears to more accurately reflect heparin anticoagulation in the critical care setting.71 Although POC devices are available, in most institutions the aPTT test is performed in the hospital laboratory with the attendant delay in obtaining results. Point-of-care devices which measure the aPTT are available, but these tests are done on whole blood samples and may not be as reliable as laboratory run tests. The laboratory aPTT may be affected by factors other than heparin effect such as factor deficiencies or presence of inhibitors. If the patient has a high platelet or white cell count, or is hypercoagulable, a large amount of heparin may be required to maintain the target aPTT. If the patient is thrombocytopenic, in renal failure, or has circulating fibrin split products, a reduced aPTT target may be appropriate. 

Diagnosis may be challenging with patients on ECMO, as thrombocytopenia from various origins (multiorgan dysfunction, sepsis, platelet activation and consumption by the ECMO circuit, bleeding, hemodilution) is common. Two types of HITT are described: type I is relatively benign, of nonimmune origin, and occurs early without thrombotic complications. It usually spontaneously resolves despite continued treatment with heparin; type II (HITT) is life threatening, of immune origin, and late onset. This syndrome leads to venous and/or arterial thrombosis.75 HITT treatment consists of stopping the UFH infusion and any contact with any form of heparin, avoiding platelet transfusions, and administering an alternative anticoagulant treatment such as one of the direct thrombin inhibitors, argatroban or bivalirudin. Argatroban is hepatically cleared whereas bivalirudin has a component of renal elimination; both drugs must be carefully dose-adjusted and monitored in critically ill patients. The Maquet circuit is always heparinbonded; it is possible to have non-heparin bonded circuitry using the Thoratec CentriMag system. As the effect of heparin-bonded circuitry on the development or maintenance of HITT is not well understood, if HITT is diagnosed there should be an effort to change to a non-heparin bonded circuit.76 

Weaning from Extracorporeal Membrane Oxygenation

ANTI-FACTOR XA (“HEPARIN LEVEL”)

WEANING FROM VA ECMO

Some institutions use the anti-factor Xa (anti-Xa) assay as the gold standard test to monitor therapeutic UFH dosing.72 The anti-Xa assay is not a measure of UFH concentration, but rather a measure of UFH effect, based on the ability of the UFH-AT3 complex to inhibit factor Xa.68 In contrast to the ACT and aPTT, the anti-Xa assay is specific to the anticoagulant effect of UFH and is not influenced by coagulopathy, thrombocytopenia, or dilution. Studies in this patient population have shown poor correlation of anti-Xa assay to ACT, suggesting the anti-Xa test to be preferable.73 In addition, the anti-Xa activity is associated with better accuracy and reproducibility than the aPTT in many clinical settings.74 

Weaning from VA ECMO is both an art and a science as every patient is different, and both pulmonary and cardiac weaning may be required. Many of the principles used in the cardiac operating room to separate a patient from CPB apply to the patient on VA ECMO. “Ramp” trials for VA ECMO patients where the ECMO support is reduced in a graded fashion while monitoring blood pressure, filling pressures, oxygenation, and often continuous echocardiography, are part of the management of the ECMO patient in the ICU.56 The pulsatility of the arterial waveform and how it is affected when the ECMO flow is reduced is also important. The desired response to a ramp trial is for the patient to maintain stable blood pressure and pulsatility on minimal inotropic and vasopressor support, with no significant increase in filling pressures, and preserved ventricular function by echocardiographic assessment. Another important consideration is resolution of pulmonary congestion or

HEPARIN-INDUCED THROMBOCYTOPENIA Heparin induced thrombocytopenia (HIT or HITT) is a relatively uncommon but severe complication of UFH therapy.

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edema before a ramp trial is performed. In general, once the patient is ready for weaning, there will be good pulsatility indicating the native cardiac output is perfusing the ascending aorta and great vessels; the blood gas from the right radial artery will reflect the native lung function. It may be desirable to reduce the FiO2 of the sweep, and reduce the sweep itself to confirm that the patient can oxygenate and ventilate adequately with their own lungs. This will require arterial blood gas analysis. Appropriate anticoagulation is important before the ramp trials; often a small bolus dose of heparin (e.g., 1000 units) is given prior to the trial, and as a general rule bedside ramp trials for VA ECMO in the ICU do not decrease the blood flow below 2 L/min. It is important to keep in mind that other cannulae that may come off the main ECMO circuit will also show a decrease in flow during ramp trials (distal perfusion cannulae or left ventricular vents). Providers should be mindful of this when managing patients with high-risk extremities or threatened limbs (large arterial cannulae and/or technical issues related to the distal perfusion cannula itself). Once it is clear that the ramp trial is successful, patients can then be taken to the operating room for decannulation where they are usually monitored with TEE and a pre-decannulation ramp trial is repeated. In some institutions decannulation can be performed in the bedside in the ICU with an operating roomlike setup for surgical repair of the artery. Weaning from VPA ECMO is similar to weaning from VA ECMO but the focus is on the right heart rather than the left heart, and with at least equal attention to the ability of the patient’s own lungs to adequately perform gas exchange. 

WEANING FROM VV ECMO VV ECMO ramp trials are often easier to perform as most of the information regarding the ability of the patient’s lungs to oxygenate and ventilate can be learned without a change in circuit flow. The purpose of the VV ECMO circuit is to perform gas exchange, but unlike VA ECMO the pump function provides no cardiac support; weaning trials therefore only need to be performed with changes in gas delivery across the membrane. Decreases in FiO2 of the sweep to reduce oxygenation support, and decreases in sweep itself across the membrane to reduce “ventilation” (CO2 removal) are all that is required to assess the adequacy of native lung function. Stopping the flow of oxygen/air across the membrane entirely may be performed as a last step prior to decannulation. This is called a “cap” trial whereby a cap is placed over the gas delivery inlet of the membrane valve itself. However, this process may damage the oxygenator, and if the trial is unsuccessful, may lead to a need to replace it. As a general principle, the sweep should not be reduced below 0.8 L/min for anything but a brief (few minutes) time. Venous ECMO cannulae can usually be removed in the ICU without the need for vascular repair. 

WEANING THE PATIENT WITH SEPARATE RVAD, LVAD, AND ECMO Some patients with biventricular failure and pulmonary edema may have cardiopulmonary support in a configuration of CentriMag LVAD, a CentriMag RVAD, and an oxygenator connected to the RVAD circuit. This cannulation strategy provides separate biventricular support with the

added benefit of an oxygenator in a VV ECMO configuration (i.e., LVAD plus VPA ECMO). It provides the ability to separately assess native lung function, right heart function, and left heart function during ramp trials. The VV ECMO weaning trial can then be performed as described, without a change in LVAD or RVAD blood flow. Reduction in FiO2 of the sweep and in the sweep itself are monitored with arterial blood gases, with the ability to remove the oxygenator but remain with biventricular support. The RVAD and LVAD can then be weaned separately as determined by the patient’s native right- and left-heart function. 

Complications of Extracorporeal Membrane Oxygenation It should not be surprising that there are many complications associated with all types of ECMO. These complications have been the subject of recent systematic reviews both for VA ECMO and for VV ECMO and are also described in the annual reports from ELSO. There is less experience with VPA and VAV ECMO configurations but many of the same issues exist with these more complex circuits. Complications of vascular cannulation, bleeding, or clotting from excessive or inadequate anticoagulation, neurologic injury (i.e., intracerebral bleed) usually related to coagulation management, and infection all occur with a significant incidence. With VA ECMO the majority of vascular complications are arterial; overall vascular complications with VV ECMO, especially the double-lumen Avalon, are less common. Renal injury occurring prior to initiation of ECMO or during an ECMO run is associated with a worse outcome.77 Vaquer and associates78 performed a systematic review and meta-analysis, selecting 12 studies from 2000 through 2015, including 1042 patients who underwent VV ECMO for ARDS. The mean hospital mortality in these studies was 38%, with a mean of 7% mortality due to complications. They found 40% of patients experienced medical complications, the most common of which was some kind of bleeding (29%). Intracerebral bleeding occurred in 5%. The 2016 ELSO report suggests a similar incidence of bleeding looking at adult ECMO for all respiratory indications. The ELSO report describes an incidence of 10% cannula infections with Vaquer and associates78 finding an incidence of all infections of 17%. The ELSO report does not indicate the mortality attributable to complications, but does give overall mortality of respiratory (VV) ECMO as 38% with 42% hospital mortality.18 For VA ECMO, the majority of which is femoral, the overall incidence of complications related to the ECMO itself is greater than for VV ECMO. This is illustrated in the 2016 ELSO report, and two recent independent reports—one single center and one meta-analysis. In the ELSO report of all cardiac ECMO in adults, the overall incidence of bleeding is 42% rather than 32% for VV ECMO. Infectious complications are comparable, but renal failure and hyperbilirubinemia are both greater. In a meta-analysis of 1866 patients who received VA ECMO for cardiac arrest or cardiogenic shock between 2005 and 2012, Cheng and associates35 found an incidence of major bleeding complications of 40% as well as a similar incidence of needing re-thoracotomy if central ECMO was used after cardiotomy. The incidence

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85  •  Extracorporeal Membrane Oxygenation and Cardiac Devices

of significant infection was 30% overall. Most strikingly the incidence of acute kidney injury was 55%, with 46% needing dialysis. They also found an incidence of lower extremity ischemia of 17%, compartment syndrome requiring fasciotomy of 10%, and amputation of 5%. They did not report mortality attributable to the ECMO. In a singlecenter report by Kaushal and associates,79 findings associated with hospital mortality included increasing age, the indication for ECMO being cardiac arrest, prolonged ECMO run, need for pre-ECMO dialysis (but not if initiated during ECMO), and limb ischemia.

PERIPHERAL EXTREMITY ISCHEMIA As indicated previously, limb ischemia, compartment syndrome requiring fasciotomy, and amputation are significant risks of peripheral cannulation for VA ECMO. Approaches to reducing this complication include careful selection of cannula size, meticulous technique in cannula insertion to prevent vessel injury, and interventions to improve flow to the distal extremity such as placement of a distal perfusion cannula or use of an arterial graft where the cannula resides, rather than the vessel itself. Compartment syndrome can be caused by a mismatch in venous outflow to the arterial inflow, which could potentially be avoided by placing the venous and arterial cannulae in different extremities. Other than use of these measures, attentive monitoring of the cannulated extremity for pulses, edema, pain, tissue tension, and temperature, and early intervention if there are ischemic changes, are essential. As mentioned, some centers use oximetry sensors to compare cannulated and noncannulated extremities. Hyperperfusion is a less common complication, usually associated with an arterial graft to either a femoral or axillary artery, which then provides the extremity with excessive perfusion leading to hyperemia, patient discomfort, and potentially, compartment syndrome. Chameogeorgakis and associates59 report that hyperperfusion syndrome occurs in 20% of patients when the axillary artery is used (with the cannula residing in an end-to-side graft to the artery), and 20% of these patients will go on to develop compartment syndrome. This is a reason why the axillary artery is not a vessel of first choice for VA ECMO. We have also seen this in a lower extremity in a small female patient who had an arterial graft due to small artery size, where the venous cannula was in the femoral vein on the same side. A number of reports have addressed the effectiveness of distal perfusion catheters80,81 and arterial grafts rather than vessel cannulation82,83; while these approaches reduce ischemic complications they do not eliminate them. Vigilance on the part of the care team and early intervention to change cannulation strategy are essential to prevent loss of the limb. 

The Anesthesiologist’s Role in Extracorporeal Membrane Oxygenation In many institutions, all ECMO cannulation, management, and decannulation is led by cardiac or thoracic surgeons.

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In others, respiratory ECMO is managed by a medical ICU team, even when the cannulation is performed by a surgeon. ECMO management in the ICU can involve cardiologists in patients needing cardiac support, pulmonary physicians in those needing only respiratory support, and critical care physicians of all backgrounds in all patients on ECMO. A critical care anesthesiologist who is also cardiac trained is an ideal participant in the management of these patients as many aspects of ECMO are related to CPB. In some institutions nonsurgical members of the critical care team may be involved in the cannulation and initiation of ECMO as well as its ongoing management. The concept of an ECMO team has been described by two of the authors of this chapter, suggesting that outcomes of ECMO can be significantly improved with the strong engagement of cardiac anesthesiologists and critical care anesthesiologists.84 This may be particularly important in “ECMO to go” where a team from the ECMO center travels to an outside hospital to initiate and then manage ECMO as well as other life-support modalities during transfer. The European experience indicates a stronger role for anesthesiologists in this process than in the United States.85 Management of patients needing what is essentially a surgical intervention for urgent cardiorespiratory support is very much part of the practice of cardiothoracic anesthesiology, as is the invaluable intraoperative guidance provided by TEE evaluation and monitoring of not only cardiac function, but placement, advancement, and correct positioning of cannulae.86 Similarly, during decannulation from cardiac ECMO, echocardiographic evaluation of the heart is essential during and after support has been removed.

Acknowledgment The editors and publisher would like to thank Drs. Zaccaria Ricci, Stefano Romagnoli, and Claudio Ronco for contributing a chapter on this topic in the prior edition of this work. It has served as the foundation for the current chapter. Complete references available online at expertconsult.com.

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References 1. Nazarnia S, Subramaniam K. Pro: Veno-arterial Extracorporeal Membrane Oxygenation (ECMO) should be used routinely for bilateral lung transplantation. J Cardiothorac Vasc Anesth. 2017;31(4): 1505–1508. 2. Ju Z, et al. Effects of pumpless extracorporeal lung assist on hemodynamics, gas exchange and inflammatory cascade response during experimental lung injury. Exp Ther Med. 2018;15(2):1950–1958. 3. Vasanthan V, et  al. Extended bridge to heart and lung transplantation using pumpless extracorporeal lung assist. Can J Cardiol. 2017;33(7):950.e11–950.e13. 4. Kirklin JW, et al. Studies in extracorporeal circulation. I. Applicability of Gibbon-type pump-oxygenator to human intracardiac surgery: 40 cases. Ann Surg. 1956;144(1):2–8. 5. Warden HE, et al. Direct vision intracardiac surgery by means of a reservoir of “arterialized venous” blood; description of a simple method and report of the first clinical case. J Thorac Surg. 1955;30(6):649– 656. discussion, 656-7. 6. Iwahashi H, Yuri K, Nose Y. Development of the oxygenator: past, present, and future. J Artif Organs. 2004;7(3):111–120. 7. Hill JD, et  al. Prolonged extracorporeal oxygenation for acute posttraumatic respiratory failure (shock-lung syndrome). Use of the Bramson membrane lung. N Engl J Med. 1972;286(12):629–634. 8. Bartlett RH. Esperanza: the first neonatal ECMO patient. Asaio j. 2017;63(6):832–843. 9. Bartlett RH, et  al. Extracorporeal circulation in neonatal respiratory failure: a prospective randomized study. Pediatrics. 1985;76(4): 479–487. 10. UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. UK Collaborative ECMO Trail Group. Lancet. 1996;348(9020):75–82. 11. Green TP, et al. The impact of extracorporeal membrane oxygenation on survival in pediatric patients with acute respiratory failure. Pediatric Critical Care Study Group. Crit Care Med. 1996;24(2):323–329. 12. Zapol WM, et  al. Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study. JAMA. 1979;242(20):2193–2196. 13. Peek GJ, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet. 2009;374(9698):1351–1363. 14. Davies A, et  al. Extracorporeal membrane oxygenation for 2009 influenza A(H1N1) acute respiratory distress syndrome. JAMA. 2009;302(17):1888–1895. 15. Combes A, et  al. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. N Engl J Med. 2018;378(21):1965–1975. 16. Mi MY, Matthay MA, Morris AH. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. N Engl J Med. 2018;379(9):884–887. 17. Bartlett RH. Extracorporeal membrane oxygenation for acute respiratory distress syndrome: EOLIA and beyond. Crit Care Med. 2019;47(1):114–117. 18. ELSO. 2018. https//www.elso.org/. 19. Murray JF, et al. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis. 1988;138(3):720–723. 20. Ranieri VM, et al. Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012;307(23):2526–2533. 21. Combes A, et al. Extracorporeal membrane oxygenation: beyond rescue therapy for acute respiratory distress syndrome? Curr Opin Crit Care. 2017;23(1):60–65. 22. Mason DP, et al. Should lung transplantation be performed for patients on mechanical respiratory support? the US experience. J Thorac Cardiovasc Surg. 2010;139(3):765–773.e1. 23. Salam S, et  al. Lung transplantation after 125 days on ECMO for severe refractory hypoxemia with no prior lung disease. Asaio j. 2017;63(5):e66–e68. 24. Tsiouris A, Budev MM, Yun JJ. Extracorporeal membrane oxygenation as a bridge to lung transplantation in the United States: a multicenter survey. Asaio j. 2018;64(5):689–693. 25. Raleigh L, Ha R, Hill C. Extracorporeal membrane oxygenation applications in cardiac critical care. Semin Cardiothorac Vasc Anesth. 2015;19(4):342–352.

26. Loor G, Simpson L, Parulekar A. Bridging to lung transplantation with extracorporeal circulatory support: when or when not? J Thorac Dis. 2017;9(9):3352–3361. 27. Machuca TN, et al. Outcomes of intraoperative extracorporeal membrane oxygenation versus cardiopulmonary bypass for lung transplantation. J Thorac Cardiovasc Surg. 2015;149(4):1152–1157. 28. Hoetzenecker K, et al. Intraoperative extracorporeal membrane oxygenation and the possibility of postoperative prolongation improve survival in bilateral lung transplantation. J Thorac Cardiovasc Surg. 2018;155(5):2193–2206. e3. 29. Thiagarajan RR, et al. Extracorporeal Life Support Organization registry international report 2016. Asaio j. 2017;63(1):60–67. 30. Gilotra NA, Stevens GR. Temporary mechanical circulatory support: a review of the options, indications, and outcomes. Clin Med Insights Cardiol. 2014;8(suppl 1):75–85. 31. Touchan J, Guglin M. Temporary mechanical circulatory support for cardiogenic shock. Curr Treat Options Cardiovasc Med. 2017;19(10):77. 32. Khorsandi M, et  al. Extra-corporeal membrane oxygenation for refractory cardiogenic shock after adult cardiac surgery: a systematic review and meta-analysis. J Cardiothorac Surg. 2017;12(1):55. 33. Wang L, Wang H, Hou X. Clinical outcomes of adult patients who receive extracorporeal membrane oxygenation for postcardiotomy cardiogenic shock: a systematic review and meta-analysis. J Cardiothorac Vasc Anesth. 2018;32(5):2087–2093. 34. den Uil CA, et  al. Short-term mechanical circulatory support as a bridge to durable left ventricular assist device implantation in refractory cardiogenic shock: a systematic review and meta-analysis. Eur J Cardiothorac Surg. 2017;52(1):14–25. 35. Cheng R, et al. Clinical outcomes in fulminant myocarditis requiring extracorporeal membrane oxygenation: a weighted meta-analysis of 170 patients. J Card Fail. 2014;20(6):400–406. 36. Debaty G, et  al. Prognostic factors for extracorporeal cardiopulmonary resuscitation recipients following out-of-hospital refractory cardiac arrest. A systematic review and meta-analysis. Resuscitation. 2017;112:1–10. 37. Holmberg MJ, et al. Extracorporeal cardiopulmonary resuscitation for cardiac arrest: a systematic review. Resuscitation. 2018;131:91–100. 38. Schmidt M, et al. Predicting survival after extracorporeal membrane oxygenation for severe acute respiratory failure. The Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) score. Am J Respir Crit Care Med. 2014;189(11):1374–1382. 39. Schmidt M, et al. Predicting survival after ECMO for refractory cardiogenic shock: the survival after veno-arterial-ECMO (SAVE)-score. Eur Heart J. 2015;36(33):2246–2256. 40. Courtwright AM, et al. Ethics committee consultation and extracorporeal membrane oxygenation. Ann Am Thorac Soc. 2016;13(9):1553– 1558. 41. Abrams D, et al. Position paper for the organization of ECMO programs for cardiac failure in adults. Intensive Care Med. 2018;44(6):717–729. 42. Brodie D, et al. Treatment limitations in the era of ECMO. Lancet Respir Med. 2017;5(10):769–770. 43. J, H. Adult cardiac support Ann Arbor, Michigan. In: Annich GM, Lynch WR, MacLaren G, et al., eds. ECMO. Extracorporeal Cardiopulmonary Support in Critical Care. 4th ed. ; 2012:323–330. 44. Sunagawa K. Guyton’s venous return curves should be taught at medical schools (complete English translation of Japanese version). J Physiol Sci. 2017;67(4):447–458. 45. R, B. Physiology of extracorporeal life support Ann Arbor, Michigan. In: Annich GM, Lynch WR, MacLaren G, et al., eds. ECMO. Extracorporeal Cardiopulmonary Support in Critical Care. 4th ed. ; 2012. 46. Tominaga R, et al. Chronic nonpulsatile blood flow. III. Effects of pump flow rate on oxygen transport and utilization in chronic nonpulsatile biventricular bypass. J Thorac Cardiovasc Surg. 1996;111(4):863– 872. 47. Patel SR, Jorde UP. Creating adequate pulsatility with a continuous flow left ventricular assist device: just do it!. Curr Opin Cardiol. 2016;31(3):329–336. 48. Slaughter MS. Hematologic effects of continuous flow left ventricular assist devices. J Cardiovasc Transl Res. 2010;3(6):618–624. 49. O’Brien C, et al. Centrifugal pumps and hemolysis in pediatric extracorporeal membrane oxygenation (ECMO) patients: an analysis of Extracorporeal Life Support Organization (ELSO) registry data. J Pediatr Surg. 2017;52(6):975–978.

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2712.e2 References 50. Xie A, Yan TD, Forrest P. Recirculation in venovenous extracorporeal membrane oxygenation. J Crit Care. 2016;36:107–110. 51. Pierrakos C, et  al. Injection of agitated saline to detect recirculation with transthoracic echocardiography during venovenous extracorporeal oxygenation: a pilot study. J Crit Care. 2017;37:60–64. 52. Fuhrman BP, et al. Pathophysiology of cardiac extracorporeal membrane oxygenation. Artif Organs. 1999;23(11):966–969. 53. Brasseur A, et  al. Hybrid extracorporeal membrane oxygenation. J Thorac Dis. 2018;10(suppl 5):S707–s715. 54. Bartlett RH. Management of blood flow and gas exchange during ECLS Ann Arbor, Michigan. In: 4th ed. Annich GM, Lynch WR, MacLaren G, et al., eds. ECMO. Extracorporeal Cardiopulmonary Support in Critical Care; 2012:149–156. 55. Cakici M, et  al. Controlled flow diversion in hybrid venoarterialvenous extracorporeal membrane oxygenation. Interact Cardiovasc Thorac Surg. 2018;26(1):112–118. 56. Reynolds HR, Hochman JS. Cardiogenic shock: current concepts and improving outcomes. Circulation. 2008;117(5):686–697. 57. Seto AH, et  al. Real-time ultrasound guidance facilitates femoral arterial access and reduces vascular complications: FAUST (Femoral Arterial Access With Ultrasound Trial). JACC Cardiovasc Interv. 2010;3(7):751–758. 58. Schmidt GA, et  al. Ultrasound-guided vascular access in critical illness. Intensive Care Med. 2019. 59. Chamogeorgakis T, et al. Outcomes of axillary artery side graft cannulation for extracorporeal membrane oxygenation. J Thorac Cardiovasc Surg. 2013;145(4):1088–1092. 60. Ravichandran AK, et  al. Outcomes with the tandem Protek duo dual-lumen percutaneous right ventricular assist device. Asaio j. 2018;64(4):570–572. 61. Biscotti M, et  al. Hybrid configurations via percutaneous access for extracorporeal membrane oxygenation: a single-center experience. Asaio j. 2014;60(6):635–642. 62. Ius F, et  al. Veno-veno-arterial extracorporeal membrane oxygenation for respiratory failure with severe haemodynamic impairment: technique and early outcomes. Interact Cardiovasc Thorac Surg. 2015;20(6):761–767. 63. Werner NL, et al. The University of Michigan experience with venovenoarterial hybrid mode of extracorporeal membrane oxygenation. Asaio j. 2016;62(5):578–583. 64. Steffen RJ, et  al. Using near-infrared spectroscopy to monitor lower extremities in patients on venoarterial extracorporeal membrane oxygenation. Ann Thorac Surg. 2014;98(5):1853–1854. 65. Galvagno SM, et al. Long term veno-venous extracorporeal life support without intravenous anticoagulation for diffuse alveolar hemorrhage. Perfusion. 2019. 66. Raman J, et  al. A comparison of low and standard anti-coagulation regimens in extracorporeal membrane oxygenation. J Heart Lung Transplant. 2019. 67. Kawahito K, Nose Y. Hemolysis in different centrifugal pumps. Artif Organs. 1997;21(4):323–326. 68. Hirsh J, et  al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest. 2001;119(suppl 1):64s–94s. 69. Annich GM. Extracorporeal life support: the precarious balance of hemostasis. J Thromb Haemost. 2015;13(suppl 1):S336–S342.

