Traumatic Brain Injury: Science, Practice, Evidence and Ethics [1 ed.] 3030780740, 9783030780746

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Traumatic Brain Injury Science, Practice, Evidence and Ethics Stephen Honeybul Angelos G. Kolias Editors

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Traumatic Brain Injury

Stephen Honeybul  •  Angelos G. Kolias Editors

Traumatic Brain Injury Science, Practice, Evidence and Ethics

Editors Stephen Honeybul Department of Neurosurgery Sir Charles Gairdner and Royal Perth Hospitals Perth WA Australia

Angelos G. Kolias Division of Neurosurgery Department of Clinical Neurosciences University of Cambridge and Addenbrooke’s Hospital Cambridge UK

ISBN 978-3-030-78074-6    ISBN 978-3-030-78075-3 (eBook) https://doi.org/10.1007/978-3-030-78075-3 © Springer Nature Switzerland AG 2021 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

To Louise and Robert (SH) To Jenny and Johnny (AK)

Preface

It is often stated in the literature that traumatic brain injury TBI is a silent epidemic with an estimated 64–74 million new cases presenting each year. It is called silent because the long-term impairments suffered by many TBI patients, such as memory loss, cognitive dysfunction or behavioural disturbance, are often not visible. However, there is a growing realization that robust pre-hospital, acute in-hospital, and post-acute/long-term care delivered by various disciplines with specific areas of expertise is paramount to optimize patient outcomes. As healthcare systems are implementing pathways for managing TBI patients from the scene of the injury and beyond discharge from the acute setting, we can be optimistic that the silence will eventually be broken. At the same time, the involvement of several disciplines, each approaching the TBI patient from slightly different angles, poses a challenge. Different disciplines often use “different languages” and may approach the same issue in a different way. An appreciation of the key concepts underpinning TBI management by all disciplines involved is essential if we are to develop a common “TBI language”. The present book aims to facilitate the development of a common “TBI language” by covering key concepts. We have organized it into four distinct but interrelated parts: I. Scientific background II. Current clinical practice III. Evidence IV. Ethical considerations The first part covers topics that TBI books traditionally cover (i.e. epidemiology, pathophysiology) but we also wanted to touch upon novel insights generated by new disciplines (e.g. brain mechanics). The second part covers current clinical practice from the scene of the injury to long-term rehabilitation. We decided to have separate chapters discussing the management of TBI in resource-limited settings, as there is a growing appreciation that when the resources are vastly different, a “one size fits all” approach (or guideline) for high-income countries (HICs) and low- and middle-income countries (LMICs) is inappropriate. The third part is discussing evidence. We are proponents of evidence-based medicine, but we also appreciate its limitations. Hence, this part provides a critical appraisal of the evidence underpinning key vii

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interventions (e.g. hypothermia, decompressive craniectomy) and key aspects of TBI (e.g. long-term neurological consequences). The fourth and final part is covering ethical considerations. Perhaps there is no other medical field with so many ethical issues, which is a reflection of two parameters in the definition of TBI: sudden trauma due to an external force that causes an alteration of brain functioning. We would like to thank the authors of all chapters, as without their time and effort, you would not be holding this book in your hands. We sincerely hope that this book will contribute to the development of a common “TBI language” for all disciplines striving to optimize the outcomes of patients who have been unfortunate to suffer a TBI. Financial Support  No financial support has been required for this research. Conflict of Interest  None declared.

Perth, WA, Australia Cambridge, UK 

Stephen Honeybul Angelos G. Kolias

Acknowledgements

We would like to thank the authors of all chapters for their efforts in preparing some excellent content despite the Covid-19 pandemic, which has been a huge challenge for everyone. We also thank the Springer staff for their support in completing this book. We hope that you will enjoy reading it and that you will suggest it to your colleagues. If you would like to get in touch with comments or suggestions, please feel free to email us at Stephen.honeybul@ health.wa.gov.au and [email protected].