70. Horton S, Augustin S. Activated clotting time (ACT). Methods Mol Biol. 2013;992:155–167. 71. De Waele JJ, et  al. The use of the activated clotting time for monitoring heparin therapy in critically ill patients. Intensive Care Med. 2003;29(2):325–328. 72. Becker RC. Cell-based models of coagulation: a paradigm in evolution. J Thromb Thrombolysis. 2005;20(1):65–68. 73. Delmas C, et al. Anticoagulation monitoring under ECMO support: a comparative study between the activated coagulation time and the anti-Xa activity assay. J Intensive Care Med. 2018. 74. Burki S, et al. Accuracy, reproducibility and costs of different laboratory assays for the monitoring of unfractionated heparin in clinical practice: a prospective evaluation study and survey among Swiss institutions. BMJ Open. 2018;8(6):e022943. 75. Koster A, et  al. Impact of heparin-induced thrombocytopenia on outcome in patients with ventricular assist device support: singleinstitution experience in 358 consecutive patients. Ann Thorac Surg. 2007;83(1):72–76. 76. Natt B, et al. Suspected heparin-induced thrombocytopenia in patients receiving extracorporeal membrane oxygenation. J Extra Corpor Technol. 2017;49(1):54–58. 77. Kilburn DJ, Shekar K, Fraser JF. The complex relationship of extracorporeal membrane oxygenation and acute kidney injury: causation or association? Biomed Res Int. 2016;2016:1094296. 78. Vaquer S, et al. Systematic review and meta-analysis of complications and mortality of veno-venous extracorporeal membrane oxygenation for refractory acute respiratory distress syndrome. Ann Intensive Care. 2017;7(1):51. 79. Kaushal M, et  al. Patient Demographics and Extracorporeal Membranous Oxygenation (ECMO)-related complications associated with survival to discharge or 30-day survival in adult patients receiving Venoarterial (VA) and Venovenous (VV) ECMO in a Quaternary Care Urban Center. J Cardiothorac Vasc Anesth. 2018. 80. Ranney DN, et al. Vascular complications and use of a distal perfusion cannula in femorally cannulated patients on extracorporeal membrane oxygenation. Asaio j. 2018;64(3):328–333. 81. Lamb KM, et  al. Arterial protocol including prophylactic distal perfusion catheter decreases limb ischemia complications in patients undergoing extracorporeal membrane oxygenation. J Vasc Surg. 2017;65(4):1074–1079. 82. Calderon D, et al. Modified T-graft for extracorporeal membrane oxygenation in a patient with small-caliber femoral arteries. Tex Heart Inst J. 2015;42(6):537–539. 83. Jackson KW, et  al. Side-arm grafts for femoral extracorporeal membrane oxygenation cannulation. Ann Thorac Surg. 2012;94(5):e111– e112. 84. Dalia AA, et  al. Extracorporeal membrane oxygenation is a team sport: institutional survival benefits of a formalized ECMO team. J Cardiothorac Vasc Anesth. 2018. 85. Nwozuzu A, Fontes ML, Schonberger RB. Mobile extracorporeal membrane oxygenation teams: the North American versus the European experience. J Cardiothorac Vasc Anesth. 2016;30(6):1441–1448. 86. Combes A, et  al. Position paper for the organization of extracorporeal membrane oxygenation programs for acute respiratory failure in adult patients. Am J Respir Crit Care Med. 2014;190(5):488–496.

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86

Cardiopulmonary Resuscitation and Advanced Cardiac Life Support YAFEN LIANG, ALA NOZARI, AVINASH B. KUMAR, and STEN RUBERTSSON

KEY POINTS

□ Cardiac

arrest is a major public health issue worldwide. Despite significant advances in resuscitation science, survival rates remain considerably low. Improvement of patient survival and neurologic outcome relies on the development and implementation of vigorous and evidencebased resuscitation guidelines involving basic life support (BLS), advanced cardiovascular life support, and post–cardiac arrest care. □ In cardiac arrests without hypoxic causes, oxygen content in the lungs at the time of cardiac arrest is usually sufficient for maintaining acceptable arterial oxygen content during the first several minutes of cardiopulmonary resuscitation (CPR). Blood flow rather than arterial oxygen content is the limiting factor for oxygen delivery to coronary, cerebral, and systemic circulation during CPR. Thus rescue breaths are less important than initiating effective chest compressions as soon as possible after sudden cardiac arrest (SCA). □ The mechanism through which chest compressions generate blood flow can be explained by the thoracic or cardiac pump theories. The provision of uninterrupted, high-quality chest compressions after SCA is associated with better survival and neurologic outcomes than delaying chest compressions for airway intervention in both adult and pediatric patients. Circulation, airway, breathing has replaced airway, breathing, circulation. □ A single resuscitative shock should be delivered at the earliest possible opportunity after the recognition of cardiac arrest, followed immediately by the resumption of chest compressions without postshock cardiac rhythm analysis. Outcome studies have failed to demonstrate the benefit of a period of chest compressions before shock or for a series of stacked shocks. □ Vasopressor medications during resuscitation have been de-emphasized in deference to providing uninterrupted, high-quality chest compressions. Standard-dose epinephrine (1 mg every 3-5 minutes) is recommended for patients in cardiac arrest. Vasopressin offers no advantage as a substitute for epinephrine in cardiac arrest and has been removed from the adult cardiac arrest algorithm. Steroids combined with a vasopressor bundle or cocktail of epinephrine and vasopressin improved return of spontaneous circulation (ROSC) compared with the use of placebo and epinephrine alone in out-of-hospital cardiac arrest. □ Continuous-flow left ventricular assist devices result in an unconventional, unique physiologic state of hemodynamically stable pulseless electric activity. Assessment of adequate tissue perfusion is the most important factor in determining the need for circulatory assistance such as chest compressions. Total artificial hearts (TAHs) are refractory to chest compressions, antiarrhythmic drugs, and electric therapy. Vasopressor medications are contraindicated because they increase afterload, result in complete hemodynamic collapse with pulmonary edema, and worsen TAH function. □ In consideration of opioid overdose epidemiology, patients with known or suspected opioid addiction who are in cardiac or respiratory arrest should receive intravenous, intramuscular, or intranasal naloxone in addition to standard BLS care. □ For nonshockable rhythms, the essential step will be early detection and correction of potentially reversible underlying causes. Ultrasound technology is used to assess the etiology and the management of these patients, as well as to predict the possibility of ROSC and to justify the termination of resuscitative efforts. However, utilization of this technique should not interfere with other resuscitation efforts such as chest compressions. □ Asphyxiation is a much more common cause of cardiac arrest in infants and children than the primary cardiac event, and airway management and ventilation are therefore more important during the resuscitation of children. However, in order to facilitate training, retention, and implementation of resuscitation guidelines, the pediatric resuscitation guidelines follow similar principles as adult guidelines. 2713

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2714

SECTION VII  •  Critical Care Medicine

□ Targeted

temperature management (TTM) applied to comatose survivors of out-of-hospital cardiac arrests has significantly improved the neurologic recovery in those surviving to hospital discharge. A target temperature between 32°C and 36°C is recommended for at least 24 hours, and normothermia (to treat fever) should be maintained beyond this window. Prognostication should not occur until 72 hours after ROSC or, if TTM is provided, 72 hours after completion of TTM. □ Most deaths after SCA in both adults and children typically occur within the first 24 hours. Coordinated postresuscitation care involving access to coronary catheterization capabilities and intensive care management that includes TTM represents the best chance survivors of SCA have for optimal neurologic and cardiac recovery. □ New technologies such as individualized CPR, extracorporeal CPR, controlled automated reperfusion of the whole body (CARL), and emergency preservation for delayed resuscitation may offer opportunities for patients suffering from cardiac arrest.

Sudden Cardiac Arrest and Cardiopulmonary Resuscitation BRIEF HISTORY AND PHYSIOLOGIC CONSIDERATIONS Cardiac arrest is a major public health issue, with more than 500,000 deaths per year in the United States.1-3 Seventy percent of out-of-hospital cardiac arrests (OHCAs) occur at home, and approximately 50% are unwitnessed. Despite significant advances in resuscitation science, survival rates remain considerably low for both OHCA and in-hospital cardiac arrest (IHCA). Only 10.4% of adult patients with nontraumatic cardiac arrest who receive resuscitative efforts from emergency medical services (EMS) survive to hospital discharge.4 IHCA has a better outcome, with 22.3% to 25.5% of adults surviving to hospital discharge.5 Statistics for Europe are similar, with OHCA as one of the leading causes of death in Europe and an overall survival rate of 2.6% to 10.7%.6-8 Sudden cardiac arrest (SCA) is a complex and dynamic process. Forward systemic arterial blood flow continues after cardiac arrest until the pressure gradient between the aorta and right heart reaches equilibrium. A similar process occurs with forward pulmonary blood flow between the pulmonary artery and the left atrium. As the arteriovenous pressure gradient diminishes, the left heart filling is decreased, right heart filling is increased, and the venous capacitance vessels become increasingly distended. When the arterial and venous pressures reach equilibration (approximately 5 minutes after no-flow cardiac arrest), coronary perfusion and cerebral blood flows stop. The goal of cardiopulmonary resuscitation (CPR) thus is to maintain oxygen and blood supply to vital organs, restore spontaneous circulation, minimize postresuscitation organ injury, and ultimately improve the patient’s survival and neurologic outcome. The history of CPR traces back to the biblical age. However, the more contemporary approach to CPR dates back to the 1950s.9 James Elam and Peter Safar showed that the earlier methods of resuscitation with chest-pressure and arm-lift were ineffective, and that mouth-to-mouth ventilation was an easily learned and life-saving approach. William B. Kouwenhoven of Johns Hopkins University is credited with introducing a formalized system of chest compressions. Claude Beck of Case Western Reserve University and Paul Zoll of Beth Israel Hospital introduced defibrillation to break ventricular fibrillation.

In 1966 the National Academy of Sciences National Research Council conference generated consensus standards for the performance of CPR and opened the modern era of CPR. The mechanism through which chest compressions generate blood flow can be explained by the thoracic or cardiac pump theories. The thoracic pump theory postulates that blood flows from the thorax when the intrathoracic vascular pressures exceed extrathoracic pressures.10 The venous-to-arterial blood flow direction is a result of venous valves that prevent retrograde flow at the thoracic inlet. According to the cardiac pump theory, blood flow is generated as a result of actual compression of the heart between the sternum and the vertebral column.11,12 Transesophageal echocardiography (TEE) during CPR in humans allowed direct visualization of changes in cardiac chambers and valve functions during chest compressions, as well as the direction of blood flow. During chest compression, the tricuspid and mitral valves close, the left and right ventricular volumes decrease, and blood is ejected into the arterial system.13,14 During the decompression phase of CPR, the pressure gradient between the systemic venous system and thoracic cavity facilitates blood flow into the heart chambers. Systemic blood flow during CPR is dependent on effective chest compressions but also on the venous blood return to the heart. Therefore, even modest increases in the intrathoracic pressure, as might occur with overzealous ventilation during CPR, will impair venous return and negatively impact systemic, coronary, and cerebral perfusions and also reduce the chances of return of spontaneous circulation (ROSC). Cardiac output during CPR with effective, uninterrupted chest compression is at best 25% to 30% of the normal spontaneous circulation. In cardiac arrests without hypoxic causes (e.g., suffocation, drowning), oxygen content in the lungs at the time of cardiac arrest is usually sufficient for maintaining acceptable arterial oxygen content during the first several minutes of CPR. Blood flow rather than arterial oxygen content is the limiting factor for oxygen delivery to coronary, cerebral, and systemic circulation during CPR. Thus rescue breaths are less important than initiating effective chest compressions as soon as possible after SCA. Understanding the pathophysiology during SCA and CPR is vitally important. The actual improvement of patient outcome, however, relies on development and implementation of vigorous and evidence-based resuscitation guidelines. The more recent recommendations, the 2015 American Heart Association Guidelines for Cardiopulmonary Resuscitation

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86  •  Cardiopulmonary Resuscitation and Advanced Cardiac Life Support

2715

Fig. 86.1  Basic Life Support Healthcare Provider Adult Cardiac Arrest Algorithm—2015 Update. AED, Automated external defibrillator; CPR, cardiopulmonary resuscitation. (From Kleinman ME, Brennan EE, Goldberger ZD, et al. Part 5: Adult Basic Life Support and Cardiopulmonary Resuscitation Quality: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132[18 suppl 2]: S414–S435.)

and Emergency Cardiovascular Care (2015 American Heart Association [AHA] Guidelines for CPR and ECC), represent the fourth internationally recognized resuscitation guidelines from the AHA and the European Resuscitation Council; therefore, these guidelines are practiced in many countries and medical specialties. More recently, the guidelines underwent a major updating process change. Instead of updating guidelines every 5 years, the new process involves a continuous evidence evaluation process and annual guidelines update, with the most recent one being the 2017 AHA Guidelines for CPR and ECC update. The intent of this chapter is to review the history, rationale, and current understanding of both basic life support (BLS) and advanced cardiovascular life support (ACLS) techniques based on the most recent updated guidelines. 

BASIC LIFE SUPPORT BLS is, according to the Carnegie Safety Institute, the foundation for saving lives after cardiac arrest. Fundamental aspects of adult BLS include immediate recognition of SCA and activation of the emergency response system, early CPR, and rapid defibrillation with an automated external defibrillator (AED). Initial recognition and response to heart attack and stroke are also considered as parts of the BLS. All BLS interventions are time sensitive for preventing SCA, terminating SCA, or supporting circulation until spontaneous circulation is restored. The steps of the adult BLS algorithm for healthcare providers are illustrated in Fig. 86.1.

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2716

SECTION VII  •  Critical Care Medicine

TABLE 86.1  Summary of Components of High-Quality Cardiopulmonary Resuscitation Component

Adults and Adolescents

Children (Age 1 Year to Infants (Age Less Than 1 Year, ExcludPuberty) ing Newborns)

Scene safety

Make sure the environment is safe for rescuers and victim

Recognition of cardiac arrest

Check for responsiveness No breathing or only gasping (i.e., no normal breathing) No definite pulse felt within 10 s (Breathing and pulse check can be performed simultaneously in less than 10 s)

Activation of emergency response system

If you are alone with no mobile phone, leave the victim to activate the emergency response system and get the AED before beginning CPR Otherwise, send someone and begin CPR immediately; use the AED as soon as it is available

Witnessed collapse Follow steps for adults and adolescents on the left Unwitnessed collapse Give 2 min of CPR Leave the victim to activate the emergency response system and get the AED Return to the child or infant and resume CPR; use the AED as soon as it is available

Compression-ventilation ratio without advanced airway

1 or 2 rescuers 30:2

1 rescuer 30:2 2 or more rescuers 15:2

Compression-ventilation ratio with advanced airway

Continuous compressions at a rate of 100-120/min Give 1 breath every 6 s (10 breaths/min)

Compression rate

100-120/min

Compression depth

At least 2 inches (5 cm)*

At least one-third AP diameter of chest About 2 inches (5 cm)

At least one-third AP diameter of chest About 1 1⁄2 inches (4 cm)

Hand placement

2 hands on the lower half of the breastbone (sternum)

2 hands or 1 hand (optional for very small child) on the lower half of the breastbone (sternum)

1 rescuer 2 fingers in the center of the chest, just below the nipple line 2 or more rescuers 2 thumb–encircling hands in the center of the chest, just below the nipple line

Chest recoil

Allow full recoil of chest after each compression; do not lean on the chest after each compression

Minimizing interruptions

Limit interruptions in chest compressions to less than 10 s

*Compression depth should be no more than 2.4 inches (6 cm). AED, Automated external defibrillator; AP, anteroposterior; CPR, cardiopulmonary resuscitation. From Kleinman ME, Brennan EE, Goldberger ZD, et al. Part 5: Adult Basic Life Support and Cardiopulmonary Resuscitation Quality: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132[18 suppl 2]:S414–S435. https://eccguidelines.heart.org/index.php/circulation/cpr-ecc-guidelines-2/part-5-adult-basic-life-support-and-cardiopulmonary-resuscitation-quality/.

The 2015 AHA Guidelines for CPR and ECC on BLS continue to emphasize the simplified universal adult BLS algorithm. The recommended sequence for a single rescuer is to initiate chest compressions before giving rescue breaths (circulation, airway, breathing [C-A-B] rather than airway, breathing, circulation [A-B-C]) to reduce any delay in providing effective chest compressions in adults without any known information of possible asphyxiation as the cause of cardiac arrest. The single rescuer should begin CPR with 30 chest compressions followed by 2 breaths. The guideline, in addition, also emphasizes a simultaneous, choreographed approach to the performance of chest compressions, airway management, rescue breathing, rhythm detection, and shocks (if indicated) by an integrated team of highly trained rescuers in applicable settings such as the hospital environment. With the current rhythm analysis technology, pause of chest compressions may still be required for accurate rhythm analysis, but the compressions should be resumed as soon as possible after

rhythm analysis or defibrillation. The key components of high-quality CPR for BLS providers are summarized in Table 86.1.

Recognition of Sudden Cardiac Arrest The necessary first step in the management of cardiac arrest is its immediate recognition. Studies have shown that both lay rescuers and healthcare providers have difficulty detecting a weak pulse.15 The healthcare provider should take no more than 10 seconds to check for a pulse and, if the rescuer does not definitely feel a pulse within that time period, start chest compressions. Ideally, the pulse check is performed simultaneously with the examination for breathing or gasping, to minimize delay in the detection of cardiac arrest and initiation of CPR. Cardiac arrest victims sometimes present with seizure-like activity or agonal gasps that can confuse potential rescuers. If the victim is unresponsive with absent or abnormal breathing, the rescuer should assume that the victim is in cardiac arrest. 

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86  •  Cardiopulmonary Resuscitation and Advanced Cardiac Life Support

Bystander Cardiopulmonary Resuscitation For victims of OHCA, the key determinants of survival are timely performance of high-quality bystander CPR and, in the presence of any of the shockable rhythms of ventricular fibrillation or pulseless ventricular tachycardia (VT), defibrillation. Similarly, for IHCA, the important provider-dependent determinants of survival are early defibrillation for shockable rhythms and high-quality CPR, along with recognition and response to deteriorating patients before an arrest. The implication of timely CPR is discussed in the next section of this chapter. The components of high-quality CPR include compressing the chest at an adequate rate and depth, allowing complete chest recoil after each compression, minimizing interruptions in compressions, and avoiding excessive ventilation. As previously described, chest compressions create blood flow by increasing the intrathoracic pressure and directly compressing the heart. The 2015 AHA Guidelines for CPR and ECC recommended a chest compression rate of 100 to 120/min (updated from at least 100/min), and a chest compression depth for adults of at least 2 inches (5 cm) but not greater than 2.4 inches (6 cm). Despite the “push hard and push fast” recommendation, most CPR feedback devices have shown that compressions are more often too shallow than too deep.16 In clinical practice, the compression depth may be difficult to judge without the use of feedback devices, and identification of upper limits of compression depth may be challenging. The addition of an upper limit of compression rate is based on a large registry study analysis associating extremely rapid compression rates (greater than 140/min) with inadequate compression depth.17 Overzealous and rapid chest compressions also compromise chest recoil and venous return, and can potentially have adverse effects on patient survival and outcome. The total number of compressions delivered during resuscitation is an important determinant of ROSC and survival with good neurologic function from cardiac arrest.18,19 The number of compressions delivered is affected by the compression rate (the frequency of chest compressions per minute) and by the compression fraction (the portion of total CPR time during which compressions are performed). Obviously, increases in compression rate and fraction increase the total number of compressions delivered. Compression fraction is improved by reducing the number and duration of any interruptions in compressions (such as securing the airway, delivering rescue breaths, or allowing AED analysis). Compression-only CPR is easy for an untrained rescuer to perform and can be more effectively guided by dispatchers over the telephone. Moreover, survival rates from adult cardiac arrests of cardiac etiology are similar with either compression only CPR or CPR with both compressions and rescue breaths when provided before EMS arrival.20,21 However, for the trained lay rescuer who is able, the recommendation remains for the rescuer to perform both compressions and breaths, especially for victims with asphyxiation causes of cardiac arrest or prolonged CPR. The same emphasis on rescue breathing should also apply to the pediatric population. All lay rescuers should, at a minimum, provide chest

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compressions for victims of cardiac arrest. The rescuer should continue CPR until an AED arrives and is ready for use, EMS providers take over care of the victim, or the victim starts to move. The 2015 AHA Guidelines for CPR and ECC emphasize the initiation of chest compressions before ventilation (i.e., a change in the sequence from A-B-C to C-A-B). The prioritization of circulation (C) over ventilation reflected the overriding importance of blood flow generation for successful resuscitation and practical delays inherent to initiation of rescue breaths (B). Physiologically, in most cases of SCA, the need for assisted ventilation is a lower priority because of the availability of adequate arterial oxygen content at the time of a SCA. The presence of this oxygen and its renewal through gasping and chest compressions (provided there is a patent airway) also supported the use of compression-only CPR and the use of passive oxygen delivery. 

Shock First or Chest Compressions? Previous guidelines recommended a period of chest com­ pressions before attempting defibrillation in unwitnessed cardiac arrests or when CPR had been delayed longer than 4 minutes. However, two recent randomized control trials failed to demonstrate a benefit (ROSC or hospital discharge) when CPR was performed before defibrillation.22,23 Thus the 2015 AHA Guidelines for CPR and ECC recommend that for adult witnessed cardiac arrests when an AED is immediately available, the defibrillator should be used as soon as possible. For adults with unmonitored cardiac arrest or for whom an AED is not immediately available, it is reasonable that chest compressions be initiated while the defibrillator equipment is being retrieved and applied, and that defibrillation, if indicated, be attempted as soon as the device is ready for use.  Automated External Defibrillators and Manual Defibrillation Ventricular fibrillation (VF) and pulseless VT are the most common cardiac arrhythmias encountered during witnessed cardiac arrest in adults. CPR prolongs tissue viability and the duration of VF by providing oxygen and energy substrate, but cannot convert the arrhythmia to an organized rhythm in most circumstances. Defibrillation delivers an electrical current passing through the myocardium to interrupt disorganized cardiac activity and restore an organized cardiac rhythm.24 The first AED was introduced in 1979.25 When it is applied to an individual with possible SCA, the AED analyzes the cardiac rhythm, and then automatically attempts defibrillation if it is VF or rapid VT. A trained rescuer needs to simply apply the defibrillator pads to the patient’s chest, activate the AED, and deliver the shock through the push of a button when prompted to do so by the AED. Thus the purpose is to have early defibrillation more readily available through trained bystanders, such as security guards, police, and the general public. When a standard manual defibrillator is used in resuscitation, the rescuer needs to interpret the rhythm and shock when appropriate. If a monophasic defibrillator is available,

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then a single 360 joule (J) shock should be delivered. With biphasic defibrillators, a much lower energy level (150-200 J) is usually sufficient to terminate the arrhythmia due to its ability to compensate and adjust for the patient’s impedance. If the rescuer is unfamiliar with the waveform used or the manufacturer recommendations, then the maximal available energy should be used as the default energy. There is no evidence indicating superiority of one biphasic waveform design or energy level for the termination of VF with the first shock. For subsequent shocks, it is reasonable to select fixed versus escalating energy based on the specific manufacturer’s instructions. The same protocol used with the AED should be applied when using the manual defibrillator: (1) emphasis is placed on delivering uninterrupted chest compressions while defibrillator pads are being applied and for periods when rhythm analysis is not occurring; (2) chest compressions are immediately resumed after shock delivery; (3) cardiac rhythm is reanalyzed as indicated after 2 minutes of chest compressions and rescue breathing; and (4) defibrillation is attempted only for VF and rapid VT.26 

Single versus Stacked Defibrillation The 2015 AHA Guidelines for CPR and ECC recommended a 2-minute period of chest compressions after each shock instead of immediate successive shocks for persistent VF.27 The rationale for this is that when VF is terminated, a brief period of asystole or pulseless electrical activity (PEA) typically ensues and a perfusing rhythm is unlikely to be present immediately, necessitating chest compressions to provide organ perfusion and circulation of ACLS drugs. No difference in the 1-year survival or frequency of VF recurrence was shown when a single shock protocol with 2 minutes of CPR between successive shocks was compared against a previous resuscitation protocol employing three initial stacked shocks with 1 minute of CPR between subsequent shocks.28,29 A recent study demonstrated that in monitored in-hospital VF/VT arrests, expeditious defibrillation with use of stacked shocks is associated with a higher rate of ROSC and survival to hospital discharge.30 Without further data, current AHA guidelines recommend that a singleshock strategy (as opposed to stacked shocks) is reasonable for defibrillation. Stacked defibrillation is considered only during cardiac surgery or in the cardiac catheterization laboratory where invasive monitoring and defibrillation pads are in place already.  Determination of Efficiency of Cardiopulmonary Resuscitation Immediately after cardiac arrest, when minute ventilation is constant and carbon dioxide (CO2) production is unchanged, the changes in the partial pressure of end-tidal CO2 (PETCO2) can serve as a reliable surrogate for pulmonary blood flow and cardiac output. This has been proven extensively by animal and human studies during cardiac arrest and CPR and after ROSC.31-33 Monitoring of both PETCO2 by quantitative waveform capnography with controlled ventilation and systemic arterial pressure by invasive monitoring should provide optimal assessment of the efficiency of CPR. These parameters can be monitored continuously, without interrupting chest compressions. An abrupt increase in any of these parameters is a sensitive

indicator of ROSC. The 2015 AHA Guidelines for CPR and ECC endorse this monitoring as a class I recommendation for adults with SCA with an endotracheal tube (ETT) or supraglottic airway (SGA) device in place. In addition, coronary perfusion pressure, arterial relaxation pressure, and central venous oxygen saturation can assist in determination of the efficiency of CPR, although these monitoring techniques require more complex catheters or devices.34,35 Currently there are no clinical trials that have studied whether titrating resuscitative efforts to a single or combined set of physiologic parameters during CPR results in improved survival or neurologic outcome. However, the 2010 AHA Guidelines for CPR and ECC recommended that PETCO2 should be maintained above 10 mm Hg,36 and mathematical models suggest a cumulative maximum PETCO2 above 20 mm Hg at all time points measured between 5 and 10 minutes postintubation best predicted ROSC.37 

Update to Airway Management and Ventilation in Cardiac Arrest When cardiac arrest occurs, adequate oxygen delivery is required to restore the energy state of the heart as well as other vital organs, and consequently ventilation becomes an essential part of the resuscitation. However, it also needs to be emphasized that during the first few minutes after cardiac arrest, oxygen delivery to tissues with CPR is limited more by blood flow and low cardiac output than arterial oxygen content.38 Low cardiac output associated with CPR results in low oxygen uptake from the lungs that, in turn, reduces the need to ventilate the patient during this low-flow state.38 Thus chest compressions are the priority intervention, unless the cardiac arrest is due to asphyxiation, drowning, or suffocation, which are the only circumstances in which ventilation must be provided before chest compressions.39 Healthcare providers must determine the best way to support ventilation and oxygenation. Options include standard bag-mask ventilation versus placement of an advanced airway (i.e., ETT or SGA device). Bag-mask ventilation with a head tilt–chin lift or head tilt–jaw thrust maneuver is recommended for initial airway control in most circumstances. There is inadequate evidence to show a difference in survival or favorable neurologic outcome with the use of bag-mask ventilation compared with endotracheal intubation or other advanced airway devices.40,41 There is also inadequate evidence favoring the use of endotracheal intubation compared with other advanced airway devices.42 Thus 2015 AHA/Guidelines for CPR and ECC recommend that either a bag-mask device or an advanced airway may be used for oxygenation and ventilation during CPR in both the in-hospital and out-of-hospital settings, assuming that providers have ongoing experience to insert the airway and verify proper position with minimal interruption in chest compressions. The choice of bag-mask device versus advanced airway insertion is determined by the skill and experience of the provider. Regarding the inspired oxygen concentration, the 2015 AHA Guidelines for CPR and ECC support providing the maximal inspired oxygen concentration during CPR. Since oxygen delivery is dependent on both blood flow and arterial oxygen content and blood flow is typically limited during CPR, it is theoretically important to maximize the

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86  •  Cardiopulmonary Resuscitation and Advanced Cardiac Life Support

oxygen content of arterial blood by maximizing inspired oxygen concentration. Evidence for the detrimental effects of hyperoxia that may exist in the immediate post–cardiac arrest period should not be extrapolated to the low-flow state of CPR, where oxygen delivery is unlikely to exceed demand or cause an increase in tissue PO2. Therefore, until further data are available, physiology and expert consensus support providing the maximal inspired oxygen concentration during CPR. After ETT placement, it is very important to confirm its correct placement, although this could be very challenging due to the patient’s body habitus, low-flow status, and distraction from other resuscitative tasks. In addition to observation of chest rise and auscultation of the lungs and stomach, continuous waveform capnography is recommended as the most reliable method of confirming and monitoring correct placement of an ETT.43 However, falsepositive results (CO2 detection with esophageal intubation) can still occur, especially within the first few breaths due to air/CO2 insufflation of the stomach during bag-mask ventilation. False-negative results (i.e., absent exhaled CO2 in the presence of tracheal intubation) can occur in the setting of pulmonary embolism (PE), low cardiac output, or severe obstructive pulmonary disease. If continuous waveform capnography is not available, a nonwaveform CO2 detector, fiberoptic scope, esophageal detector, or ultrasound device used by an experienced operator are reasonable alternatives. If bag-mask ventilation is chosen, 2 breaths are delivered after 30 chest compressions during one- and two-person CPR, providing that the rescuer(s) is(are) trained in CPR. Each breath is delivered over approximately 1 second. After placement of an advanced airway, it is recommended to provide 1 breath every 6 seconds (10 breaths/min) while continuous chest compressions are being performed. Extreme caution should be taken to avoid excessive airway pressure that will compromise venous return in cardiac arrest patients, as hyperventilation is common during enthusiastic resuscitation. 

ADVANCED CARDIAC LIFE SUPPORT: MANAGEMENT OF CARDIAC ARREST BLS, ACLS, and post–cardiac arrest care are integral steps in the AHA’s “chain of survival” for patients suffering from cardiac arrest. CPR almost invariably necessitates rapid progression to ACLS interventions and follow-up care. There is overlap between these steps, as each stage of care progresses to the next, but generally ACLS comprises the level of care between BLS and post–cardiac arrest care. The 2015 AHA Guidelines for CPR and ECC adult cardiac arrest algorithm is illustrated in Fig. 86.2. This section reviews the different interventions for managing cardiac arrest patients based on the presenting ECG rhythm, medications used during cardiac arrest, special situations of cardiac arrest, and new technologies developed to facilitate resuscitation and improve the patient’s survival.

Asystole Asystole is the complete and sustained absence of electrical activity and portends extremely poor prognosis. Management of a patient in cardiac arrest with asystole follows the

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same pathway as management of PEA (as discussed later). The top priorities are also similar: following the steps in the ACLS Pulseless Arrest Algorithm and identifying and correcting any treatable, underlying causes for the asystole. In most patients, asystole is irreversible, but a brief trial of resuscitation, beginning with effective chest compressions, oxygen therapy, and intravenous (IV) epinephrine, is indicated particularly in the setting of witnessed cardiac arrest. Atropine is no longer recommended for treating asystole. Asystole should be differentiated from agonal bradycardia and fine ventricular fibrillation. 

Pulseless Electrical Activity PEA refers to the presence of organized electrical activity without a palpable pulse. Priority must be given to identifying possible reversible causes of PEA, which is frequently referred to as the five Hs (Hypoxia, Hypovolemia, Hypothermia, Hyper- or Hypokalemia, Hydrogen ions or acidosis) and Ts (Tamponade, Tension pneumothorax, Toxins, Thrombosis Pulmonary, and Thrombosis Coronary). Those causes are first suspected for each patient’s special circumstance. Severe hypoxia in respiratory emergencies can result in PEA. In the traumatized patient, hypovolemia, cardiac tamponade, and tension pneumothorax are possible causes of cardiac arrest and must be considered and acutely treated. Unanticipated cardiac arrest occurring in the intraoperative and postoperative periods should include acute massive pulmonary thromboembolism or air emboli as possible causes. Electrolyte and metabolic derangements such as severe hyperkalemia, metabolic acidosis, or drug (e.g., digitalis, β-blockers, calcium channel blockers, tricyclic antidepressants) overdose frequently presents as idioventricular rhythms. In every circumstance, prompt initiation of chest compressions and the administration of 1 mg epinephrine are recommended as temporizing measures until more definitive therapy can be provided once the cause for the PEA is identified. Each of these scenarios has an associated intervention unique to that situation. Asystole or VF can develop if PEA is not corrected.  Pulseless Ventricular Tachycardia or Ventricular Fibrillation Pulseless VT and VF are shockable rhythms and hence the most treatable causes of cardiac arrest, yielding the greatest likelihood of ROSC and long-term survival in both in-hospital and out-of-hospital settings. Early defibrillation, not pharmacologic intervention, is responsible for the improved survival after VF cardiac arrest. Therefore, AEDs are placed in public locations to ensure early defibrillation can be performed by rescuers. When a pulseless VT or VF arrest occurs, defibrillation should be performed at the earliest opportunity. Chest compressions should be immediately resumed after the delivery of shock and continued for 2 minutes before reassessing the underlying cardiac rhythm, unless obvious evidence for ROSC occurs. No evidence supports one biphasic waveform over another. Defibrillation energies should be increased until VF is terminated. In circumstances in which pulseless VT or VF is terminated with defibrillation but pulseless VT or VF recurs, defibrillation should use the previously successful energy level. If ROSC does not occur after an initial defibrillatory attempt, then five cycles of CPR consisting of 30

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Fig. 86.2  2015 American Heart Association adult advanced cardiovascular life support algorithm. CPR, Cardiopulmonary resuscitation; IO, intraosseous; IV, intravenous; PEA, pulseless electric activity; VF, ventricular fibrillation; VT, ventricular tachycardia. (From Link MS, Berkow LC, Kudenchuk PJ, et al. Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132[18 suppl 2]:S444–S464.)

compressions to 2 ventilations (nonintubated patient) should be performed before recheck of rhythm. Placement of a SGA device or endotracheal intubation can be considered in this interval. Peripheral IV access should be attempted if not already established without interruption of the chest compressions. 

Resuscitation Medications During Cardiac Arrest Epinephrine. Epinephrine produces beneficial effects in patients during cardiac arrest, primarily due to its α-adrenergic effects increasing coronary perfusion pressure and cerebral perfusion pressure during CPR. The β-adrenergic effects of epinephrine are controversial

because they may increase myocardial work and reduce subendocardial perfusion. Thus standard-dose epinephrine (1 mg every 3-5 minutes) is recommended for patients in cardiac arrest. High-dose epinephrine is not recommended for routine use in cardiac arrest. The exceptions to this recommendation are special circumstances requiring higher or repeated doses of epinephrine, such as in patients with β-blocker overdose, calcium channel blocker overdose, or when epinephrine is titrated to real-time physiologically monitored parameters. Regarding the timing of epinephrine administration, multiple trials showed the early administration of epinephrine in nonshockable rhythms (asystole or PEA) was associated

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86  •  Cardiopulmonary Resuscitation and Advanced Cardiac Life Support

with increased ROSC, survival to hospital discharge, and neurologically intact survival.44,45 For shockable rhythms (VF or pulseless VT), there is insufficient evidence to make a recommendation as to the optimal timing of epinephrine, particularly in relation to defibrillation. Therefore early administration of epinephrine is recommended after the onset of cardiac arrest caused by an initial nonshockable rhythm.  Vasopressin. Vasopressin is a nonadrenergic peripheral vasoconstrictor that also causes coronary and renal vasoconstriction. Studies compared multiple doses of standarddose epinephrine with multiple doses of vasopressin (40 units IV) or vasopressin in combination with epinephrine after OHCA and showed no benefit with the use of vasopressin solely or in combination with epinephrine for ROSC or survival to discharge with or without good neurologic outcome.46 Vasopressin offers no advantage as a substitute for epinephrine in cardiac arrest and thus has been removed from the adult cardiac arrest algorithm.  Antiarrthymia Medications. The role of antiarrhythmic medications during shock-refractory VF/pulseless VT is to facilitate the restoration and maintenance of a spontaneous perfusing rhythm in concert with the shock termination of VF, instead of directly converting VF/pulseless VT to an organized perfusing rhythm. Some antiarrhythmic drugs have been associated with increased rates of ROSC and hospital admission, but none have yet been proven to increase longterm survival or survival with good neurologic outcome. Thus the 2015 AHA Guidelines for CPR and ECC on ACLS recommend that amiodarone may be considered for VF/pulseless VT that is unresponsive to CPR, defibrillation, and a vasopressor therapy; and lidocaine may be considered as an alternative to amiodarone. Routine use of magnesium for VF/pulseless VT is not recommended in adult patients, nor is the routine use of sodium bicarbonate for any patient in cardiac arrest.  Steroids. The use of steroids in cardiac arrest has been assessed in both IHCA and OHCA settings. In IHCA, patients administered steroids combined with a vasopressor bundle or cocktail of epinephrine and vasopressin had improved ROSC compared with patients given a saline placebo and epinephrine.47 However, further studies are needed before recommending the routine use of this therapeutic strategy. For patients with OHCA, studies showed inconsistent benefit of use of steroids alone during CPR and thus routine use is not recommended. 

Cardiopulmonary Resuscitation in Patients With Mechanical Circulatory Support Cardiac arrest in patients on mechanical circulatory support (MCS) has become a much more common clinical scenario due to the increased use of this therapy in patients with endstage heart failure. Because of the unique characteristics of mechanical support, these patients have physical findings that cannot be interpreted the same as for patients without MCS. This section briefly describes the common types of MCS devices that healthcare providers may encounter and presents expert, consensus-based recommendations from the recent AHA guidelines for the evaluation and resuscitation of adult patients with MCS, and suspected cardiovascular collapse or cardiac arrest.48

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MCS with ventricular assist devices (VADs) can support function of the left ventricle (LV), the right ventricle (RV), or both ventricles with a biventricular assist device. A total artificial heart (TAH) replaces the heart itself. Most patients who are discharged home with MCS currently have a durable left ventricular VAD (LVAD). Continuous-flow LVADs are the more current generation of VADs. It results in an unconventional, unique physiologic state of hemodynamically stable PEA, which we refer to in this population as pseudo-PEA. Vital signs such as noninvasive blood pressure or oxygen saturation may be difficult to obtain. These factors can easily confuse healthcare providers rendering care to these patients. Lack of a pulse alone in a patient with a continuous-flow LVAD is common and cannot be used as a means to determine whether a patient is in cardiac arrest or a low-flow, low-perfusion state. Assessment of adequate tissue perfusion is the most important factor in determining the need for circulatory assistance such as chest compressions. Clinical findings such as skin color and capillary refill are reasonable predictors of the presence of adequate flow and perfusion. If an LVAD is definitively confirmed by a trained person and there are no signs of life, bystander CPR, including chest compressions, is recommended. Many tachyarrhythmias are tolerated well in patients with an LVAD, although they can affect RV filling. Similar to the decision made for patients without VADs, the decision to cardiovert or to defibrillate a patient with an LVAD with VT or VF is based on the adequacy of mental status and perfusion. Fig. 86.3 outlines consensusderived recommendations for first-responder assessment of a patient with an LVAD. For patients with a TAH, the native ventricles are removed completely; therefore, there is no electric depolarization and therefore no detectable ECG tracing. Chest compressions are ineffective because the mechanical ventricles are rigid and cannot be compressed. Antiarrhythmic drugs and electric therapy (e.g., pacing, defibrillation/cardioversion) are also futile for similar reasons. Standard vasopressor drugs used in ACLS such as epinephrine or vasopressin are contraindicated because they increase afterload, result in complete hemodynamic collapse with pulmonary edema, and worsen TAH function. The only therapeutic option is to try to restore mechanical function of the device. One liter of normal saline solution should be administered intravenously to treat for possible hypovolemia. Assisted ventilation should be performed as needed, and the patient should be transported to the hospital as soon as possible. Fig. 86.4 provides an algorithm for evaluation and treatment of a patient with a TAH who is altered mentally, unresponsive, or in respiratory distress. 

Cardiopulmonary Resuscitation Using a Mechanical Cardiopulmonary Resuscitation Device Delivering high-quality chest compressions to achieve ROSC and maintain perfusion to vital organs is vitally important to improving survival and neurologic outcome after cardiac arrest. However, manual conventional chest compressions are frequently affected by fatigue, varying skill levels and training, pauses during defibrillation and the switch of rescuers, and adherence to protocols.49 It is even more difficult to ensure high-quality chest compressions

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(e.g. King) airway results in a falsely

Fig. 86.3  Algorithm showing response to a patient with a left ventricular assist device (LVAD) with unresponsiveness or other altered mental status. ACLS, Advanced cardiovascular life support; EMS, emergency medical services; ET, endotracheal tube; MAP, mean arterial pressure; PETCO2, partial pressure of end-tidal carbon dioxide; VAD, ventricular assist device. (From Peberdy MA, Gluck JA, Ornato JP, et al. Cardiopulmonary Resuscitation in Adults and Children With Mechanical Circulatory Support: A Scientific Statement From the American Heart Association. Circulation. 2017;135[24]:e1115–e1134.)

during transport.50 Studies showed that manual compressions provide only approximately 30% of normal cardiac output, at best.51 Mechanical chest compression devices have therefore been developed to improve CPR. These devices are designed to deliver compressions of consistent rate and depth, eliminate fatigue as a factor, and provide an opportunity to reduce the frequency and length of pauses in compression. Initial experimental studies with the mechanical chest compression device showed improved organ perfusion pressures, enhanced cerebral blood flow, and higher endtidal CO2 compared with manual CPR.52,53 A recent large multicenter randomized controlled trial showed, nevertheless, that an algorithm combining mechanical chest compressions and defibrillation during ongoing compressions provided no survival advantage over manual CPR administered according to guidelines.54 No difference in survival or neurologic outcome was seen for up to 6 months after the cardiac arrest, even though the mechanical chest compression devices reduced interruptions in chest compressions, and enabled defibrillation during ongoing compressions.

The possible explanation for this discrepancy between early studies and the large clinical trial is that application of the mechanical device resulted in long pauses of chest compression (median device application time 36.0 seconds), and pause in chest compression is clearly associated with worse clinical outcome. Therefore the 2015 AHA Guidelines for CPR and ECC recommended that manual chest compressions remain the standard of care for the treatment of cardiac arrest, but mechanical CPR devices may be a reasonable alternative for use by properly trained personnel in specific settings where the delivery of high-quality manual compressions may be challenging or dangerous for the provider (e.g., limited rescuers available, prolonged CPR, during hypothermic cardiac arrest, during preparation for extracorporeal CPR [ECPR]). Future emphasis should be placed on streamlining and appropriately timing the deployment of these compression devices. 

Echocardiography in Cardiac Arrest For nonshockable rhythms, the essential step will be early detection and correction of potentially reversible underlying

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86  •  Cardiopulmonary Resuscitation and Advanced Cardiac Life Support

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Fig. 86.4  Algorithm showing response to a patient with a total artificial heart (TAH) with altered mental status, unresponsiveness, or respiratory distress. AED, Automated external defibrillator; BP, blood pressure; IV, intravenous; NS, normal saline; SBP, systolic blood pressure. (From Peberdy MA, Gluck JA, Ornato JP, et al. Cardiopulmonary Resuscitation in Adults and Children With Mechanical Circulatory Support: A Scientific Statement From the American Heart Association. Circulation. 2017;135[24]:e1115–e1134.)

causes, such as the Hs and Ts of PEA arrest, as described earlier. Echocardiography has revolutionized our ability to assess the etiology and hence the management of these patients. However, performing and interpreting echocardiography frequently proves much more challenging in the real scene of cardiac arrest. Point-of-care (POC) focused echocardiography can help assess the volume status, ventricular function, valvular disease, cardiac tamponade, PE, and tension pneumothorax. The TEE, compared with transthoracic echocardiography, provides constant visualization of the heart during chest compressions and gives live feedback on cardiac contractility and the quality of compressions.

It is less affected by the body habitus, presence of subcutaneous air, and by chest movements. Several studies have evaluated the feasibility and clinical influence of TEE in cardiac arrest patients. TEE showed moderate sensitivity and specificity for diagnosing cause of arrest, and may further impact treatment.55,56 However, it is unclear if these benefits will be translated to improved patient outcome. Thus the 2015 AHA Guidelines for CPR and ECC suggested that if a qualified sonographer is present and use of ultrasound does not interfere with the standard cardiac arrest treatment protocol, then ultrasound may be considered as an adjunct to standard patient evaluation and resuscitation measures.

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More recently, POC focused echocardiography has also been used to predict short-term outcome in patients with cardiac arrest. Recent meta-analysis showed spontaneous cardiac movement had a sensitivity of 95% and specificity of 80% to predict ROSC, and sensitivity 90% and specificity 78% to predict survival to hospital admission.57 Absence of spontaneous cardiac movement on echocardiography has a low likelihood of favorable outcome and can aid in the decision of termination of resuscitation. The caveat is that the interpretation of spontaneous cardiac movement is still very operator-dependent. In addition, in cases of significant bradycardia, the image could be potentially interpreted as cardiac standstill between the cardiac contractions. 

Cardiac or Respiratory Arrest Associated With Opioid Overdose In the United States in 2013, 16,235 people died of prescription opioid toxicity, and an additional 8257 died of heroin overdose.58 In 2012, opioid overdose became the leading cause of unintentional injurious death in people aged 25 to 60 years in the United States, accounting for more deaths than motor vehicle collisions.59 A majority of these deaths are associated with prescription opioids. In consideration of this epidemiology, the 2015 AHA Guidelines for CPR and ECC on BLS recommended that for patients with known or suspected opioid addiction who are unresponsive with no normal breathing but a pulse, it is reasonable for appropriately trained lay rescuers and BLS providers, in addition to providing standard BLS care, to administer intramuscular (IM) or intranasal naloxone. The ideal dose of naloxone is unknown. In the 2010 AHA Guidelines for CPR and ECC, an empiric starting dose of 0.04 to 0.4 mg IV or IM was recommended to avoid provoking severe opioid withdrawal in patients with opioid dependency and to allow for consideration of a range of doses, depending on the clinical scenario. Repeat doses or dose escalation to 2 mg IV or IM was recommended if the initial response was inadequate. Regardless of the care setting and route of administration, the initial goal of therapy is to restore and maintain patent airway and ventilation, preventing respiratory and cardiac arrest, without provoking severe opioid withdrawal.  Recognition and Emergency Response for Suspected Stroke Each year, about 6.5 million people die from stroke worldwide, and 1 million from cerebrovascular diseases in the 15 countries of the European Union.60,61 According to the 2013 Global Burden of Disease study, stroke is the second largest contributor to disability-adjusted life years (113 million disability-adjusted life years) in the world after ischemic heart disease, is a major cause of disability, and is the second most common cause of dementia, after Alzheimer disease. Identifying clinical signs of possible stroke (sudden weakness or numbness of the face, arm, or leg, especially on one side of the body; sudden confusion, trouble speaking, or understanding; sudden trouble seeing in one or both eyes; sudden trouble walking, dizziness, loss of balance, or coordination; or sudden severe headache with no known cause) is important because fibrinolytic treatment must be provided within a few hours of onset of symptoms.62,63 Community and professional education is essential to increase the early recognition and treatment to improve patient outcome.

The AHA and American Society of Anesthesiologists developed a community-oriented “stroke chain of survival” that links actions to be taken by patients, family members, and healthcare providers to maximize stroke recovery. Important components of this chain are rapid recognition and reaction to stroke warning signs, rapid EMS dispatch, transport and hospital pre-notification, and rapid diagnosis and treatment in the hospital. The algorithm goals for management of patients with suspected stroke is illustrated in Fig. 86.5. 

Recognition and Management of Specific Arrythmias This section highlights recommendations for management of patients with acute symptomatic arrhythmias. It needs to be emphasized that electrocardiographic and rhythm information should be interpreted within the context of total patient assessment. For example, when a patient with respiratory failure and severe hypoxemia becomes hypotensive and develops a bradycardia, the bradycardia is not the primary cause of instability. Treating the bradycardia without treating the hypoxemia is unlikely to improve the patient’s condition. Errors in diagnosis and treatment are likely to occur if ACLS providers base their treatment decisions solely on rhythm interpretation and neglect the clinical evaluation of each specific patient. In general, “unstable arrhythmias” refer to a condition in which vital organ function is acutely impaired due to inefficient cardiac contractions and insufficient cardiac output, or cardiac arrest is ongoing or imminent. When an arrhythmia causes a patient to be unstable, immediate intervention is indicated. “Symptomatic arrhythmias” imply that an arrhythmia is causing symptoms, such as palpitations, lightheadedness, or dyspnea, but the patient is stable and not in imminent danger. In such cases, more time is available to decide on the most appropriate intervention. In both unstable and symptomatic cases, the provider must make an assessment as to whether the arrhythmia is causing the patient to be unstable or symptomatic. It is critically important to determine the cause of the patient’s instability in order to properly direct the treatment.

BRADYARRHYTHMIAS Bradycardia is defined as a heart rate of less than 60 beats/ min. However, when bradycardia is the cause of symptoms, the rate is generally less than 50 beats/min. A slow heart rate may be physiologically normal for some patients, whereas a heart rate of more than 50 beats/min may be inadequate for others. Hence, 50 beats/min is a relative number, and it is important to also assess the patient’s clinical presentation. Depending on the origin of the arrhythmia, bradyarrhythmias can be classified as supraventricular (sinus, junctional, or various degrees of atrioventricular [AV] block) or ventricular (complete heart block with a very slow idioventricular escape rhythm). Sinus (or junctional) bradycardia and type I (AV nodal) second-degree block are usually manifestations of increased vagal tone. AV blocks are classified as first, second, and third degree. A first-degree AV block is defined

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Fig. 86.5  American Heart Association Algorithm for Suspected Stroke. ABC, Airway, breathing, circulation; BP, blood pressure; CT, computed tomography; EMS, emergency medical services; IV, intravenous. (From ECC Committee, Subcommittees and Task Forces of the American Heart Association: Part 9: Adult Stroke: 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2005;112:IV-111–IV-120.)

by a prolonged PR interval (>0.20 second) and is generally benign. Second-degree AV block is divided into Mobitz types I and II. In Mobitz type I block, the block is at the AV node and is often transient and asymptomatic. In Mobitz type II block, the block is usually below the AV node within the HisPurkinje system; this block is often symptomatic, with the potential to progress to complete (third-degree) AV block. Third-degree AV block may occur at the AV node, bundle of His, or bundle branches. When third-degree AV block is present, the atria and ventricles are completely dissociated. Third-degree AV block can be permanent or transient, depending on the underlying cause. Because hypoxemia is a common cause of bradycardia, initial evaluation of any patient with bradycardia should

focus on signs of increased work of breathing (tachypnea, intercostal retractions, suprasternal retractions, paradoxical abdominal breathing) and oxygen saturation as determined by pulse oximetry. If oxygenation is inadequate or the patient shows signs of increased work of breathing, supplementary oxygen should be provided. A monitor should be attached to the patient for blood pressure, ECG, and oxygen saturation monitoring, and IV access should be established. If possible, obtain a 12-lead ECG to better define the rhythm. While initiating treatment, evaluate the patient’s clinical status and identify potentially reversible causes. The provider must identify signs and symptoms of poor perfusion and determine if those signs are likely to be caused by the bradycardia. If the signs and symptoms are not due

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SECTION VII  •  Critical Care Medicine

to bradycardia, the provider should reassess the underlying cause of the patient’s symptoms. Asymptomatic or minimally symptomatic patients do not necessarily require treatment unless there is suspicion that the rhythm is likely to progress to symptoms or more advanced bradyarrhythmias (e.g., Mobitz type II second-degree AV block in the setting of acute myocardial infarction). If the bradycardia is suspected to be the cause of acute altered mental status, ischemic chest discomfort, acute heart failure, hypotension, or other signs of shock, the patient should receive immediate treatment. Atropine remains the first-line drug for acute symptomatic bradycardia. The recommended atropine dose for bradycardia is 0.5 mg IV every 3 to 5 minutes to a maximum total dose of 3 mg. Doses of atropine sulfate of less than 0.5 mg may result in paradoxical bradycardia. Atropine will also unlikely be effective in patients who had heart transplantation because the transplanted heart lacks vagal innervation. Since atropine works by reversing the muscarinic effects of the parasympathetic nervous system, it is not the preferred drug of choice for type II second-degree or third-degree AV block or in patients with third-degree AV block with a new wide-QRS complex where the location of block is likely to be more distal than the AV nodes. These bradyarrhythmias are not likely to be responsive to atropine and should be treated with transcutaneous pacing (TCP) or β-adrenergic agonists as temporizing measures while the patient is prepared for transvenous pacing. If bradycardia is unresponsive to atropine, IV infusion of β-adrenergic agonists (dopamine, epinephrine) can be considered. Dopamine is a catecholamine with both α- and β-adrenergic actions. It can be titrated to more selectively target heart rate or vasoconstriction. At lower doses, dopamine has a more selective effect on inotropy and heart rate; at higher doses (>10 μg/kg/min), it also has vasoconstrictive effects. Epinephrine, as described previously, is a catecholamine with α- and β-adrenergic actions. Isoproterenol is a β-adrenergic agent with β-1 and β-2 effects, resulting in an increase in heart rate and vasodilation. The recommended adult dose is 2 to 10 μg/min by IV infusion, titrated to the appropriate heart rate and rhythm response. TCP can be done through the multifunctional pacing/ defibrillating pads. It is painful, and sedation should be considered in all awake patients. TCP should be considered a temporary measure only, and the patient should always be prepared for transvenous pacing. Expert consultation should be obtained as soon as possible. Transesophageal atrial pacing can be effective in treating intraoperative supraventricular bradyarrhythmias such as sinus or junctional bradycardia. This device is compatible with most external pacing devices and defibrillators. However, transesophageal pacing is only effective at pacing the atria, at least in its current configuration. In a patient who has AV conduction issues, such as complete heart block, this intervention is ineffective. Effective and consistent pacing also relies on normal acid-base status and electrolyte concentrations; thus acidemia and electrolyte abnormalities such as severe hyperkalemia need to be corrected if pacing is not successful. Fig. 86.6 illustrates the bradyarrhythmias treatment algorithm recommended in the 2015 AHA Guidelines for CPR and ECC. 

TACHYARRHYTHMIA Tachyarrhythmia is defined as an arrhythmia with a rate of more than 100 beats/min, although, as with defining bradycardia, an arrhythmia rate of 150 or more beats/min is more likely to cause clinical symptoms. When encountering patients with tachycardia, efforts should be made to determine whether the tachycardia is the primary cause of the presenting symptoms, or secondary to an underlying condition that is causing both the presenting symptoms and the faster heart rate. Tachycardia can be classified in several ways, based on the appearance of the QRS complex, heart rate, and regularity. Narrow-complex tachycardias (supraventricular tachycardia [SVT], QRS < 0.12 second) include sinus tachycardia, atrial fibrillation, atrial flutter, AV nodal reentry, accessory pathway–mediated tachycardia, atrial tachycardia (including automatic and reentry forms), multifocal atrial tachycardia, and junctional tachycardia. Wide–QRS-complex tachycardias (QRS ≥ 0.12 second) include VT and VF, SVT with aberrancy, preexcited tachycardias (Wolff-ParkinsonWhite syndrome), and ventricular-paced rhythms. Because hypoxemia is a common cause of tachycardia, initial evaluation of any patient with tachycardia, similar to those with bradycardia, should focus on identifying signs of increased work of breathing and oxygen saturation. Patients should be closely monitored and supplemental oxygen provided. A 12-lead ECG better defines the rhythm, but the process should not delay immediate cardioversion if the patient is unstable. If signs and symptoms persist despite provision of supplementary oxygen and support of airway and ventilation, the provider should assess the patient’s degree of instability and determine if the instability is related to the tachycardia. If the patient demonstrates rate-related cardiovascular compromise with signs and symptoms such as acute altered mental status, ischemic chest discomfort, acute heart failure, hypotension, or other signs of shock suspected to be due to a tachyarrhythmia, the provider should proceed to immediate synchronized cardioversion, which can terminate tachyarrhythmias by interrupting the underlying reentrant pathway. The recommended initial biphasic energy dose for cardioversion of atrial fibrillation is 120 to 200 J. Cardioversion of atrial flutter and other SVTs generally requires less energy; an initial energy of 50 J to 100 J is often sufficient. If the initial 50 J shock fails, the provider should increase the dose in a stepwise fashion. Monomorphic VT with a pulse responds well to monophasic or biphasic waveform cardioversion (synchronized) shocks at initial energies of 100 J. If a patient has polymorphic VT, treat the rhythm as VF and deliver high-energy unsynchronized shocks (defibrillation doses). If the patient with tachycardia is stable, then determine if the patient has a narrow-complex or wide-complex tachycardia, whether the rhythm is regular or irregular, and for wide complexes whether the QRS morphology is monomorphic or polymorphic. Therapy is then tailored accordingly. For regular narrow-complex SVT, vagal maneuvers such as carotid massage or Valsalva maneuver are used first to terminate the arrhythmia. If vagal maneuvers are unsuccessful, then adenosine is the drug of choice for terminating organized rapid supraventricular

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Fig. 86.6  2015 American Heart Association Adult Bradycardia With a Pulse Algorithm. IV, Intravenous. (From Link MS, Berkow LC, Kudenchuk PJ, et al. Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132[18 suppl 2]:S444–S464.)

arrhythmias. Adenosine slows sinoatrial and AV nodal conduction and prolongs refractoriness, which is very effective in terminating paroxysmal SVT (PSVT), the most common cause of which is reentry within the AV node. The drug is also used to diagnose the underlying mechanism in tachyarrhythmias of uncertain origin (e.g., atrial fibrillation, atrial flutter) by inducing transient block of AV nodal conduction. If adenosine or vagal maneuvers fail to convert PSVT, PSVT recurs after such treatment, or these treatments disclose a different form of SVT (such as atrial fibrillation or flutter), it is reasonable to use longer-acting AV nodal blocking agents, such as the nondihydropyridine calcium channel blockers (verapamil and diltiazem) or β-blockers. Treatable causes of VT should always be sought before or during pharmacologic or electrical interventions. Hypoxemia, hypercapnia, hypokalemia or hypomagnesemia (or both), digitalis toxicity, and acid-base derangements are obvious causes for VT and should be quickly evaluated and corrected if present. If antiarrhythmic therapy is pursued, procainamide, amiodarone, or sotalol are recommended. Importantly, only one drug should be administered; a second drug should not be added without expert consultation. Hypotension is common with all three of these medications. The evaluation and management of tachyarrhythmias is illustrated in the 2015 ACLS Tachycardia with Pulse

Algorithm (Fig. 86.7). The medications used for tachyarrhythmia are listed in Tables 86.2 and 86.3. 

Postresuscitation Interventions Hypoxemia, ischemia, and reperfusion occurs during cardiac arrest and resuscitation, regardless of cause of cardiac arrest, and this may cause damage to multiple organ systems. Therefore, effective post–cardiac arrest care consists of identification and treatment of the precipitating cause of cardiac arrest combined with the assessment and mitigation of ischemia-reperfusion injury to multiple organ systems. The severity of damage can vary widely among patients and among organ systems within individual patients. Care must be tailored to the particular disease and dysfunction that affect each patient. Therefore, individual patients may require few, many, or all of the specific interventions discussed in the following part of this section.

EMERGENCY PERCUTANEOUS CORONARY INTERVENTION Acute coronary syndromes are a common etiology for OHCA in adults with no obvious extracardiac cause of arrest and also can precipitate some IHCA. One study examined

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SECTION VII  •  Critical Care Medicine

Fig. 86.7  2015 American Heart Association Adult Tachycardia With a Pulse Algorithm. IV, Intravenous; NS, normal saline; VT, ventricular tachycardia. (From Link MS, Berkow LC, Kudenchuk PJ, et al. Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132[18 suppl 2]:S444–S464.)

a consecutive series of post–cardiac arrest patients with suspected cardiovascular cause, and found a coronary artery lesion amenable to emergency treatment in 96% of patients with ST elevation and in 58% of patients without ST elevation during subsequent coronary angiography.64 Thus urgent coronary angiography with prompt recanalization of any infarct-related artery is crucially important to improving the patient’s survival, enhancing neurologic outcome, and preventing recurrence of arrest. Evidence regarding the timing of coronary angiography immediately after cardiac arrest (defined variously, but within 24 hours) is limited to observational studies. Data from studies with more than 3800 patients having ST elevation on ECG after ROSC after cardiac arrest demonstrated a benefit of immediate coronary angiography with improved survival to hospital discharge, while more than half of these studies also demonstrated a benefit with improved neurological outcomes.65-67 Fewer data are available to evaluate coronary angiography in patients without ST elevation on the initial post–cardiac arrest ECG. Two studies demonstrated a benefit with

improved survival to hospital discharge and improved neurologic outcome when patients received immediate coronary angiography.65,68 In these studies, the decision to undertake the intervention was influenced by a variety of factors such as patient age, duration of CPR, hemodynamic instability, presenting cardiac rhythm, neurologic status upon hospital arrival, and perceived likelihood of cardiac etiology. The 2015 AHA Guidelines for CPR and ECC recommended that coronary angiography should be performed emergently (rather than later in the hospital stay or not at all) for OHCA patients with suspected cardiac etiology of arrest and ST elevation on ECG. Emergency coronary angiography should be considered for select (e.g., electrically or hemodynamically unstable) adult patients who are comatose after OHCA of suspected cardiac origin but without ST elevation on ECG. Overall, coronary angiography is reasonable in post–cardiac arrest patients where coronary angiography is indicated, regardless of the patient’s mental status. The 2015 acute coronary syndrome algorithm is illustrated in Fig. 86.8.69 

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TABLE 86.2  Summary of Medications Used for Supraventricular Tachycardia Drug

Characteristics

Indication(s)

Adenosine

Endogenous purine nucleoside; briefly depresses sinus node rate and AV node conduction; vasodilator

□ 

□

□

Diltiazem, Verapamil

Non-dihydropyridine calcium channel blockers; slow AV node conduction and increase AV node refractoriness; vasodilators, negative inotropes

Atenolol, β-Blockers; reduce Esmolol, effects of circulatMetoprolol, ing catecholamines; Propranolol reduce heart rate, AV node conduction and blood pressure; negative inotropes

□

Stable, narrowcomplex tachycardias if rhythm remains uncontrolled or unconverted by adenosine or vagal maneuvers or if SVT is recurrent Control ventricular rate in patients with atrial fibrillation or atrial flutter

Diltiazem: Initial dose 15-20 mg (0.25 mg/kg) IV over 2 min; additional 20-25 mg (0.35 mg/kg) IV in 15 min if needed; 5-15 mg/h IV maintenance infusion (titrated to AF heart rate if given for rate control) Verapamil: Initial dose 2.5-5 mg IV given over 2 min; may repeat as 5-10 mg every 15-30 min to total dose of 20-30 mg

Hypotension, Should only be given bradycardia, to patients with precipitanarrow-complex tion of heart tachycardias (regular failure or irregular). Avoid in patients with heart failure and preexcited AF or flutter or rhythms consistent with VT

Stable, narrowcomplex tachycardias if rhythm remains uncontrolled or unconverted by adenosine or vagal maneuvers or if SVT is recurrent Control ventricular rate in patients with atrial fibrillation or atrial flutter Certain forms of ­polymorphic VT (associated with acute ischemia, familial LQTS, catecholaminergic)

Atenolol (β1 specific blocker) 5 mg Hypotension, Avoid in patients with IV over 5 min; repeat 5 mg in 10 bradycardia, asthma, obstrucmin if arrhythmia persists or recurs precipitative airway disease, Esmolol (β1 specific blocker with tion of heart decompensated 2- to 9-min half-life) IV loading failure heart failure and dose 500 mcg/kg (0.5 mg/kg) pre-excited atrial over 1 min, followed by an fibrillation or flutter infusion of 50 mcg/kg per min (0.05 mg/kg/min); if response is inadequate, infuse second loading bolus of 0.5 mg/kg over 1 min and increase maintenance infusion to 100 mcg/kg (0.1 mg/ kg) per min; increment; increase in this manner if required to maximum infusion rate of 300 mcg/kg [0.3 mg/kg] per min Metoprolol (β1 specific blocker) 5 mg over 1-2 min repeated as required every 5 min to maximum dose of 15 mg Propranolol (nonselective β-blocker) 0.5-1 mg over 1 min, repeated up to a total dose of 0.1 mg/kg if required

Preexcited atrial fibrillation

20-50 mg/min until arrhythmia suppressed, hypotension ensues, or QRS prolonged by 50%, or total cumulative dose of 17 mg/kg; or 100 mg every 5 min until arrhythmia is controlled or other conditions described above are met

Procainamide

Sodium and potas­ sium channel blocker

□ 

Amiodarone

Multichannel blocker (sodium, potassium, calcium channel, and noncompetitive α/β-blocker)

□ 

□

□

Precautions or Special Considerations

Hypotension, Contraindicated in bronchopatients with asthma; spasm, chest may precipitate atrial discomfort fibrillation, which may be very rapid in patients with WPW; thus a defibrillator should be readily available; reduce dose in post–cardiac transplant patients, those taking dipyridamole or carbamazepine and when administered via a central vein

□ 

□

Side Effects

Stable, narrow-complex 6 mg IV as a rapid IV push followed regular tachycardias by a 20 mL saline flush; repeat if Unstable narrowrequired as 12 mg IV push complex regular tachycardias while preparations are made for electrical cardioversion Stable, regular, ­monomorphic, widecomplex tachycardia as a therapeutic and diagnostic maneuver

□ 

□

Dosing

Stable irregular narrow- 150 mg given over 10 min and complex tachycardia repeated if necessary, followed (atrial fibrillation) by a 1 mg/min infusion for 6 h, Stable regular narrowfollowed by 0.5 mg/min. complex tachycardia Total dose over 24 h should not To control rapid exceed 2.2 g. ventricular rate due to accessory pathway conduction in pre-excited atrial arrhythmias

Bradycardia, hypotension, torsades de pointes

Avoid in patients with QT prolongation and CHF

Bradycardia, hypotension, phlebitis

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SECTION VII  •  Critical Care Medicine

TABLE 86.2  Summary of Medications Used for Supraventricular Tachycardia—cont’d Drug

Characteristics

Indication(s)

Digoxin

Cardiac glycoside with positive inotropic effects; slows AV node conduction by enhancing parasympathetic tone; slow onset of action

□ 

□

Dosing

Side Effects

Stable, narrow-complex 8-12 mcg/kg total loading dose, regular tachycardias if half of which is administered rhythm remains unconinitially over 5 min, and trolled or unconverted remaining portion as 25% by adenosine or vagal fractions at 4- to 8-h intervals maneuvers or if SVT is recurrent Control ventricular rate in patients with atrial fibrillation or atrial flutter

Bradycardia

Precautions or Special Considerations Slow onset of action and relative low potency renders it less useful for treatment of acute arrhythmias

AF, Atrial fibrillation; AV, atrioventricular; CHF, congestive heart failure; IV, Intravenous; LQTS, long QT syndrome; SVT, supraventricular tachycardia; VT, ventricular tachycardia; WPW, Wolff-Parkinson-White syndrome. From https://eccguidelines.heart.org/index.php/tables/2010-iv-drugs-used-for-tachycardia-2/.

TABLE 86.3  Summary of Medications Used for Ventricular Tachycardia Drug

Characteristics

Indication(s)

Side Effects

Hemodynamically stable monomorphic VT

20-50 mg/min until arrhythmia suppressed, hypotension ensues, or QRS prolonged by 50%, or total cumulative dose of 17 mg/kg; or 100 mg every 5 min until arrhythmia is controlled or other conditions described previously are met

Bradycardia, hypotension, torsades de pointes

Hemodynamically stable monomorphic VT Polymorphic VT with normal QT interval

150 mg given over 10 min and Bradycardia, repeated if necessary, followed hypotension, by a 1 mg/min infusion for phlebitis 6 h, followed by 0.5 mg/min. Total dose over 24 h should not exceed 2.2 g.

Hemodynamically stable monomorphic VT

In clinical studies 1.5 mg/kg infused over 5 min; however, U.S. package labeling recommends any dose of the drug should be infused slowly over a period of 5 h

Bradycardia, hypotension, torsades de pointes

Hemodynamically stable monomorphic VT

Initial dose range from 1 to 1.5 mg/kg IV; repeated if required at 0.5-0.75 mg/kg IV every 5-10 min up to maximum cumulative dose of 3 mg/kg; 1-4 mg/min (30-50 mcg/kg/ min) maintenance infusion

Slurred speech, altered consciousness, seizures, bradycardia

Polymorphic VT associated with QT prolongation (torsades de pointes)

1-2 g IV over 15 min

Hypotension, CNS Follow magnesium toxicity, respiralevels if frequent or tory depression prolonged dosing required, particularly in patients with impaired renal function

Procainamide Sodium and potassium channel blocker

□ 

Amiodarone

Multichannel blocker (sodium, potassium, calcium channel, α- and noncompe­ titive β-blocker)

□ 

Sotalol

Potassium channel blocker and nonselective β-blocker

□ 

Lidocaine

Relatively weak sodium channel blocker

□ 

Magnesium

Cofactor in variety of cell processes including control of sodium and potassium transport

□ 

□

Precautions or Special Considerations

Dosing

Avoid in patients with QT prolongation and CHF

Avoid in patients with QT prolongation and CHF

CHF, Congestive heart failure; CNS, central nervous system; IV, intravenous; VT, ventricular tachycardia. From https://eccguidelines.heart.org/index.php/tables/2010-iv-drugs-used-for-tachycardia-2/.

TARGETED TEMPERATURE MANAGEMENT Devastating neurologic injury, particularly anoxic brain injury, is frequent in post–cardiac arrest patients. Over the years, numerous pharmacologic interventions, including steroids, barbiturates, and nimodipine, have been tried for cerebral protection in this patient population with unsatisfactory results. This was until the seminal publications

describing the use of systemic hypothermia to 33°C within 2 hours of OHCA and maintained for 12 or 24 hours, which showed improved outcomes among survivors.70,71 The mechanism of cerebral protection with hypothermia is complex, but is suggested to include its effect on the cerebral metabolic rate. For every 1°C reduction in brain temperature, a 6% reduction in cerebral metabolic rate is

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Fig. 86.8  2015 American Heart Association Acute Coronary Syndrome Algorithm. ABC, Airway, breathing, circulation; CPR, cardiopulmonary resuscitation; EMS, emergency medical services; IV, intravenous. (From O’Connor RE, Al Ali AS, Brady WJ, et al. Part 9: Acute Coronary Syndromes: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132[18 suppl 2]:S483–S500. https:// eccguidelines.heart.org/index.php/circulation/cpr-ecc-guidelines-2/part-9-acute-coronary-syndromes/.)

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observed. By limiting the metabolic demand and decreasing the utilization of oxygen and glucose, targeted temperature management (TTM) reduces the risk of energy depletion, preserving the ion channel’s integrity and decreasing the intracellular calcium influx that can trigger neuronal apoptotic pathways.72 Indeed, animal models have been used to evaluate the mitigating effects of hypothermia on pathways leading to excitotoxicity, apoptosis, inflammation, and free radical production, as well as its significance in preserving the blood–brain barrier integrity, neuronal viability, and neurologic outcome.73 TTM encompasses therapeutic hypothermia, controlled normothermia, and treatment of fever. The HACA trial was the first study to show clinical benefit in a focused patient cohort.71 Following the publication of this study, a number of other studies also evaluated induced hypothermia after cardiac arrest, which gained widespread use and is now advocated by international guidelines. Of note, the Target Temperature Management After Cardiac Arrest (or the TTM) trial74 found no difference in neurologic outcome when comparing 939 OHCA victims after cooling to 33°C versus controlled temperature maintenance at 36°C, but both arms of this trial involved a form of TTM as opposed to no TTM. Consequently, the TTM trial might underscore the importance of active temperature management after ROSC. The 2015 AHA Guidelines for CPR and ECC recommend TTM in all comatose (i.e., lack of meaningful response to verbal commands) adult patients with ROSC after cardiac arrest, irrespective of the initial rhythm (shockable or not). A target temperature between 32°C and 36°C is recommended for at least 24 hours. It is also recommended to continue to monitor the temperature and maintain normothermia (treat fever) beyond this window. Prognostication should not occur until 72 hours after ROSC, or if TTM is provided, 72 hours after completion of TTM. Experimental studies also suggest that the greatest benefit of hypothermia in neuroprotection is achieved when it is effectively applied within hours of the event, with likely benefit being within 6 hours or earlier after the insult. Although human studies have yet not confirmed the critical window for effective implementation of TTM to improve neurologic outcome after cardiac arrest, they have established that the target temperature is more rapidly obtained in cohorts where intranasal, surface, or intravascular temperature-modulating devices (servo-controlled or inbuilt feedback mechanisms) were used, as compared to surface cooling with air-cooling blankets, cooling fans, or ice cooling packs. There was also a lower likelihood to overshoot the target temperature when these devices were employed. Intravascular heat exchange catheters are currently the most efficient technique for achieving the target temperature within a short period after ROSC, and can also be used in combination with surface-cooling modalities.75 Their use is nevertheless limited by their invasive nature and associated risks such as vascular injury, bleeding, or thrombosis. In addition, no benefit in survival has been shown using these more invasive devices. The use of cold saline as an adjunctive therapy in the prehospital setting is not recommended because the data from the RINSE trial showed that prehospital cold IV fluids in victims of cardiac arrest did not

improve outcome, but resulted in an increased incidence of pulmonary edema during the first 24 hours after ROSC.76 

POSTRESUSCITATION OXYGEN AND VENTILATION THERAPY Hyperoxia in preclinical studies was associated with worsening oxidative stress, free radical production, and worsened organ function.77 Importantly, Kilgannon and colleagues reported an association between hyperoxia and in-hospital mortality after resuscitation from cardiac arrest.78 Consequently, the AHA guidelines recommend that once reliable oxygenation and ventilation monitors are in place, the fraction of inspired oxygen (FiO2) should be decreased to avoid hyperoxia.69,77 It is worth noting that in the immediate post-ROSC period, the intense systemic vasoconstriction may make it challenging for pulse oximetry to work optimally; thus access and use of arterial blood gases to guide therapy should be part of the management strategy. Post–cardiac arrest patients are at increased risk for developing ARDS. Some of the contributing factors include aspiration pneumonia, pulmonary contusions after aggressive CPR, ventilator-associated lung injury, and the pulmonary manifestations of the post–cardiac arrest syndrome. The optimal mechanical ventilation strategy after cardiac arrest has, nevertheless, not been well defined. Although more focused studies are still needed, it is suggested that patients with ARDS should be ventilated according to the Acute Respiratory Distress Syndrome Network (ARDSNet) low-tidal volume strategy.79 Excessive hyperventilation and hypocarbia can also adversely affect the outcome, as it can lead to cerebral vasoconstriction and worsening blood flow, in particular in areas with no reflow or hypoperfusion after ROSC. A recent systematic review evaluating data from at least eight studies found that both hypocarbia and hypercarbia are associated with worse neurologic outcomes in the post–cardiac arrest syndrome patient.23 Therefore, it is recommended that after resuscitation from cardiac arrest, the PaCO2 be maintained within the normal physiologic range (end-tidal CO2 30-40 mm Hg or PaCO2 35-45 mm Hg), taking into account any temperature correction.69 

GLYCEMIC CONTROL IN THE POST–CARDIAC ARREST PATIENT Hyperglycemia is frequently encountered in survivors of cardiac arrest because of a combination of several factors including the effect of counter-regulatory hormones in the immediate post-ROSC period. Poor glycemic control has been associated with poor neurologic outcome in critically ill patients. Hyperglycemia is thought to cause secondary injury by exacerbating intracellular acidosis, increasing free radical formation, increasing extracellular glutamate levels, and disrupting the blood–brain barrier. On the other hand, tight glucose control at low levels has also been associated with increased frequency of hypoglycemic episodes and poor patient outcome.80 Although the data on glycemic control in the post-cardiac arrest patient are not definitive, it is reasonable to monitor blood glucose concentration and avoid extreme levels of blood glucose in this population. 

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DETERMINE THE CAUSE AND EXTENT OF INJURY AFTER CARDIAC ARREST Laboratory Testing Laboratory testing may provide insight into the etiology of cardiac arrest, help identify potentially reversible and/ or intervenable factors, and may allow the evaluation of the extent of end-organ damage. In addition to the standard laboratory tests such as a complete blood count, electrolyte and lactate levels, arterial blood gases, and cardiac enzymes, it is reasonable to obtain a repeat ECG to identify ischemic changes and direct management toward emergency reperfusion therapy. Arrhythmias are not unusual in the post–cardiac arrest patient and, if not managed appropriately, may place the patient at risk for recurrent arrest. It is worth noting that besides coronary ischemia etiology, cardiomyopathies and electrical conduction abnormalities constitute the major etiologies for cardiac arrest. A prolonged QTc interval may reflect a primary arrhythmia such as Brugada syndrome, congenital QT prolongation syndromes, or a multitude of acquired etiologies of prolonged QTc in critically ill patients, including medications, hypothermia, electrolyte abnormalities, and bradycardia. In select patients, toxicology testing may be of value to rule out cocaine or methamphetamine intoxication. Cardiopulmonary collapse may also be precipitated by overdose of antidepressants, sedatives, and opioids, leading to profound hypoxemia triggering cardiac arrest. 

Chest Radiographs The value attributed to the diagnostic yield of chest radiographs has diminished over the past decade. However, radiographs can be valuable for rapid diagnosis of conditions such as a pneumothorax, or for confirmation of the position of the ETT and central venous catheters. Lung parenchymal pathology and mediastinal pathology should prompt other imaging modalities, such as computed tomography (CT) imaging.  Computed Tomography Imaging CT imaging can be valuable to determine if pulmonary embolus is present and to examine the presence and extent of pulmonary aspiration or edema after resuscitation from cardiac arrest. CT imaging of the brain can also help identify the presence of intracranial hemorrhage, larger areas of cerebral ischemia, or cerebral edema.  Magnetic Resonance Imaging of the Brain The role of magnetic resonance imaging (MRI) in the evaluation of the post–cardiac arrest patient is discussed in this section.  Echocardiography and Critical Care Ultrasonography The widespread availability of echocardiographic equipment and its proficient use in intensive care have enabled early identification of important treatable causes of cardiac arrest. Examples include:   

Pericardial tamponade. It is worth noting that the size of pericardial effusion, which is a relatively common finding, is not diagnostic of tamponade, as the rate of fluid

□ 

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accumulation is more likely to determine tamponade pathophysiology. Usually the chamber with the lowest pressure, the right atrium, begins to collapse during ventricular diastole and can be visualized by echocardiography at the time of diagnosis. □  Acute myocardial ischemia with new regional wall motional abnormalities. □  Acute PE. Echocardiography can be very useful in the early diagnosis of PE, especially when the patient is too unstable to be transported for CT scans. Important echocardiographic findings include the demonstration of the McConnell sign (akinesia of the mid free wall but normal motion at the RV apex) or other RV strain patterns such as an RV diameter greater than 30 mm in the parasternal long-axis view, or an increase in the area of the RV relative to the LV in the apical four-chamber view. Flattening of the interventricular septum is another feature (D-shaped septum) that suggests the diagnosis of acute massive PE. □  Tension pneumothorax. Ultrasonography offers a higher sensitivity to the detection of an otherwise clinical diagnosis of tension pneumothorax. The quick demonstration of the “seashore sign,” “B-lines,” comet tails, and the “lung pulse” confirms the apposition of the visceral and parietal pleura and excludes pneumothorax. □  Severe hypovolemia. Inadequate circulating intravascular volume is frequently a precipitating cause of cardiac arrest of nonmyocardial etiology. Ultrasound/echocardiography allows for rapid evaluation of intravascular fluid status and response to a fluid challenge to guide management in the post–cardiac arrest patient. However, one has to be aware of the pitfalls of assessing volume status based on static indices. 

TERMINATION OF RESUSCITATION EFFORTS— INDICATORS OF POOR OUTCOME POST-RETURN OF SPONTANEOUS CIRCULATION The 2015 AHA Guidelines for CPR and ECC discussed the use of clinical examination, electrophysiologic measurements, imaging studies, and evaluation of blood or cerebrospinal fluid markers of brain injury to estimate the prognosis for neurologic improvement in patients who are comatose after cardiac arrest and the decision to terminate resuscitative efforts. Because sedatives or neuromuscular blockers received during TTM may be metabolized more slowly in post–cardiac arrest patients, and injured brains may be more sensitive to the depressant effects of various medications, residual sedation or paralysis can confound the accuracy of clinical examinations. Multiple investigations suggest that it is necessary to wait to prognosticate for a minimum of 72 hours after ROSC to minimize the rate of false-positive results in patients who had not undergone TTM and to wait for some period of time after return of normothermia for those using TTM. In many cases, clinicians choose to complete their final evaluation for prognostication 5 to 7 days after the arrest. Studies have shown that factors such as the patient’s prearrest comorbidities are associated with poor survival and outcome. The initial cardiac rhythm, the no-flow (arrest) and low-flow (CPR) times, and the quality of chest compressions (as indicated by the ETCO2) are also associated with patient outcome. Clinical examinations, such as loss

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of corneal and pupillary light reflexes, extensor posturing, and the presence of status myoclonus, also point to a poor prognosis. In comatose patients who are treated with TTM or not, the absence of pupillary reflex to light at 72 hours or more after cardiac arrest has the lowest false-positive rate (FPR) of 0% to 1% to predict poor neurologic outcome compared with other clinical examination indicators.69 It is also important to distinguish myoclonus from status myoclonus (continuous, repetitive myoclonic jerks lasting more than 30 minutes) because the presence of any myoclonus is not a reliable predictor of poor functional recovery, but status myoclonus during the first 72 hours after cardiac arrest achieved an FPR of 0%.69 EEG has been used widely in the diagnosis of seizures and prognostication after cardiac arrest, even though the lack of standardized EEG terminology continues to limit its use in research and practice. In comatose post–cardiac arrest patients who are treated with TTM, persistent absence of EEG reactivity to external stimuli at 72 hours after cardiac arrest and persistent burst suppression on EEG after rewarming, has a FPR of 0%. Intractable and persistent (more than 72 hours) status epilepticus in the absence of EEG reactivity to external stimuli is also an indicator of poor outcome. In comatose post–cardiac arrest patients who are not treated with TTM, the presence of burst suppression on EEG at 72 hours or more after cardiac arrest, in combination with other predictors, has a FPR of 0%, and can be used to predict poor outcome. In patients who are comatose after resuscitation from cardiac arrest regardless of treatment with TTM, bilateral absence of the N20 somatosensoryevoked potentials wave 24 to 72 hours after cardiac arrest or after rewarming predicts poor outcome (FPR 1%). Brain imaging studies, including CT or MRI scans, can define structural brain injury or detect focal injury. In patients who are comatose after resuscitation from cardiac arrest and not treated with TTM, the presence of a marked reduction of the gray-white ratio on brain CT obtained within 2 hours after cardiac arrest could be used to predict poor outcome, as well as extensive restriction of diffusion on brain MRI at 2 to 6 days after cardiac arrest. However, it needs to be noted that both imaging modalities have higher FPRs and wider confidence intervals compared with clinical examination predictors, and thus should be used in combination with other established predictors to predict a poor neurologic outcome. There is currently no established role of laboratory biomarkers of brain injury in predicting neurologic outcome. 

Pediatric Resuscitation Pediatric cardiac arrest portends similar poor prognosis as adults. Data from the 2005 to 2007 Resuscitation Outcomes Consortium, a registry of 11 U.S. and Canadian emergency medical systems, showed age-dependent discharge survival rates of 3.3% for infants (younger than 1 year), 9.1% for children (1-11 years), and 8.9% for adolescents (12-19 years).81 More recently, published data from this network demonstrated 8.3% survival to hospital discharge across all age groups.82 Outcomes from pediatric IHCA, however, have markedly improved over the past decade. From 2001 to 2009, rates of pediatric IHCA survival to hospital

discharge improved from 24% to 39%.83 Prolonged CPR is not always futile, with 12% of patients who receive CPR for more than 35 minutes surviving to discharge and 60% of those survivors having a favorable neurologic outcome.84 This improvement in survival rate from IHCA can be attributed to multiple factors, including emphasis on high-quality CPR and advances in postresuscitation care. Pediatric resuscitation requires clinical expertise including understanding of its unique pathophysiology, clinical implications, and therapeutic considerations. Even though asphyxiation is the leading cause of pediatric cardiac arrest and warrants initial focused investigation and management, the pediatric resuscitation guidelines closely follow the adult guidelines in order to facilitate training, retention, and implementation of resuscitation guidelines. For example, minimally interrupted and effectively performed chest compressions, ventilation, and prompt defibrillation are emphasized to improve outcome from cardiac arrest and should always be the focus of resuscitation effort.

PEDIATRIC BASIC LIFE SUPPORT Asphyxiation is a much more common cause of cardiac arrest in infants and children than a primary cardiac event, and airway management and ventilation are therefore more important during the resuscitation of children. Data from animal studies85,86 and pediatric studies87,88 suggest that resuscitation outcomes for asphyxial cardiac arrest are better with a combination of ventilation and chest compressions. Therefore, historically, the preferred sequence of CPR was A-B-C (Airway-Breathing-Circulation). However, a universal CPR algorithm for victims of all ages minimizes the complexity of CPR and offers consistency in CPR training. In addition, there is inadequate data to identify which resuscitation method offers better survival in this population: beginning with ventilations (A-B-C) first or with chest compressions (C-A-B). The 2015 AHA Guidelines for CPR and ECC maintained the changes of the 2010 recommendations that the C-A-B sequence should be used to decrease the time to initiation of chest compressions and reduce “no blood flow” time in acute pediatric cardiac arrest. The 2015 AHA Guidelines for CPR and ECC on pediatric BLS algorithms separated one-person from two-person or more healthcare provider CPR to better guide rescuers through the initial stages of resuscitation (Figs. 86.9 and 86.10).89 In an era where cellular telephones with speakers are common, this technology can allow a single rescuer to activate the emergency response system while beginning CPR. These algorithms continue to emphasize the importance of obtaining an AED quickly in a sudden, witnessed collapse, because such an event is likely to have a cardiac etiology. The 2015 AHA Guidelines for CPR and ECC on pediatric BLS continue to emphasize the five components of highquality CPR, which includes:   

Ensuring chest compressions of adequate rate Ensuring chest compressions of adequate depth □  Allowing full chest recoil between compressions □  Minimizing interruptions in chest compressions □  Avoiding excessive ventilation □  □ 

  

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Fig. 86.9  2015 American Heart Association Pediatric Cardiac Arrest Algorithm for Single Rescuer. AED, Automated external defibrillator; CPR, cardiopulmonary resuscitation. (From Atkins DL, Berger S, Duff JP, et al. Part 11: Pediatric Basic Life Support and Cardiopulmonary Resuscitation Quality: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132[18 suppl 2]:S519–525.)

The guidelines recommend the same chest compression rate as in adults: 100/min to 120/min. In infants, the rescuer should place two fingers just below the inframammary line on the sternum. In children, chest compressions should be performed by compressing the lower half of the sternum (avoiding the xiphoid process) with one or two hands. The guidelines also recommend that for pediatric patients (birth to the onset of puberty) the depth of chest compression should be at least one-third

the anterior-posterior diameter of the chest. This equates to approximately 1.5 inches (4 cm) in infants to 2 inches (5 cm) in children. Once children have reached puberty, the recommended adult compression depth of at least 5 cm, but no more than 6 cm, is used for the adolescent of average adult size. Conventional CPR (chest compressions and rescue breaths) should be provided for pediatric cardiac arrests. The guidelines also recommended the use of feedback devices to help the rescuer optimize adequate

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Fig. 86.10  2015 American Heart Association Pediatric Cardiac Arrest Algorithm for Two or More Rescuers. AED, Automated external defibrillator; CPR, cardiopulmonary resuscitation. (From Atkins DL, Berger S, Duff JP, et al. Part 11: Pediatric Basic Life Support and Cardiopulmonary Resuscitation Quality: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132[18 suppl 2]:S519–S525.)

chest-compression rate and depth. End-tidal CO2 (ETCO2) monitoring may evaluate the quality of chest compressions, but specific values to guide therapy have not been established in children. For patients with invasive hemodynamic monitoring in place at the time of cardiac arrest, it may be reasonable for rescuers to use blood pressure to guide CPR quality. The asphyxial nature of the majority of pediatric cardiac arrests necessitates ventilation as part of effective CPR. This survival benefit has been further supported by one recent large observational study where CPR using chest compressions with rescue breaths had higher survival to discharge rates than either no CPR or chest compression–only CPR.90 However, because compression-only CPR is effective in patients with a primary cardiac event, if rescuers are unwilling or

unable to deliver breaths, compression-only CPR is recommended for infants and children in cardiac arrest. Sudden witnessed collapse in a child is likely to be from VF. For infants, a manual defibrillator is preferred when a shockable rhythm is identified by a trained healthcare provider. An AED with a pediatric attenuator and pediatric defibrillation pads is also preferred for children under 8 years of age. Pediatric defibrillator pads should be applied in the anteroposterior position. In pediatric cardiac arrest, initial defibrillation energy is 2 J/kg and increased to 4 J/kg if a second shock is indicated. For subsequent energy levels, a dose of 4 J/kg may be reasonable and higher energy levels may be considered, but should not exceed 10 J/kg or the adult maximum dose. If no pediatric defibrillator is available, then an adult AED should be applied and used without hesitation. 

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86  •  Cardiopulmonary Resuscitation and Advanced Cardiac Life Support

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Fig. 86.11  2015 American Heart Association Pediatric Bradycardia With a Pulse and Poor Perfusion Algorithm. ABC, Airway, breathing, circulation; AV, atrioventricular; CPR, cardiopulmonary resuscitation; IO, intraosseous; IV, intravenous. (From de Caen AR, Berg MD, Chameides L, et al. Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132[18 suppl 2]:S526–S542.)

PEDIATRIC ADVANCED LIFE SUPPORT Given the fact that asphyxiation is a much more common etiology of cardiac arrest in infants and children than primary cardiac events, effective basic and advanced airway management, oxygenation, and ventilation are of utmost importance. However, as with adult cardiac arrests, airway management should not cause prolonged interruption of chest compressions. Similarly, the placement of an advanced airway warrants confirmation of placement using a CO2 detector and bilateral breath sounds. If the infant or child is intubated, ventilate at a rate of about 1 breath every 6 to 8 seconds (8-10 times/min) without interrupting chest compressions. Because vascular access can be challenging in critically ill children and circulating medication levels between IV and intraosseous (IO) routes are equivalent, IO access is often

pursued as an alternative in these patients. All resuscitation medications and blood products can be injected into IO catheters. Because of the resistance to fluid flow from the IO catheter into the IO space, fluids must be pressurized to carry fluid into circulation. As in adults, ECG monitoring permits the immediate recognition of the arrest rhythm or the prearrest rhythm. Prompt intervention and correction in the latter event may prevent cardiac arrest of hypoxia etiology. For pediatric patients, management of different life-threatening arrhythmias, PEA arrest/ asystole, or VF/VT arrest is similar to adults except the dosage (defibrillation/medication) for children is weight-based. Actual body weight is recommended to calculate initial resuscitation drug doses. The 2015 AHA Guidelines for CPR and ECC on pediatric ACLS for bradycardia, tachycardia, and pulseless arrest are illustrated in Figs. 86.11–86.13.91

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Fig. 86.12  2015 American Heart Association Pediatric Tachycardia With a Pulse and Poor Perfusion Algorithm. IO, Intraosseous; IV, intravenous. (From de Caen AR, Berg MD, Chameides L, et al. Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132[18 suppl 2]:S526–542.)

For bradycardia, continue to support airway, ventilation, oxygenation, and chest compressions. Emergency TCP may be lifesaving if the bradycardia is due to complete heart block or sinus node dysfunction unresponsive to the aforementioned measurements and medications, especially if it is associated with congenital or acquired heart disease. For SVT, attempt vagal stimulation first, unless the patient is hemodynamically unstable or the procedure will delay chemical or electric cardioversion. An IV/IO dose of adenosine 0.1 mg/kg rapid bolus is used first; if it fails, then a second dose of 0.2 mg/kg rapid bolus is given, the maximum second dose is 12 mg. Verapamil, 0.1 to 0.3 mg/ kg, is also effective in terminating SVT in older children, but it should not be used in infants without expert consultation because it may cause potential myocardial depression, hypotension, and cardiac arrest. When cardioversion is indicated in unstable SVT, start with a dose of 0.5 to 1 J/

kg. If unsuccessful, increase the dose to 2 J/kg. For a patient with SVT unresponsive to vagal maneuvers and adenosine and/or electric cardioversion, consider amiodarone 5 mg/ kg IO/IV or procainamide 15 mg/kg IO/IV; for hemodynamically stable patients, expert consultation is strongly recommended prior to administration. For wide-complex (>0.09 second) tachycardia, consider electric cardioversion after sedation using a starting energy dose of 0.5 to 1 J/kg. If that fails, increase the dose to 2 J/kg. Regarding resuscitation medication, it is reasonable to administer epinephrine in pediatric cardiac arrest. For shock-refractory VF or persistent VT, either amiodarone or lidocaine may be used. Calcium administration is not recommended for pediatric cardiopulmonary arrest in the absence of documented hypocalcemia, calcium channel blocker overdose, hypermagnesemia, or hyperkalemia. Routine administration of sodium bicarbonate is not

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Fig. 86.13  2015 American Heart Association Pediatric Cardiac Arrest Algorithm. CPR, Cardiopulmonary resuscitation; IO, intraosseous; IV, intravenous; PEA, pulseless electric activity; VF, ventricular fibrillation; VT, ventricular tachycardia. (From de Caen AR, Berg MD, Chameides L, et al. Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132[18 suppl 2]:S526–S542.)

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recommended in cardiac arrest. A dose of 0.02 mg/kg of atropine may be considered before emergency intubation. Observational data from a registry of pediatric IHCA showed improved survival to hospital discharge with the use of ECMO cardiopulmonary resuscitation (ECPR) in patients with surgical cardiac diagnoses.92 For children with underlying cardiac disease, when ECPR is initiated in a critical care setting, long-term survival has been reported even after more than 50 minutes of conventional CPR.93 When ECPR is used during cardiac arrest, the outcome for children with underlying cardiac disease is better than for those with noncardiac disease.94 Therefore, ECPR may be considered for pediatric patients with cardiac diagnoses who have IHCA in settings with existing extracorporeal membrane oxygenation (ECMO) protocols, expertise, and equipment. For infants and children remaining comatose after OHCA, it is reasonable either to maintain 5 days of continuous normothermia (36°C-37.5°C) or to maintain 2 days of initial continuous hypothermia (32°C-34°C), followed by 3 days of continuous normothermia. Fever (temperature 38°C or higher) should be aggressively treated with antipyretics and cooling devices after ROSC. Myocardial dysfunction and vascular instability are common after resuscitation from cardiac arrest.95 After ROSC, IV fluids and/or inotropes or vasoactive drugs is recommended to maintain a systolic blood pressure greater than fifth percentile for age. When appropriate resources are available, continuous arterial pressure monitoring is recommended to identify and treat hypotension. 

HIGHLIGHTING THE SIMILARITIES OR DIFFERENCES VERSUS ADULT RESUSCITATION The similarities and differences of pediatric and adult BLS are listed in Table 86.1 and discussed in the Basic Life Support section. The asphyxial nature of the majority of pediatric cardiac arrests necessitates effective ventilation as part of the CPR. Conventional CPR (rescue breathing and chest compressions) should be provided for pediatric cardiac arrests. For infants, a manual defibrillator is preferred when a shockable rhythm is identified by a trained healthcare provider. An AED with a pediatric attenuator is also preferred for children less than 8 years of age. If neither is available, an AED without a dose attenuator may be used. As previously described, the defibrillation energy dose and resuscitation medication doses are all weight based. 

FOREIGN BODY AIRWAY OBSTRUCTION Although recognition and management has improved, foreign body aspiration (FBA) remains common in children. FBA can occur in children of all ages, although most occur in children younger than 4 years of age, with a peak incidence between the first and second years of age.96 Liquids are the most common source for infant choking while small objects (e.g., balloons, food) are responsible for most childhood choking.97 Clinical symptoms and signs vary based on the location of the foreign body and the degree of obstruction. The clinical presentation may also change over time as a result of movement of the foreign body within the respiratory tract.

If a child is making sounds or coughing, the adult should carefully monitor but not intervene. If the child is choking, abdominal thrusts (the Heimlich maneuver) or back blows should be performed until the obstruction is relieved. In either circumstance, if the choking infant or child becomes unresponsive, CPR should be started with 30 chest compressions, followed by an airway examination to identify the presence of the foreign body. Two rescue breaths should be attempted. If the airway obstruction is not relieved, then CPR should be restarted and continued until the airway obstruction is relieved. If a foreign body is visible above the vocal cords during laryngoscopy, an attempt should be made to extract it with Magill forceps. If the foreign body is below the vocal cords, it is reasonable to attempt to push the foreign body more distally to reestablish a patent airway. This may allow for rescue oxygenation and ventilation while preparing for more definitive management. 

DROWNING Drowning is an important cause of OHCA in children and results in approximately 1100 pediatric deaths in the United States annually.98 It remains one of the leading causes of death in children and adolescents worldwide. The most important positive prognostic indicators include shorter submersion time, salt versus freshwater submersion, and time from rescue to receiving CPR.99,100 Thus prehospital care is paramount to improve patient outcome. When a drowning infant or child is encountered by a single rescuer, a CPR pattern of 2 minutes of 30:2 compression-to-ventilation should be provided before summoning help. If two or more rescuers are available, then help should be immediately summoned. Oxygen and ventilation should be provided at the earliest opportunity because respiratory arrest is usually the primary etiology. Heimlich maneuver is not beneficial in the case of drowned patients because it potentially increases time to intubation and the possibility of gastric aspiration.101 Cuffed ETTs are preferred due to decreased lung compliance secondary to submersioninduced lung injury. The outcomes of survivors of cardiac arrest secondary to drowning are usually better compared with other respiratory etiologies.102 However, it is very difficult to predict prognosis from initial presentation, with many of the most unexpected physiologic recoveries occurring in the young; therefore, aggressive resuscitation of a patient following submersion should always be undertaken until either ROSC or arrival at the emergency department, at which point further efforts such as ECMO may be considered. 

SUDDEN UNEXPLAINED DEATHS Unexpected and unexplained deaths in infants and children can result from cardiac and noncardiac etiology. Cardiac etiology is often attributed to cardiac arrhythmia caused by cardiac ion-channel dysfunction secondary to genetic variations or mutations, which may be undetectable in a conventional autopsy. In 2% to 10% of infants or children and 14% to 20% of young adults who experience sudden cardiac death, channelopathies are found on autopsy.103,104 First- and second-degree relatives of young children who unexpectedly die should undergo a genetic

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86  •  Cardiopulmonary Resuscitation and Advanced Cardiac Life Support

analysis to detect undiagnosed channelopathies. Noncardiac conditions include epilepsy, upper airway obstruction from infectious/noninfectious reasons resulting in respiratory arrest, febrile seizures, infection, metabolic disorders, and hippocampal pathology.105 

TERMINATION OF PEDIATRIC RESUSCITATION ATTEMPTS Accurate and reliable prognostication during pediatric cardiac arrest would allow termination of CPR when it is futile, while encouraging continued CPR in patients with a potential for good recovery. Several post-ROSC factors have been studied as possible predictors of survival and neurologic outcome after pediatric cardiac arrest. These include the presence of hypotension, serum neurologic biomarkers, and serum lactate. Although these factors are associated with better or worse outcomes, no single factor predicts outcome with sufficient accuracy to recommend termination or continuation of CPR. The AHA 2015 Guidelines for CPR and ECC on pediatric ACLS recommend that multiple variables are used when attempting to prognosticate outcomes during cardiac arrest. Observational data from two small pediatric studies showed that a continuous and reactive tracing on an EEG performed in the first 7 days after cardiac arrest is associated with a significantly higher likelihood of good neurologic outcome at hospital discharge. In contrast, an EEG demonstrating a discontinuous or isoelectric tracing is associated with a poor neurologic outcome at hospital discharge.106,107 Thus EEG within the first 7 days after pediatric cardiac arrest may be considered in prognosticating neurologic outcome at the time of hospital discharge, although it should obviously never be used as the sole criterion. Prolonged resuscitations might be considered for infants and children with recurring or refractory VF or VT, particularly if cardiopulmonary support with ECMO is available and the source for the cardiac arrest is believed reversible.108 

Future of Resuscitation Science and Care INDIVIDUALIZED CARDIOPULMONARY RESUSCITATION As described earlier in this chapter, survival and neurologic outcome in victims of cardiac arrest are critically dependent on the duration of the “no-flow” arrest (circulatory arrest with no chest compressions), as well as the quality of chest compressions during the “low-flow” phase of CPR. Therefore, it is important to provide early and high-quality chest compressions and to use every measure to facilitate early ROSC, irrespective of the cause of the arrest. Recent data have, nevertheless, shown that in addition to this general approach, interventions aimed at specific conditions or physiologic parameters can also affect the chance of ROSC and survival. This individualized approach to CPR has become increasingly important given the persistent poor outcome after cardiac arrest despite efforts to improve implementation of current guidelines, AED accessibility, and provider training.

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The use of ECG filtering techniques and fibrillation analysis algorithms has been investigated to identify the optimal time for successful defibrillation from VF. A problem coherent to this technique has been the need to stop chest compressions for rhythm analysis, which is proven to adversely affect the effectiveness of the subsequent chest compressions. The recent development of the “See-Through” technology to extract CPR artifacts from the ECG is promising, as it allows continued chest compressions during ECG analysis but has been criticized for a relatively low specificity that prohibits its incorporation into the AED diagnostic algorithm.109 Amplitude spectral area (AMSA) is an index for analyzing ventricular fibrillation waveforms to predict ROSC after defibrillation. Nakagawa and associates showed that change in AMSA (ΔAMSA) before the electric shock reliably predicted ROSC in 285 VF patients.110 Segal and associates report a moderate positive correlation between ETCO2 and AMSA during CPR in pigs.111 As was described in the 2015 AHA Guidelines for CPR and ECC ACLS update, provider performance feedback during CPR can also help optimize CPR quality. Despite the absence of convincing evidence, it is reasonable to use quantitative waveform capnography, arterial pressure monitoring, and central venous oxygen saturation when feasible to monitor and optimize CPR quality and guide vasopressor therapy. Gonzalez-Otero and associates recently reported that an accelerometer-based real-time feedback system to guide rescuers during CPR can improve adherence to published resuscitation guidelines. Spectral analysis of chest acceleration was used to compute the depth and rate of chest compressions.112 The use of a novel CPR card feedback device was also shown to improve the quality of chest compressions.113 In addition to interventions aimed at improving the quality of chest compressions, recent data suggest that optimization of oxygen delivery to the ischemic tissue can also be complemented by enhanced ventilation strategies. Chest Compression Synchronized Ventilation (CCSV) is designed to detect starting chest compression efforts and to initiate an instant inspiratory pressure through reprogramming of the Pressure Support Ventilation mode. It comprises an inverse trigger, cycling mechanisms, and higher inspiratory pressure levels up to 60 mbar. Kill and colleagues showed that when compared with Intermitted Positive Pressure Ventilation (IPPV), CCSV results in a higher PaO2 without an arterial blood pressure drop during resuscitation in pigs.114 The same group of investigators reported that CCSV is associated with better delivery of the respiratory parameters and minimizes excessive inspiratory pressures that can potentially lead to pulmonary injury during simulated CPR.115

Extracorporeal Membrane Oxygenation ECMO with CPR (ECPR) continues to evolve as a therapeutic option for refractory cardiac arrest.116 Its use has significantly increased over the last few years, and new techniques are being developed to enhance its feasibility and access.117 In a meta-analysis of 10 recent publications, Kim and associates reported a trend toward improved short-term (3-6 months) survival and neurologic outcome with ECPR as compared with conventional CPR.118 Debaty and associates reported that shorter low-flow duration, shockable cardiac rhythm, higher arterial pH value, and lower serum lactate

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SECTION VII  •  Critical Care Medicine

concentration on hospital admission are associated with better outcomes for ECPR recipients after OHCA.119 Dennis and associates confirmed that in selected patients with refractory cardiac arrest, ECPR may provide temporary support as a bridge to intervention or recovery. Favorable survival and neurologic outcomes were reported in one-third of patients with pre-ECMO lactate levels predictive of mortality.120 Controlled Automated Reperfusion of the whole body (CARL) is a new type of extracorporeal circulation device that provides continuous adjustments of reperfusion conditions with the recirculating blood according to the individual readings of each patient. It combines measures to control arterial blood pressure and blood flow with TTM, as well as control of the acid-base status, oxygen content, osmolarity, and electrolytes to minimize the ischemiareperfusion injuries. Based on data from experimental studies, recently Trummer and associates successfully employed CARL after 120 minutes of normothermic CPR in a patient. Except for a spinal cord injury resulting in lower extremity weakness, the patient was reported to have survived without any neurologic deficits.121 Emergency preservation for delayed resuscitation (EPR) or suspended animation is another promising approach to enable intact survival in patients who are expected to fail conventional resuscitation techniques. It was developed by the Safar team at the University of Pittsburgh to apply profound hypothermia to preserve the organism and avoid irreversible organ damage and buy enough time to obtain surgical hemostasis in victims of exsanguination cardiac arrest. This concept has been tested successfully in multiple large animal studies, confirming that full recovery is possible for up to 2 hours of no-flow cardiac arrest when profound hypothermia to 10°C is induced within minutes, and is then followed by delayed resuscitation using cardiopulmonary bypass or extracorporeal circulation. Tisherman and associates recently reported the development of the first multicenter clinical trial of EPR in victims of traumatic cardiac arrest.122 If successful, EPR can also be employed as an alternative resuscitation approach in patients with refractory intraoperative exsanguination cardiac arrest. 

window. Prognostication should not occur until 72 hours after ROSC or, if TTM is provided, 72 hours after completion of TTM. A useful tool to predict outcome after cardiac arrest is the GO-FAR score, which was derived from the Get With the Guidelines-Resuscitation registry and identifies a large proportion of patients (28.3%) who have a low or very low likelihood (20% of TBSA in other age groups Second- and third-degree burns that involve the face, hands, feet, genitalia, perineum, and major joints Third-degree burns on >5% TBSA in any age group Electrical burns, including lightning injury Chemical burns Inhalation injury Burn injury in patients with preexisting medical disorders that could complicate management, prolong recovery, or affect mortality Any patients with burns and concomitant trauma (such as fractures) in which the burn injury poses the greatest risk of morbidity or mortality; in such cases, if the trauma poses the greater immediate risk, the patient may be treated initially in a trauma center until stable before being transferred to a burn center Hospitals without qualified personnel or equipment for the care of children with burns should transfer the patient to a burn center with these capabilities Burn injury in patients who will require special social/emotional and/or long-term rehabilitative support, including cases involving suspected child abuse and substance abuse

TBSA, Total body surface area.

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SECTION VIII  •  Ancillary Responsibilities and Problems

10% TBSA; those with burns of the face, hands, feet, genitals, perineum, or across major joints; and those with full thickness (third degree) burns of any size. Evidence suggests that burn injury patients have improved outcomes if transferred early to a facility capable of providing an advanced level of burn care.95,96 Therefore it is important to accurately identify those patients with burns severe enough to merit transfer so that outcomes will be optimized. Burn centers have been developed to standardize and optimize the overall quality of care delivered to burn-injured patients.97 Burn centers provide acute care using a multidisciplinary team that includes burn surgeons, anesthesiologists with special interest in burns, critical care physicians, burn-trained nurses, physical and occupational therapists, pharmacists, and dietitians. In addition, improvements in burn survivors’ long-term functional and psychological outcomes and quality of life have resulted from burn units having integrated relationships with physiatrists and rehabilitation facilities as well as burn psychologists and exercise therapists. Since an important part of functional recovery includes returning to work or school, newer additions to the burn team include vocational counselors, recreational therapists, child life specialists, and teachers. 

than 2 weeks to heal. Deep partial thickness burns extend into the reticular dermis and appear yellow or white and dry and often are extremely painful; however, in some cases, the sensation in the deep partial thickness may become diminished. Full thickness or third-degree burns extend through the entire thickness of the dermis. These may appear dry, leathery, black, or white and are usually painless since nerves and endings are destroyed. They do not blanch under pressure. Although initially painless, the subcutaneous inflammation associated with deep dermal burn often becomes more painful than more superficial burns.103 The designation, fourth-degree burns, is used to describe those that have injured deeper structures, such as muscle, fascia, and bone. Deep second-, third-, and fourth-degree burns require surgical debridement and grafting, whereas more superficial burns do not. Since the area of injury may progress over the first 2 to 3 days after the initial insult due to the effects of coagulation and ischemia, burn depth estimation may be greater when examined later compared to the initial evaluation. Close reevaluation may be required to determine the actual burn size and depth. 

Estimation of Size and Depth of Burn Injury

Current fluid therapy is based on knowledge gained over the last century. Major breakthroughs in fluid management were made by Underhill, who described the pathophysiology of burn injury in detail in the 1920s.104 In 1940, after the Coconut Grove night club disaster in Boston, Massachusetts, the first attempts were made to use intravenous fluids to treat a large group of burn injury patients, and the result was that the mortality was significantly lower than expected. In 1953, the first fluid formula based on the size of the burn and the patient’s weight was introduced by Evans.105 The formula most widely used today is the one that was published in 1974 by Charles Baxter, who was then working at the Parkland Memorial Hospital in Dallas, Texas. The Parkland formula calls for 4 mL/kg/%TBSA of Ringer lactate solution given over the first 24 hours, half of which is given within the first 8 hours from the time of injury.106 The main advantages of the Parkland formula are use of an easily obtainable fluid (Ringer lactate), low cost, and a strategy that is easy to start and follow. A number of other formulations have been reported over the years, but none has the global impact of the Parkland formula. Some of the more common options are listed in Table 87.1.107,108 Today, few centers in Europe or the United States use formulations other than the Parkland initially.109 Appropriate resuscitation should be initiated promptly and tailored based on patient parameters to avoid over- and under-resuscitation. Delayed or inadequate fluid replacement results in hypovolemia, tissue hypoperfusion, hypovolemic shock, and multiple organ failure. Morbidities associated with overresuscitation include pulmonary edema, compartment syndromes (muscle compartments, abdomen, and the orbits), and even cerebral edema. As a general rule, burns of less than 15% TBSA can be managed with oral or intravenous fluid administered at 1.5 times maintenance rate (Box 87.2) and careful attention to hydration status. Maintenance fluids, including a source of glucose, should be added to pediatric patient resuscitation fluid as hepatic glycogen stores will be depleted after 12 to 14 hours of fasting.110

The magnitude of burn injury is classified according to the percentage of total body surface area (%TBSA) involved, depth of the burn, and the presence or absence of inhalational injury. Accurate estimation of burn magnitude is needed to guide the initial resuscitation strategy, make the referral to a burn center, ascertain the need for surgery, and to estimate prognosis.98 Whereas a detailed evaluation of the extent of the thermal injury is assessed during the secondary survey, an early estimate of burn size and depth is needed during the primary survey to calculate initial resuscitation fluid requirements for circulatory support. Three of the most commonly used methods to estimate %TBSA are the “rule of nines,” palmar surface area, and the Lund-Browder diagram. The rule of nines is used in adults and is less accurate in children. This method divides the body into body surface areas of 9% (the head, each upper limb, the front of the trunk, the back of the trunk, the front of each lower extremity, and the back of each lower extremity).99 The surface area of the patient’s palm (excluding the fingers), approximately 0.5% of the TBSA, is used to estimate small (25 or as necessary for mechanical ventilation), hyperglycemia (plasma glucose ≥230 mg/mL) in the absence of diabetes mellitus, thrombocytopenia (will not apply until 3 days after initial resuscitation; platelet count ≤100,000 μ/L), and the inability to continue enteral

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87  •  Acute and Anesthetic Care of the Burn-Injured Patient

feeding for more than 24 hours. Other clinical indicators of sepsis may include increased fluid requirements, hypotension, altered mental status, and worsening renal status. It is likely that use of multiple indicators of sepsis will improve the sensitivity and specificity of early sepsis diagnosis in this clinically more difficult setting.195 Burn wounds are particularly known to be tetanus prone. Patients who are current with vaccination status require no further treatment while those with unknown or inadequate vaccination status should receive tetanus toxoid in addition to tetanus immune globulin.196,197 

Metabolic Considerations The hypermetabolic response after burn injury is more severe and sustained than any other form of trauma. Burn injury patients have increased resting energy expenditures, increased myocardial oxygen consumption, marked tachycardia, increased body temperature, glycolysis, proteolysis, lipolysis, and futile substrate cycling.198 Marked and sustained increases in catecholamine, glucocorticoid, glucagon, and dopamine secretions are thought to initiate the cascade of events leading to the acute hypermetabolic response with its ensuing catabolic state. The role of DAMPS in this hypercatabolic state has not been elucidated.199 The metabolic rate of patients with greater than 40% TBSA burn can exceed 180% of non-burned levels during admission and 150% at the time of complete wound healing.200 Furthermore, the hypermetabolic response to burn injury persists well beyond wound closure, with metabolic and inflammatory changes that can occur up to 3 years after the injury, especially in children with very large burns.201 This high metabolic demand and energy expenditure results in the catabolism of lean muscle mass, which may have important detrimental effects for the complete recovery processes.198 The relevance of the postburn hypermetabolic and inflammatory effects includes prolonged insulin resistance, increased fracture risk, increased liver size due to steatosis, growth impairment, increased cardiac work and dysfunction, protein catabolic state, and impaired muscle strength, hormonal abnormalities, and increased risk for infection. Consequently, severe burn injury is not an acute illness but rather a chronic health problem. Numerous strategies have been employed to modify this catastrophic response including early excision and grafting, thermoregulation, and early aggressive enteral feeding. There are several proven pharmacologic approaches to attenuate the hypermetabolic flow phase of a burn. Adrenoceptor blockade (most commonly with the nonselective β-blocker, propranolol) has favorable effects on heart rate, resting energy expenditure, oxygen consumption, and net muscle-protein balance.203 Insulin therapy promotes maintenance of muscle mass and improved donor site healing, without increasing hepatic triglyceride synthesis. It also attenuates the inflammatory response.204-206 Oxandrolone, a synthetic androgen, has been shown to increase both muscle protein synthesis and muscle strength as well as improve bone mineral content, and is today recommended in burn care guidelines.207 Despite these pharmacologic therapies, muscle wasting of burn injury persists for several years. More research is needed to better manage these functional deficits. 

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Nutrition Nutrition is of critical importance for the burn injury patient. It has been estimated that a patient’s basal energy needs may benefit up to 200%.208 Nutritional support not only partially abates the hypermetabolic response and attenuates muscle protein loss but also modulates stress hormone levels, improves gut mucosal integrity, improves wound healing, and decreases the risk of stress ulcer formation. Growing evidence suggests that early nutrition is safe, efficacious, and leads to better outcomes. In addition, evidence suggests that delay in enteral nutrition leads to a higher incidence of gut mucosal atrophy, microbial translocation, which can lead to sepsis, and multiorgan failure. The potential disadvantage of early feeding is a higher risk of complications when the patient is being resuscitated from burn shock. Gastric ileus is not uncommon in the early phase, and feeding could lead to a higher risk of aspiration. In addition, there is a concern that burn injury patients who are still in shock may be at risk of intestinal necrosis if fed. Enteral nutritional support should be used in preference to parenteral nutritional support. Parenteral nutrition should be reserved for those with prolonged ileus and or enteral feeding intolerance. Oral feeding is preferred to enteral feeding (liquid formulae given through nasoenteric tubes) because of the reduction in both cost and complications. However, the severely injured are unable to eat enough to satisfy the hypermetabolic response. While underfeeding can result in complications, it is important to recognize that overzealous nutritional support offers little additional benefit and may be harmful. Overfeeding can result in fluid and electrolyte imbalances, hyperglycemia, and hepatic steatosis. Although formulae exist to predict total caloric requirements, these often lead to underfeeding during periods of highest energy utilization and to overfeeding late in the treatment course. As there is also a large interindividual variability, actual caloric requirements should be determined by measuring resting energy expenditure with indirect calorimetry.209 Patients who suffer from extensive burn injury will often undergo multiple operative procedures often under general anesthesia. Historically, the use of general anesthesia requires patient’s to be nil per os (nothing by mouth, NPO) at midnight of the intended procedure day. This practice can lead to a major void in a burn patient’s caloric support. The feasibility and safety of continuing enteral feeding throughout operative procedures has been studied.210 Enteral feeding using post-pyloric tubes has been successful, provided the airway was secured via a cuffed ETT or tracheostomy (to prevent aspiration of gastric contents).211,212 Nevertheless, it is prudent to hold enteral feedings when there is potential for increasing abdominal pressure (e.g., prone position or surgery on the abdomen) or when an airway procedure such as tracheostomy is to be performed. 

Anesthetic Management PREOPERATIVE EVALUATION Patients are often brought to the operating room in the early phase of burn injury, when they are undergoing significant

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SECTION VIII  •  Ancillary Responsibilities and Problems

BOX 87.3  Major Perioperative Concerns for the Burn Patient □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □ □

 ge of patient A Extent of burn injury (total body surface area, depth, and location) Mechanism of injury Elapsed time from injury Associated injuries Inhalational injury and/or lung dysfunction Adequacy of resuscitation Coexisting diseases Airway patency Difficult vascular access Gastric stasis Altered drug responses Altered mental states Pain/anxiety Presence of organ dysfunction Presence of infection Susceptibility to infection Hematologic issues (anemia, coagulopathy) Magnitude of surgical procedure

fluid shifts with corresponding cardiovascular instability and/or respiratory insufficiency. Early excision of dead/ necrotic tissue with temporary or permanent coverage of the open areas is important for decreasing the burden of wound colonization and systemic sepsis. In addition to standard preoperative evaluation, there are specific features of the history and physical examinations, which deserve additional focus in the burn injury patient. These include the time and extent of burn injury, airway evaluation, presence of inhalation injury, quantity of fluid received, current resuscitation regimen and the patient’s response, vascular access/sites, and tolerance of enteral feeding and NPO status (Box 87.3). Communication with the surgeons and the critical care team is crucial to manage perioperative care in a manner that is compatible with treatment goals of the intensive care unit (ICU). Details of the surgical plan, including the extent and anticipated duration of the procedure, are also essential to estimate blood loss and to plan appropriate vascular access, invasive monitors, arrange thermoregulation, and to order appropriate blood products. Conferring with the nurse taking care of the patient will provide valuable information about the current status of the patient. 

Intraoperative Management AIRWAY MANAGEMENT Airway management in the burn injury patient may be challenging and warrants particular consideration (see Fig. 87.2). Key features of airway assessment include preexisting airway abnormality, current airway injury (i.e., inhalation injury), and signs of glottic obstruction. The type of airway abnormalities may vary depending on the stage of the injury. In the acute burn setting, mandibular mobility and mouth opening may be limited because of edema or, in later care, the developing contractures. Preanesthetic assessment of the patency and soft-tissue compliance of the

Fig. 87.3  Burn-injured patient with a severe neck contracture undergoing general anesthesia with a laryngeal mask airway.

airway are essential. Palpation of the neck and submandibular space may reveal tightness that will limit displacement of the tongue and soft tissues into the submandibular area, making laryngoscopy challenging. Dressings and nasogastric tubes may make face mask seal difficult. Facial wounds may be painful, and exudate and topical antibiotics may result in a slippery skin surface and difficulty holding the mask. Burn victims, who are beyond the acute phase of injury, may have significant scarring and contractures in the face, mouth, nares, neck, and chest, which can make airway management very difficult.213,214 The airway sequelae of burn and inhalation injury or tracheostomy can also include subglottic stenosis, tracheomalacia, granuloma formation, obstruction of the nares, and fixation of the neck in a flexed position. If a patient is suspected to be difficult to mask ventilate, it is wise to either confirm the ability to mask ventilate prior to giving drugs that promote apnea or maintain spontaneous ventilation throughout the induction and intubation. The utility of traditional adjuncts used to facilitate mask ventilation, such as an oral airway, nasal airway, jaw thrust, chin-lift, and two-hand mask ventilation, may be limited in the burn injury patient. An oral airway may be difficult to insert in patients with microstomia, as would a nasal airway in patients with scarring of the nares. Chin-lift and jaw-thrust may be impossible because of scarring and contractures, which can limit neck extension and anterior displacement of the mandible. The laryngeal mask airway (LMA), a supraglottic airway device, has been successfully used as both an alternative to tracheal intubation and a rescue airway device for burn injury patients (Fig. 87.3).215 Use of the LMA for airway management may help avoid further laryngeal injury associated with tracheal intubation. It can also serve as an aid to fiberoptic intubation. However, microstomia and fixed neck flexion from contractures can limit its use. Microstomia can impair the ability to insert the LMA into the oropharynx. Fixed neck flexion makes insertion difficult because the distal end of the LMA abuts the chest wall. Surgical release of neck contractures under local anesthesia prior to intubation may be required in severe cases. If the preoperative examination reveals concern for upper airway patency, mobility, or mask ventilation, fiberoptic

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87  •  Acute and Anesthetic Care of the Burn-Injured Patient

Fig. 87.4  Pediatric patient with burns of the face and neck. The patient underwent early tracheostomy due to profound swelling of the airway present.

intubation while maintaining spontaneous ventilation should be considered. If the patient is uncooperative, inhalational induction or the use of ketamine preserving spontaneous ventilation may permit the advancement of the fiberoptic scope. It is important to avoid gag and laryngospasm during the fiberoptic intubation. Traditional methods to topicalize the airway to prevent gag include using preinduction nebulized lidocaine or lidocaine gargle and postinduction lidocaine sprayed directly on the vocal cords via the fiberscope. Video laryngoscopy is an alternative intubating tool that also permits assessment of hypopharyngeal and glottic anatomy. In children awake intubation is not a viable option. Ketamine-induced sedation/anesthesia maintains the pharyngeal muscle tone and can be used for fiberoptic intubation in children. Tracheostomy completely done under local anesthesia is also at times a viable option (Fig. 87.4). A surgeon capable of performing a potentially difficult tracheostomy should be readily available when there is any question of inability to manage a patient with an anticipated difficult airway. The distorted anatomy can make a surgical tracheostomy difficult in both elective and urgent situations. Gastric emptying may or may not be delayed in burn injury patients.216 Sepsis, intestinal edema, and opioids may slow gastric emptying, with increased risk of aspiration. If there is concern for ileus, rapid sequence induction is generally required. The use of the LMA in the presence of decreased chest or abdominal compliance can result in redirection of ventilated volume from the lungs to the stomach. Regurgitation of gastric contents can occur in these instances significantly complicating the procedure. It is essential to secure the ETT to avoid unintentional extubation. Traditional securing methods using adhesive tapes or ties are unsuitable in patients with facial burns since tape or ties crossing burned areas can irritate the wound or cause injury to grafts. Placement of a circumferential tie around the patient’s head, using wire to secure the tube to a tooth, or use of arch bars can provide safe fixation.217-220 The use of cuffed ETTs in the pediatric burn population, both in the operating room and in the ICU, is safe and

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recommended regardless of the child’s age.221 Considerable fluctuation in airway diameter can occur throughout the patient’s acute hospital course because of laryngeal, tracheal, and bronchial edema. With fluctuations in airway diameter, the ETT cuff may need to be readjusted to facilitate mechanical ventilation without a leak or prevent overpressure in the cuff, which can cause tracheomalacia. Severely burn-injured patients may require tracheostomies because of potential complications from long-term translaryngeal intubation for mechanical ventilation. The optimal timing and indications for tracheostomy remain unresolved.222 In general, early tracheostomy should be considered if prolonged mechanical ventilation is anticipated (inhalation injury, advanced age, chronic pulmonary disease, other significant systemic comorbidities, and large burn size). Complications can occur, particularly when tracheostomies are performed under nonelective conditions, through burned tissue or in the presence of edema. Tracheostomy-related dysphagia, dysphonia, and other laryngeal pathologies have been described in burn injury patients.223 

VASCULAR ACCESS Vascular access in burn injury patients can be challenging. The anatomy of typical vascular access sites can be distorted by the burn injury and in the setting of acute injury, patients can be hypovolemic, making venous access technically difficult to obtain. In addition, resuscitation can result in edema. In pediatric patients, the task can be even more difficult. It may be necessary to place vascular catheters through burn-injured tissue or wounds. On occasion, it may be necessary to have the surgeons debride the insertion site just before placement of the vascular catheter. If no intravenous access is available, temporary intraosseous cannulation may safely be placed in patients of any age. This technique obviates the need for venous cutdowns and can be useful in emergency situations. A multiport central venous catheter is usually necessary in patients with large burn injuries because of incompatibility of resuscitation fluids with drugs, blood, and the need for hyperalimentation. Localization of vessels using ultrasonographic guidance can be useful in placing peripheral and central catheters in patients when access is difficult.224 Because burn injury patients undergo multiple surgical procedures during their hospitalization, access is required multiple times. Central venous catheters can be kept in place without changing them for more than 7 to 14 days, provided extreme aseptic techniques are practiced during their insertion and use. When a new catheter is needed, the insertion can be rotated and include the jugular, subclavian, and femoral veins. For excision and grafting procedures, securing adequate vascular access before the surgical procedure begins is necessary as blood loss can be rapid and substantial. 

VENTILATOR MANAGEMENT Respiratory failure is common after serious burns caused by inhalation injury, due to inflammatory mediators from the burn, effects of fluid resuscitation, and infection. In providing intraoperative mechanical ventilation, the same considerations used in the ICU must be followed to avoid

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SECTION VIII  •  Ancillary Responsibilities and Problems

barotrauma. Although the concept has not been tested in this population, growing evidence supports the importance of maintaining lung protective ventilation even in the operating room. During the hypermetabolic state (beginning ∼48-72 hours after burn injury), oxygen consumption and carbon dioxide production can be significantly increased. Consequently, minute ventilation can exceed 20 L/min in an adult patient with a large burn. Extensive excision and grafting procedures may result in such a physiological disturbance that postoperative mechanical ventilation is needed. The reabsorption of tumescent fluid used during surgery and the surgeryinduced bacterial and cytokine release can aggravate the lung dysfunction. The decision to wean from mechanical ventilation and extubate after surgery is based on the same considerations as in the nonburn patient. Extubation should not be performed in the presence of hemodynamic instability, significant metabolic derangement, hypothermia, sepsis, or worsening pulmonary function. Assessment of extubation readiness should include assessment for edema in the upper airway and glottis. The presence of a good air leak after deflation of the endotracheal cuff is an indirect estimate of an adequate glottic opening. Direct visualization using direct laryngoscopy or with flexible FOB is often performed in the operating room prior to planned weaning and extubation. 

MONITORING As with any patient suffering from multiorgan dysfunction, intraoperative monitoring of the burn injury patient depends on the patient’s physiologic status and extent of planned surgery. The injury per se can make placement of these monitors challenging when standard sites are burned or are within the surgical field. Difficulty may be encountered in adherence of standard electrocardiogram (ECG) electrodes as a result of exudation of fluid from the injured sites or the presence of topical antibiotic ointment. Use of needle electrodes or surgical staples to fix the electrodes can be effective. Alternatively, placing the electrodes on the back or dependent sites may hold them in place. Application of pulse oximetry probes can also be difficult and may require alternative sites, such as the ear, nose, or tongue in such circumstances. In an extensively burned patient, a blood pressure cuff may have to be placed directly over injured or recently grafted tissue. In this circumstance, great care should be taken to protect the underlying area and a sterile cuff should be used. If rapid or extensive bleeding is expected, an arterial line should be considered for continuous measurement of blood pressure and blood sampling. In addition, the arterial pressure waveform and its alterations in relation to respiration provide continuous hemodynamic information about fluid responsiveness and cardiac output and can be used to guide volume and vasoactive therapy.225 Temperature monitoring is imperative as these patients are susceptible to and intolerant of hypothermia. Monitoring of body temperature is also useful for detection of blood transfusion reactions intraoperatively (>2°C rise in temperature). Neuromuscular function monitoring in patients receiving neuromuscular blocking drugs is required as dose requirements can be significantly altered. However, continuous use of muscle relaxants

during burn surgery is seldom needed. Multiport central venous catheters are useful for simultaneous monitoring of central pressures and administering of drugs and fluids. Meticulous care to prevent contamination from exogenous sources of all existing or planned introduction of catheters and tubes should always be observed. 

PHARMACOLOGIC CONSIDERATIONS Burn injury causes pathophysiologic changes in the cardiovascular, pulmonary, renal, and hepatic systems, as well as in concentrations of circulating plasma proteins as a result of the release of endogenous mediators, and hormones together with exogenous ligands that are administered affect receptor plasticity. These changes result in altered pharmacokinetic and pharmacodynamic responses to many drugs, and these responses may vary depending on the burn severity and the time elapsed after the injury.226,227 The two distinct phases of cardiovascular and metabolic responses to burn injury can affect pharmacokinetics in different ways. During the acute injury phase (0-48 hours), there is rapid loss of fluid from the intravascular space, resulting in decreased cardiac output and blood flow to organs and tissues. Despite adequate resuscitation, patients may continue to have decreased cardiac output and decreased renal and hepatic blood flow. During this phase, there will be decreased elimination of some drugs by the kidney and liver. Because of decreased intestinal blood flow, absorption of oral drugs will also be delayed. Following the resuscitation phase, the hyperdynamic phase begins, which is characterized by increased cardiac output and increased blood flow to the kidneys and liver. Drugs dependent on organ blood flow will have increased clearances; drug doses may have to be adjusted upward accordingly. The two major drug-binding proteins, albumin and α1acid glycoprotein (AAG), are altered in opposite ways after burn injury.227 The concentration of albumin, which binds to mostly acidic and neutral drugs, is decreased in burn injury patients while AAG, which binds cationic drugs, is an acute-phase reactant and its concentration increases twofold or greater in these patients.229 Cationic drugs (lidocaine, propranolol, muscle relaxants, and some opioids) bind to AAG, resulting in decreases in free fraction. Most likely related to the decreased albumin levels and continued fluid leak through burn wounds and/or resuscitation fluids, there is an increase in volume of distribution of almost every drug studied (propofol, fentanyl, muscle relaxants). In addition, pharmacodynamic changes at target organs alter drug-receptor interactions causing variable and at times unpredictable changes in responses to drugs. Consequently, changes in the usual dosages of drugs or complete exclusion of other drugs (e.g., succinylcholine) may be necessary to ensure efficacy, patient safety, or avoid toxicity. Clearance of drugs highly extracted by the liver depends primarily on hepatic blood flow and is relatively insensitive to alterations in protein binding. Thus clearance of highly extracted drugs (e.g., propofol, fentanyl) may decrease during the early postburn phase as a result of hypoperfusion from hypovolemia and hypotension, and subsequently increase during the hyperdynamic phase when hepatic blood flow increases.230,231 During the hypermetabolic phase, renal blood flow and glomerular filtration rate

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87  •  Acute and Anesthetic Care of the Burn-Injured Patient

increase. Thus renal clearance of some drugs (antibiotics [gentamicin, cephalosporins] and H2-receptor antagonists [ranitidine]) will have enhanced elimination.232,233 In contrast, clearance of drugs that have a low hepatic extraction coefficient is unaffected by changes in hepatic blood flow, but is sensitive to alterations in plasma protein levels as it is the unbound fraction of drug that is metabolized. Hepatic enzyme activity also appears to be altered in patients with burns.226 Phase I reactions, which include oxidation, reduction, hydroxylation, and demethylation, are impaired after burn injury (e.g., diazepam). Phase II reactions involving conjugation, glucuronidation, and sulfation seem to be relatively unaffected (e.g., lorazepam).235 Additionally, systemically administered drugs may leak out through the burn wound, and blood loss during surgery can potentially exaggerate the elimination of drugs. 

ANESTHETIC DRUGS Many inhalation and intravenous drugs have been used successfully for the induction and maintenance of anesthesia in burn injury patients.230 Choice of drug should be based on the patient’s hemodynamic and pulmonary status and the potential difficulty in securing the patient’s airway. Because of its rapid onset and lack of pungency, sevoflurane offers advantages for smooth inhalation induction in children or adults with abnormal airways or those without intravenous lines. The choice of volatile aesthetic does not appear to influence outcome in these patients. Long-term sequelae of repetitive anesthetics in pediatric patients is unknown. Propofol clearance and volume of distribution are increased in patients with major burns during the hyperdynamic phase of injury.230 Therefore in comparison with nonburned patients, those with major burn injury may require larger bolus doses and/or increased infusion rates of propofol to attain or maintain therapeutic plasma drug concentrations. Attention to the hemodynamic consequences of administering larger doses of propofol is warranted.

Opioids Opioids are the mainstay of analgesia in this population of patients because (1) they are potent, (2) the benefits and risks of their use are familiar to the majority of care providers, and (3) they provide a dose-dependent sedation that is beneficial during painful and anxiety-provoking woundcare procedures.238 The wide spectrum of opioids available for clinical use provides dosing flexibility (i.e., variable routes of administration, time until effect, and duration of analgesia), which can target different pain qualities and contexts. For example, oral opioids with delayed systemic uptake (e.g., sustained-release morphine, fentanyl patch) or prolonged terminal half-life (e.g., methadone) are effective in treating background pain. In contrast, short-acting agents with rapid onset (e.g., intravenous fentanyl, alfentanil) are better suited for procedural pain alleviation. During the acute phase of injury, potent opioids such as morphine sulfate, hydromorphone, and fentanyl should be given intravenously and titrated based on patient response. It is not clear that the use of any one opioid offers fewer side effects than another. Many patients are receiving continuous infusions of opiates and sedatives before surgery. These infusions have

2765

been maintained to reach a steady state of effect and should not be stopped. Intraoperative analgesia can be achieved by increasing these infusions or turning to other drugs. Fentanyl is commonly used as an analgesic in the operating room as well as for sedation in burn care units. The volume of distribution and clearance of fentanyl are increased following burn injury partly explaining the increased dose requirement of this drug.239,240 A decreased volume of distribution and clearance of morphine has been reported in burn patients, with an expected increase in elimination half-life.241 However, other literature has suggested no significant difference in morphine pharmacokinetics between adults with and without burn injury.242 Patient-controlled analgesia (PCA) with intravenous opioids has been shown to be a safe and effective method of opioid delivery for acute or procedure-related pain in both children and adults with burn injury.243-246 PCA also provides benefit by allowing the patient to retain some degree of control over his/her medical care (i.e., control coping). The analgesic efficacy of opioids decreases with time resulting in the need for increasing dosage requirements to achieve an equivalent effect. Opioid tolerance, a diminished opioid anti-nociceptive effect following repeated exposure to opioid, may be apparent as early as after 1 week of uninterrupted opioid use.175 It is not uncommon for these patients to manifest opioid tolerance requiring dosage amounts that far exceed standard textbook recommendations.248 Studies with burned animals have suggested intrinsic pharmacodynamic opioid receptor alterations. These include desensitization and downregulation in μ-opioid receptors, and upregulation of protein kinase C-γ and N-methyl-d-aspartate (NMDA) receptors.249 In view of the NDMA upregulation following burns, it is not surprising that ketamine requirements to anesthetize patients also are increased following burn injury.250 Adverse effects of opioids, such as respiratory depression, acute opioid tolerance, and hyperalgesia, particularly with the need for rapidly escalating doses, have generated increasing attention to multimodal strategies. Clonidine, dexmedetomidine, ketamine, and methadone have been found to be effective in the treatment of pain in patients with extreme tolerance to morphine.251,252 A variety of non-opioid analgesics are useful for treating burn pain since their benefit and side effect profiles differ from opioid analgesics (Table 87.2). 

NSAIDS Acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs) are useful first-line analgesics for minor burns.253 However, NSAIDs and acetaminophen exhibit a ceiling effect in their dose-response relationship, rendering them inadequate as a single agent for the treatment of severe burn pain. NSAIDs can also have deleterious effects including bleeding risk, gastrointestinal, cardiovascular, and renal complications. As a consequence, NSAIDs are generally avoided in patients with major burns.  α2 Agonists Clonidine or dexmedetomidine (α2-adrenoceptor agonists) can be useful analgesic adjuncts without causing respiratory depression.254 However, the α2-adrenoceptor agonists can cause hypotension in higher doses and in the presence of hypovolemia; therefore these should not be

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SECTION VIII  •  Ancillary Responsibilities and Problems

TABLE 87.2  Sedation and Analgesia Treatment Guideline Stage of Injury

Background Anxiety

Background Pain

Procedural Anxiety

Procedural Pain

Acute burn mechanically ventilated

Midazolam infusion or Dexmedetomidine infusion Antipsychotics Propofol infusion

Morphine infusion

Midazolam bolus Dexmedetomidine at higher infusion rates Antipsychotics Propofol boluses

Morphine bolus Ketamine IV

Acute burn not mechanically ventilated

Scheduled lorazepam PO or IV or Dexmedetomidine

Scheduled morphine PO or IV

Lorazepam PO or IV

Morphine PO or IV

Chronic acute burn

Scheduled lorazepam or antipsychotics (PO)

Scheduled morphine or methadone

Lorazepam or antipsychotics (PO)

Morphine PO or oxycodone

IV, Intravenous; PO, per os (orally).

given to hemodynamically unstable patients. Dexmedetomidine has been used to provide sedation–analgesia for burned patients and to decrease opioid requirements.255 However, α2 agonists have also been reported to increase excitability of heat-sensitive cutaneous nociceptors but the clinical relevance of this finding in burn patients remains unclear.256 The use of dexmedetomidine has recently been reported to reduce the risk of developing delirium when used for ICU sedation, especially in comparison to benzodiazepines.257 

Anxiolytics The recognition that anxiety can exacerbate acute pain has led to increased use of anxiolytic drugs in combination with opioid analgesics. The combination of benzodiazepines and opioids is particularly useful in premedicating patients for wound care to help reduce the anticipatory anxiety related to such procedures. Patients most likely to benefit from this combined treatment are those with either high anxiety at the time of the procedure or high baseline pain scores.258 The tolerance to opiates seems to be exaggerated by long-term administration of the benzodiazepine, midazolam.259  Gabapentin Gabapentin is an anticonvulsant that has increasingly been used for chronic and neuropathic pain, and as an adjunct pain medication that may play a role in modulating central sensitization and hyperalgesia. Several studies have shown gabapentin to be a beneficial addition to an opioid analgesic regimen in this population.260,261  Ketamine Ketamine is a dissociative anesthetic that induces rapid and profound sedation, analgesia, and amnesia. It causes functional dissociation between the limbic and the cortical systems, producing a trance-like cataleptic state that impairs sensory recognition of painful stimuli and memory. In addition, by acting as a noncompetitive NMDA receptor antagonist, it is thought to both prevent the induction of central pain sensitization and its windup, thereby reducing the development and maintenance of opioid tolerance and hyperalgesia. Ketamine is a widely used analgesic agent in all stages of burn injury, both primarily and as an adjunct to other analgesic regimens.262 Intravenous ketamine is commonly used for procedures

requiring deep sedation such as dressing changes and line placement because of its rapid onset and short duration of action, which is due to rapid redistribution. Intravenous ketamine infusions can be continued safely in the ward environment after discharge from ICU. Ketamine can also be used for long-term administration although tolerance develops with time. The other advantage is that it can be weaned rapidly without adverse consequences even after long-term use.263 Ketamine has many potential advantages for induction and maintenance of anesthesia in burn patients.264 Ketamine is associated with hemodynamic stability, preservation of hypoxic and hypercapnic responses, and decreasing airway resistance. Ketamine may exert beneficial antiinflammatory effects in patients with burns and or sepsis. Also, by causing peripheral vasoconstriction, ketamine may be advantageous for patients at risk for hypothermia.265 Whether peripheral vasoconstriction occurs in patients with major burns, and whether this causes a reduction in blood loss, is unknown. It is important that bolus doses of ketamine can cause hypotension in some patients with burn injury, despite ketamine-induced catecholamine release. This occurs because of the persistently high levels of catecholamines in these patients that result in desensitization and downregulation of β-adrenoreceptors.266 As a result, direct myocardial depressant effects of ketamine can manifest. Another important feature of ketamine is that, unlike all other anesthetic agents, muscle tone and protective airway reflexes are preserved. Consequently, ketamine may be the agent of choice if one wishes to avoid manipulation of the airway (e.g., after placement of fresh facial grafts, for stent or dressing removal, for brief procedures such as dressing or line changes, or for patients with TENS). Ketamine administration can result in a number of side effects including nausea and vomiting, hallucinations, mood alteration, bizarre dreams, and emergence delirium, which tend to occur when ketamine is used as a single agent, when given in large doses, and if administered rapidly. The administration of a benzodiazepine in combination with ketamine has been shown to decrease the frequency and severity of emergence reactions.267 

Regional Anesthesia Regional anesthesia can be advantageous in targeting specific aspects of burn-injury pain. In its simplest form,

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87  •  Acute and Anesthetic Care of the Burn-Injured Patient

regional anesthesia may be tumescent local anesthesia injected into a donor site prior to harvesting or it can take the form of subcutaneous catheter infusions, peripheral nerve blocks, or central neuraxial blockade.268–271 While regional anesthesia can be the primary anesthetic management for surgical burn care, it is frequently also utilized as an analgesic adjunct, enabling opioid sparing and improved postoperative analgesia. Placement must take into consideration that skin donor sites and injury sites are often in different anatomic locations and that patients often have more intense postoperative pain from the split-thickness skin donor site than from the grafted burn wound. Central neuroaxial techniques (spinals, epidurals) have been used with good effect as both primary anesthetics and postoperative adjuncts.272-274 However, fear of meningeal spread in patients densely colonized with infectious organisms, reluctance to inserting a needle through burned tissue, and anatomic surgical incompatibilities (e.g., the need to graft lower extremities but donor sites are on upper extremities or trunk) may limit their use. There are no reports suggesting epidural abscesses are more common in burn patients, but reports have suggested that intravascular catheters are more likely to become infected if placed in or near burned tissue.275 Administration of local anesthetics (and/or opioids) via an epidural catheter would seem to be of benefit in patients with lower extremity burns, resulting in both background and procedural analgesia, as well as autonomic sympathectomy and peripheral vasodilation. Truncal blocks (paravertebral and transversus abdominis plane [TAP] can be very useful to provide analgesia for donor-site harvesting, and both block techniques are also amenable to placement of catheters to extend duration of postoperative analgesia.276 As for central neuraxial catheters, there are theoretical concerns of increased infection with placement of a foreign body (i.e., catheter) in these patients, but such infections have not been reported. It is also likely that infection from a paravertebral or TAP catheter would be a less catastrophic event than an infection from a central neuraxial catheter (e.g., epidural abscess). The lateral femoral cutaneous nerve is particularly well suited to block because it is exclusively a sensory nerve and innervates an area (the lateral thigh) that is frequently chosen for split-thickness skin grafts.277,278 Sometimes there is a need to cover the anterior and medial thigh due to the extent of skin harvest, and therefore a fascia iliaca block can also be performed. The pharmacology of local anesthetics in burn injury patients may be altered by changes in hepatic function, protein binding, and volumes of distribution.279 The incidence of adverse effects of local anesthetics or tolerance does not appear altered in the burn patient, per se, but caution is advised in the use of these potentially neuro/cardiotoxic agents in critically ill burn patients. Recent advances in local anesthetics, such as liposomally enclosed lidocaine and bupivacaine, have the potential to offer longer duration of action with greater safety (i.e., local anesthetics stay locally), but studies specific to burn patients have yet to be performed.280 

Muscle Relaxants Muscle relaxant pharmacology is significantly and consistently altered after burn injury.281 Exposure to succinylcholine can result in an exaggerated hyperkalemic response,

2767

which can induce cardiac arrest. The current recommendation is to avoid succinylcholine administration in patients 48 to 72 hours after burn injury.282,283 An increase in the number of extrajunctional acetylcholine receptors that release potassium during depolarization with succinylcholine is the cause for increased hyperkalemia. The duration of the hyperkalemic response most likely varies with the severity of the injury and accompanying critical illness, and the extent of muscle recovery. The presence of aggravating factors such as disuse (contractures), immobilization due to long-term bed rest, inadequate nourishment, and possibly ICU myopathy may also contribute to these changes and would likely make the potential of hyperkalemia more likely.281 Almost paralleling the hyperkalemia to succinylcholine, there is concomitantly a decreased sensitivity to the neuromuscular effects of nondepolarizing muscle relaxants (NDMRs). Resistance to NDMRs has been reported in pediatric patients 463 days after burn injury, suggesting that the hyperkalemic response to succinylcholine could also persist for more than a year.284 Although a hyperkalemic response to succinylcholine may be seen, whether lethal levels would be reached is unknown after such a long period. Whether small doses (0.1 mg/kg) of succinylcholine, as might be used for treatment of laryngospasm, would result in less hyperkalemia has been inadequately studied.285 NDMRs are the relaxants of choice in burn patients. However, the dose and duration of onset required to achieve effective paralysis can be substantially increased while the duration of paralysis is reduced. The etiology of the altered response to NDMRs is multifactorial: (1) upregulation of acetylcholine receptors, including upregulation of fetal and α7 (neuronal type) acetylcholine receptors at the muscle membrane; and (2) increased binding to AAG and, enhanced adrenal and hepatic elimination of the NDMRs.286,287 Resistance to the effects of NDMR is highly correlated with the magnitude of the burn and time after burn.288 Rocuronium is the drug of choice in burn patients when rapid onset of paralysis is necessary and succinylcholine is contraindicated. An increased rocuronium dose of 1.2 to 1.5 mg/kg for rapid sequence induction has been recommended in patients with major burn injury.289,290 It must be noted, however, that even with a dose of 1.5 mg/kg of rocuronium, the onset time to effective paralysis approximates 90 seconds in burned patients compared with less than 60 seconds in nonburned patients with a dose of 0.9 mg/kg (Fig. 87.5). Even at the higher doses, the duration of action of rocuronium can be quite variable; therefore monitoring of neuromuscular function is essential to specifically determine the dose requirement and the adequacy of reversal in patients with major burns. Preliminary evidence suggests that sugammadex, a modified cyclodextrin used for reversal of rocuronium- and vecuronium-induced nondepolarizing muscle block, can be used in burn patients, with recovery times for muscle activity similar to that in other types of patients.291 Atracurium, broken down by organ-independent pathways (e.g., Hofmann elimination), also exhibits reduced neuromuscular effect following burns.292 This suggests that the major component to resistance to NDMRs is pharmacodynamic in nature. No research study has specifically addressed the effect of cisatracurium following burn injury. However, it

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SECTION VIII  •  Ancillary Responsibilities and Problems

Onset of Muscle Paralysis With Rocuronium 40% Burn vs. Non-Burn (n = ~25 per Group)

100

TOF Ratio

80 60 40 Burn 1.5 mg/kg Control 0.9 mg/kg

20 0 0

30

60

Burn 0.9 mg/kg

90 120 150 Time in Seconds

180

210

240

Fig. 87.5 Dose-response curves and time to maximal effect of rocuronium in adult burned and non-burned patients. Dose versus time to percent twitch suppression for rocuronium in control subjects and burned subjects of mean 40% total body surface area (TBSA) burn and studied at least 1 week after burn. In unburned patients the rocuronium dose of 0.9 mg/kg caused 95% twitch suppression in ≤60 seconds. The same dose has an onset of >120 seconds following major burn. Increasing doses of rocuronium shifted dose-response curves to the left. However, even with 1.5 mg/kg dose, the onset was still >90 seconds. TOF ratio refers to train-of-four ratio recorded in muscle during 2 Hz nerve stimulation.

can be inferred that cisatracurium may, too, have an altered pharmacodynamic profile, and dosing should be adjusted accordingly. Pharmacologic reversal of neuromuscular blockade with acetylcholine esterase inhibitors (e.g., neostigmine) poses no special problems in patients with burn injury.283 Recovery of neuromuscular blockade has been observed at serum concentrations that would cause 100% twitch depression in nonburned patients. 

FLUID MANAGEMENT AND BLOOD LOSS DURING EXCISION Intraoperative fluid administration must be carefully optimized so as not to under-resuscitate or over-resuscitate, both of which may lead to further complications in the postoperative period. Considerations for intraoperative fluid management include the magnitude of burn excision (large excisions incur more blood loss), the depth of burn (partial-thickness burn excisions involve more blood loss than full-thickness burn excisions or fascial excision), the specific hemostatic techniques used (e.g., topical or subcutaneous epinephrine), and the volume of tumescent fluid administered. Injection of tumescent fluid into the burn or donor site should be minimized in the very young as gradual absorption of the tumescent fluid several hours later can lead to pulmonary edema.294 Correction of intravascular volume before induction of anesthesia is essential. Good communication between the surgical and anesthesia teams and limiting the operative duration and extent of excision can prevent such problems. Blood should be readily available before extensive burn excision is initiated. Surgical excision of burn wounds is often associated with substantial bleeding. The hyperdynamic circulation and the inflammation-induced hyperemia exaggerate the blood loss. Published estimates of the amount of blood loss during burn excision operations are in the range of 3.5% to

5% of the blood volume for every 1% TBSA excised.295 It is not uncommon for the surgical team to remove eschar so rapidly that the patient becomes hypovolemic and hypotensive. Increased blood loss also occurs because diffuse bleeding is used as an endpoint for excision, informing the surgeon that the tissue is viable. It is difficult to estimate blood loss during burn excision because shed blood cannot be efficiently collected in a suction canister, sponges may be presoaked with hemostatic agents, and substantial bleeding can continue unobserved beneath bulky dressings. As with the initial resuscitation, there is no single physiologic endpoint to rely on for titrating fluid replacement. Clinical judgment remains a vital component, using markers of hypoxemia, perfusion (base deficit, serum lactate), erythrocyte mass, coagulation, and pulse or arterial waveform as key assessment tools. In clinical practice, serial hemoglobin measurement in euvolemic patients is commonly used to determine the need for intraoperative transfusion. Rather than focusing on a single transfusion trigger, blood component therapy should be reserved for patients with a demonstrated physiologic need. Anticipation of continued blood loss may indicate transfusion to prevent significant anemia rather than waiting to treat it when it occurs. Recent experience with civilian and military trauma with massive bleeding has demonstrated that mortality is decreased with an earlier and more aggressive administration of fresh-frozen plasma.296 Criteria for massive bleeding include loss of total blood volume in 24 hours, 4 units of packed erythrocytes transfused in an hour, or ongoing loss of more than 150 mL of blood per minute and are not unusual for patients with large burns during burn wound excision. Although clinical experience with burn patients undergoing fluid resuscitation is not exactly equivalent to hemorrhagic shock of nonburned trauma patients, it is logical to assume that more aggressive use of fresh-frozen plasma to prevent development of coagulopathy may also benefit the burn injury population who also experience massive hemorrhage. The use of platelet transfusion may also be indicated in situations with larger losses, but endpoints for such transfusions remain unclear. Targeted correction of coagulopathy using thromboelastometry may reduce transfusion requirements during surgical burn wound excision as it may indicate which blood product is needed.297 Surgical hemostasis should be maintained during the burn wound excision in order to limit complications, sustain hemodynamic stability, and limit the number of blood transfusions necessary. Increased transfusion requirement is associated with poorer outcomes. Several methods have been used to maintain hemostasis, including topical application or subcutaneous infiltration of the burn wound and donor sites with diluted epinephrine solutions, limb elevation and use of tourniquets for extremity surgery, use of compression dressings, and topically applied thrombin and fibrinogen. In addition, a brisk operative pace is beneficial. 

TEMPERATURE MANAGEMENT Patients with major burn injury have an impaired ability for thermoregulation and therefore require close monitoring of body temperature. The anesthetic-induced vasodilatation and surgical preparation with alcohol may aggravate the heat loss. The inflammatory response to large burns causes

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87  •  Acute and Anesthetic Care of the Burn-Injured Patient

an increase in the hypothalamic core temperature set point and the metabolic rate is increased to maintain this increased temperature. Hypothermia is therefore poorly tolerated as it causes an exaggerated increase in oxygen consumption and exacerbates the catabolic response to the injuries. Consequences of hypothermia during burn excisions also include decreased cardiac output, arrhythmias, abolition of hypoxic pulmonary vasoconstriction, left shift of the hemoglobin dissociation curve, interference with the normal blood coagulation mechanisms, and reduction of hepatic and renal function, as well as the reduced effect of inotropes. Intraoperative hypothermia (3 feet from source Lead aprons Leaf shields Lead surgical caps Periodic radiation monitoring

Nonionizing radiation

LASER

Eye injury Vaporization of bacterial or viral matter

Protective eyewear Laser-specific surgical masks

Microdebris from smoke

Surgical cautery Ultrasonic scalpel

Exposure to bacterial, viral, and carcinogenic matter

Surgical smoke evacuators FFP 2 particulate masks

by laser.77,78 Even laser-specific masks were many-fold less effective at particle removal than the comparator, a protection class FFP level 2 dust and fine particle mask.77 The median size of particles in plume samples obtained intraoperatively is 0.31 μm in diameter (range, 0.1-0.8 μm). Even after filtration of particles greater than 0.5 μm in diameter, exhaust smoke from tissues treated with a carbon dioxide laser causes pulmonary lesions in laboratory animals. If all particles larger than 0.1 μm are scavenged, no lung damage occurs, emphasizing the importance of scrupulous removal of the plume,70,79 a practice advocated by the CDC, OSHA, and the Association of Perioperative Registered Nurses. By using adequate evacuation and filtration equipment specifically designed to scavenge such vapors, it may be less likely that operating room personnel will be contaminated by laser-dispersed HPV DNA.67 However, laser-specific surgical masks should also be used whenever lasers are in use, and institutions should evaluate the use of smoke evacuators for the surgical field (Table 88.2). 

Infectious Exposures Understanding the basic principles of infection control is essential to the safe and responsible practice of anesthesia.

INFECTION PRECAUTIONS Infection control standards have changed dramatically over the past 50 years, with the introduction of protocols for handwashing, use of personal protective equipment (PPE), incorporation of environmental controls, and implementation of sharp safety devices. Beginning in 1985 in response to the HIV/AIDS epidemic, the CDC released recommendations for “universal precautions” to be used by all health care workers exposed to blood or body fluids, regardless of the infectious status of a patient.80 These recommendations were expanded in 1996 into the concept of standard precautions (SP), which are to be used with all patients at all times. The CDC also introduced airborne, droplet, and contact transmission-based precaution guidelines for diseases spread by those specific routes.80

Standard Precautions SP encompass hand hygiene between every patient contact event, before aseptic tasks, and after contact with bodily fluids. Hand hygiene includes both the use of plain or antibacterial soap and water and the use of alcoholbased gels without water. Unless hands are visibly soiled, hand hygiene with an alcohol-based gel has greater antimicrobial effect and is preferred to soap and water.81 It is estimated that every anesthesia procedure presents at least 25 hand hygiene opportunities and hundreds of contact events with the patient and then surfaces in the anesthesia environment but that anesthesiologists are compliant with hand hygiene recommendations only approximately 1% to 10% of the time.82,83 Importantly, using gloves does not obviate the need for hand hygiene, because 1% to 2% of examination gloves have microperforations that can allow bacteria to penetrate the glove surface.84 SP include the application of PPE such as a gown, gloves, a mask, or eye protection as appropriate during patientcare activities likely to expose a health care worker to a patient’s blood or secretions. The need for PPE differs depending on the specific task at hand. During intubation, it is recommended that the anesthesiologist perform hand hygiene and use gloves, a mask, and eye protection.85 One study estimated the frequency of glove use by anesthesiologists during intubation, extubation, and IV line placement at only 10% for attending anesthesiologists and 50% for trainees.86 When a patient is known or suspected to have an infection transmitted by a specific route, such as contact, airborne particles, or droplets, specific transmission-based precautions should be used in addition to SP. These precautions are discussed in more detail later. When transporting a patient on transmission-based precautions, it is important to ensure that the infectious areas of the patient are appropriately contained. For example, if a patient is on airborne precautions for active TB, then the patient should wear an N95 mask or higher during transport. If a patient is on contact precautions, the patient should be covered in a gown or sheets and providers should wear clean PPE during transport.80 

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SECTION VIII  •  Ancillary Responsibilities and Problems

TABLE 88.3  Immunizations Recommended for Health Care Workers Infection

Risk to Health Care Workers

Immunization

Special Considerations

Hepatitis B

Percutaneous or mucosal exposure to infectious blood/body fluid

3-dose series at 0, 1, and 6 months

Approximately 1% receiving the complete series will not have full immunity

Influenza

Infectious transmission via droplet route Yearly

Effectiveness of vaccine varies with year

Measles, Infectious transmission through dropmumps, rubella let and airborne routes

2-dose vaccine for measles, mumps and rubella together (usually as a child)

1% of health care workers who were vaccinated may have lost immunity

Pertussis

Contact or droplet transmission

Every 10 years (usually as Tdap with tetanus and diphtheria toxoids)

Even immunized health care workers need postexposure prophylaxis

Varicella

Contact or airborne transmission

2-dose series (not needed if history of past varicella infection)

Information from Immunization of health-care personnel, recommendations of the Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention 2011- REF 20.

Environmental Controls Environmental controls are additional safety measures used to prevent the spread of airborne infectious particles; examples in hospitals include engineering systems to manage ventilation (e.g., negative pressure rooms), use of high-efficiency particulate air (HEPA) filtration, frequent air exchange rates, and ultraviolet irradiation of air in the upper portion of a room or in air ducts.87,88 Because operating rooms are kept at positive pressure with respect to hallways (to prevent the introduction of infectious particles into a sterile area), elective procedures on patients with active TB or other airborne diseases should be postponed. If it is not possible to delay surgery, the procedure should be performed in an operating room with an anteroom.89 A HEPA filter should be placed in the circuit after the Y-connector, to prevent contamination of the anesthesia machine.  Needlestick and Sharps Safety A key element of universal precautions and SP is the prevention of injuries due to sharps and the use of safe injection practices. In 2000 the CDC estimated that health care workers experience more than 600,000 needlestick and other percutaneous injuries yearly.90 OSHA has developed standards to protect health care workers from exposure to bloodborne pathogens. These standards were most recently updated in 2001 after the passage of the federal Needlestick Safety and Prevention Act of 2000.91 OSHA standards mandate that employers make available safety-engineered sharps devices, provide for safe disposal of sharps, make appropriate PPE available, offer free hepatitis B virus (HBV) vaccination to workers who have been exposed to potentially infectious fluids, and have procedures for medical evaluation and PEP for employees exposed to bloodborne pathogens.92 With the implementation of safety-engineered sharps, overall needlestick injury rates have dropped significantly from before 2000 to after 2004, in some studies, by well over 50%.93 The risk of a sharps injury correlates with medical specialty and clinical experience. The Duke Health and Safety Surveillance System Study quantified the risk of percutaneous exposures to body fluids by various health care worker groups. In this study, anesthesia residents had 19 needlestick events per 100 residents per year, compared with an exposure rate for all anesthesia providers of 6.9 events per 100 employees per year and an overall exposure rate of 3.9 events per 100 full-time employees.94 In addition, night

work and shifts lasting greater than 24 hours were associated with an increased rate of needlestick injury.95 Injuries from the use of hollow-bore needles account for more than half of sharps injuries.90 Percutaneous injuries can occur during and after use of a sharp device. Wearing gloves, double gloving, and avoiding recapping needles by using a two-handed technique can reduce the risk of a needlestick injury.90,96 In addition, the use of a curved suture needle with a needle holder for suturing is safer than the use of a handheld straight suture needle.97 Accidental needlesticks are underreported. The CDC estimates that only approximately 54% of percutaneous exposures are reported to occupational health, perhaps because of fears that reporting will be time consuming or nonconfidential.98 All occupational needlesticks and exposures should be reported to a hospital occupational health program for evaluation, testing, and possible PEP. 

Vaccine Preventable Illness The CDC Advisory Committee on Immunization Practices recommends that all health care providers be vaccinated against a variety of vaccine-preventable diseases to reduce the risk of occupational exposure and transmission of these pathogens (Table 88.3). The most up-to-date infection control guidelines are available at the CDC website.99 Recommendations for infection control specific to the practice of anesthesia have been published by the ASA Committee on Occupational Health Task Force on Infection Control.6 

TRANSMISSION OF INFECTIOUS AGENTS Anesthesia providers are exposed to a wide range of infectious pathogens, including bacteria, viruses, fungi, parasites, and prions. The three principle routes of pathogen transmission are via contact, droplet, and airborne spread. Bloodborne infectious agents, such as HIV and HBV, are transmitted to the health care worker via percutaneous injuries or direct contact of nonintact skin or mucous membranes with infected blood or other serum derived body fluids (Table 88.4).100,101

Contact Transmission Contact transmission, the most common type of infectious transmission,80 can either be direct, from an infected person to another person, or indirect, with a contaminated

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88  •  Occupational Safety, Infection Control, and Substance Abuse

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TABLE 88.4  Infectious Precautions for Selected Transmissible Diseases* Infection

Type of Infectious Precaution Special Considerations

AIDS/HIV

Standard

Aspergillosis

Standard

Clostridium difficile

Contact

Ectoparasites (i.e., lice, scabies)

Contact

Gastroenteritis

Standard

Contact precautions if rotavirus, or if the patient is diapered or incontinent

Hepatitis (A-E)

Standard

Postexposure prophylaxis may be indicated for HBV percutaneous exposure

Herpes simplex Severe primary mucocutaneous All other infections (including encephalitis)

Contact Standard

Until lesions are dry and crusted

Herpes zoster (Varicella-zoster) Local Disseminated

Standard Airborne, Contact

Nonimmunized health care workers should not enter room if immunized caregivers are available.

Influenza

Droplet

Postexposure prophylaxis may be indicated in some circumstances

Measles

Airborne

Nonimmunized health care workers should not enter room if immunized caregivers are available.

Meningococcal disease

Droplet

Postexposure prophylaxis may be indicated in some circumstances

Mumps

Droplet

Nonimmunized health care workers should not enter room if immunized caregivers are available.

Multidrug resistant organisms (including MRSA, VRE, ESBLs)

Standard or Contact

Contact precautions are recommended in settings with evidence of ongoing transmission, acute care settings, or wounds that cannot be contained by dressings

Pertussis

Droplet

Postexposure prophylaxis may be indicated in some circumstances

Prion diseases

Standard

Use special sterilization procedures for contaminated surgical equipment

Respiratory syncytial virus

Contact

Use mask for actively coughing patient according to standard precautions

Rhinovirus

Droplet

Rubella

Droplet

Severe acute respiratory syndrome (SARS)

Airborne, Droplet, Contact

Staphylococcus (excluding MRSA) Major draining wounds Minor wounds or infections

Contact Standard

Streptococcus (group A)

Droplet Contact-only for major wounds

Droplet if major infectious, involves the respiratory tract. Standard precautions if a minor or limited infection

Tuberculosis (active) Pulmonary Extrapulmonary

Airborne Airborne, Contact*

Contact if active draining lesions present

Standard precautions include needlestick safety. Postexposure prophylaxis indicated for some exposures Handwashing is required after patient contact, spores are not removed with alcohol-based gels

Nonimmunized health care workers should not enter room if immunized caregivers are available.

Viral hemorrhagic fevers Droplet, Contact, and Airborne (including Ebola, Marburg, Lassa) *Excerpted from Appendix A. Type and duration of precautions recommended for selected infections and conditions. Centers for Disease Control and Prevention (CDC) 2007 guideline for isolation precautions: preventing transmission of infectious agents in health care settings.80 HBV, Hepatitis B virus; MRSA, methicillin-resistant Staphylococcus aureus.

intermediate such as a laryngoscope handle in an operating room.102 When a patient has a contact-transmitted infection, contact precautions should be used at all times. These include keeping patients separated at least 3 feet from neighbors and wearing a gown and gloves for all patientcare interactions. Examples of microorganisms commonly transmitted via contact include respiratory syncytial virus,

herpes simplex virus, Staphylococcus aureus (including methicillin-resistant S. aureus), and scabies.80 Clostridium difficile is an epidemiologically important contact-transmitted organism in health care facilities. C. difficile is a gram-positive spore-forming anaerobe that causes diarrhea and pseudomembranous colitis. The use of broadspectrum antibiotics such as cephalosporins, clindamycin,

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2782

SECTION VIII  •  Ancillary Responsibilities and Problems

and vancomycin are associated with C. difficile infection. Notably, C. difficile spores are not removed by the use of alcohol-based hand disinfectants. Health care workers who are in contact with patients suspected of having C. difficile infection should use contact precautions at all times and wash hands with soap and water after patient contact.80 Norovirus, a single-stranded RNA virus, is an important contact-transmitted organism and the most common cause of acute gastroenteritis in health care settings.103 Health care workers should use standard and contact precautions any time a patient presents with diarrheal symptoms. Health care workers who contract norovirus should check with their institutional policy, which may require that the worker be excluded from work for at least 24 hours after symptoms have resolved.103 Parasitic skin diseases caused by lice and scabies are also spread via contact transmission. Anesthesiologists should be aware of the highly contagious nature of these conditions and use a gown and gloves for all interactions with patients who have an undiagnosed rash or are suspected of carrying ectoparasites. PEP is not routinely recommended.104 

Droplet Transmission Droplet transmission occurs when an infectious agent travels a short distance directly from the respiratory tract of an infected source to a susceptible mucosal surface in a recipient.80 Droplet transmission can occur during intubation, airway suctioning, or if the patient coughs or sneezes.105 The risk of droplet transmission is believed to be greatest at a distance of less than 3 feet from an infected person. For this reason, appropriate PPE precautions for patients with droplet-transmitted infections include keeping patients separated at least 3 feet from neighbors and wearing a mask for all close patient contact. Microorganisms commonly transmitted via droplets include influenza and other respiratory viruses, group A streptococcus, and Neisseria meningitidis.80 Influenza virus types A and B cause respiratory illness in humans, ranging from mild to severe disease (influenza A infection generally causes more severe disease). Subtypes of influenza A virus are named for the surface antigens they display: H (hemagglutinin) and N (neuraminidase). Because these surface antigens change over time (termed antigenic drift), protective immunity from prior exposure to the influenza virus is partially lost. More infrequently, the surface antigens can change significantly (antigenic shift) and cause pandemic disease because the population has no immunity against the new virus strain. A pandemic H1N1 influenza A strain in 2009 caused illness in an estimated 60 million Americans.106 Because influenza virus subtypes change yearly, the CDC recommends that all persons older than 6 months be vaccinated yearly.107 The influenza vaccine cannot cause influenza infection.107 Anesthesiologists are at particular risk for exposure to influenza because of close contact with nasopharyngeal secretions. Increasingly, health care organizations are making yearly flu vaccination a mandatory condition of medical credentialing.108 Pertussis, a respiratory illness caused by Bordetella pertussis, and invasive meningococcal infections caused by N. meningitidis are two droplet-transmitted infections for which PEP is recommended for exposed health care workers.80,105

Because intubation and suctioning are considered high-risk exposures to these infections, even vaccinated anesthesiologists should be aware of the need for chemoprophylaxis if they are involved in the care of infected patients.24 The CDC recommends 5 to 7 days of macrolide therapy for pertussis exposure and single-dose oral ciprofloxacin or intramuscular ceftriaxone for exposure to invasive meningococcal disease.109,110 Droplet transmission of oral flora from health care workers to patients during lumbar puncture where the provider was not wearing a face mask has been implicated as a cause of bacterial meningitis.80,111-113 Anesthesia providers should wear face masks when placing invasive catheters or needles, including into the spinal, epidural, or central venous spaces to reduce the risk of droplet transmission of infectious agents. 

Airborne Transmission Airborne transmission occurs when infectious particles are carried in the air and remain infective over time and distance, such as when infected droplets dry into much smaller particles called droplet nuclei or when small infectious particles (i.e., spores) are created. These small (