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Contents

Part I Scientific Background 1 Epidemiology of Traumatic Brain Injury��������������������������������������   3 Corrado Iaccarino, A. Gerosa, and E. Viaroli 2 Pathophysiology of Traumatic Brain Injury ��������������������������������  13 Katherine R. Giordano and Jonathan Lifshitz 3 Mechanics of Brain Tissue Deformation and Damage Following Trauma����������������������������������������������������������������������������  19 Michael Sutcliffe and Shijia Pan 4 Evidence Pyramid, Comparative Effectiveness Research, and Randomised Trials��������������������������������������������������������������������  29 Kwok M. Ho 5 Big Data Collection and Traumatic Brain Injury ������������������������  35 Rianne G. F. Dolmans, Brittany M. Stopa, and Marike L. D. Broekman Part II Current Clinical Practice 6 Prehospital and Emergency Department Management of TBI������������������������������������������������������������������������������������������������  47 David J. Barton and Francis X. Guyette 7 Monitoring the Injured Brain��������������������������������������������������������  53 Enza La Monaca, Orazio Mandraffino, Deepak Gupta, and Anna Teresa Mazzeo 8 Contemporary Medical Management of Traumatic Brain Injury: High-Income Countries ������������������������������������������  69 Marcel Aries and Gerrit Schubert 9 Contemporary Management of Traumatic Brain Injury: Low and Middle-Income Countries ����������������������������������������������  79 Andrés M. Rubiano and Jeffrey V. Rosenfeld

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10 Contemporary Surgical Management of Traumatic Brain Injury��������������������������������������������������������������������������������������  93 Wellingson Silva Paiva, Davi J. Fontoura Solla, and Stephen Honeybul 11 Military Management of Traumatic Brain Injury������������������������ 111 Brian P. Curry, Michael Cirivello, Melissa Meister, Jeffrey V. Rosenfeld, and Randy S. Bell 12 Contemporary Management of Paediatric Head Injuries ���������� 123 Snigdha Saha and Stephen Honeybul 13 Sports-Related Traumatic Brain Injury���������������������������������������� 137 Niklas Marklund 14 Rehabilitation After Traumatic Brain Injury������������������������������� 147 H. Mee, L. M. Li, and F. Anwar Part III Evidence 15 Predicting Outcome Following Traumatic Brain Injury�������������� 161 Kwok M. Ho 16 Biomarkers in Traumatic Brain Injury ���������������������������������������� 169 Jussi P. Posti and Olli Tenovuo 17 Erythropoietin, Progesterone, and Amantadine in the Management of Traumatic Brain Injury: Current Evidence������ 179 Davi Jorge Fontoura Solla and Wellingson Silva Paiva 18 Tranexamic Acid in the Management of Traumatic Brain Injury�������������������������������������������������������������������������������������� 187 Omar K. Bangash, Kwok M. Ho, and Stephen Honeybul 19 Hypothermia in the Management of Traumatic Brain Injury�������������������������������������������������������������������������������������� 197 Stephen Honeybul 20 Decompressive Craniectomy in the Management of Traumatic Brain Injury������������������������������������������������������������������ 205 Sara Venturini, Peter Hutchinson, and Angelos G. Kolias 21 Cranioplasty Following Traumatic Brain Injury�������������������������� 215 Stephen Honeybul 22 Thromboembolic Prophylaxis in Traumatic Brain Injury���������� 229 Kwok M. Ho and Stephen Honeybul 23 Long-Term Neurological Consequences of Traumatic Brain Injury�������������������������������������������������������������������������������������� 237 Stephen Honeybul

Contents

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24 Post-Traumatic Epilepsy ���������������������������������������������������������������� 247 L. G. Viswanathan, Harsh Deora, Ajay Asranna, and Andrés M. Rubiano 25 Brain Death: Current Evidence and Guidelines �������������������������� 259 Anna Teresa Mazzeo and Deepak Gupta Part IV Ethical Considerations 26 Introduction to Bioethics ���������������������������������������������������������������� 269 Ahmed Ammar and Stephen Honeybul 27 Consent for Neurosurgery in Cases of Traumatic Brain Injury�������������������������������������������������������������������������������������� 277 Camilla Louise Scanlan, Cameron Stewart, and Ian Kerridge 28 Team-Based Decision-Making in Traumatic Brain Injury���������� 285 Timothy R. Smith, Brittany M. Stopa, Caroline M. W. Goedmakers, and Aakanksha Rana 29 Traumatic Brain Injury and Resource Allocation������������������������ 295 Allan Taylor, Solomon Benatar, and Bettina Taylor 30 Research Ethics in Clinical Trials�������������������������������������������������� 301 Stephen Honeybul and Kwok M. Ho 31 Artificial Intelligence and Healthcare Ethics�������������������������������� 315 Aakanksha Rana, Caroline M. W. Goedmakers, and Timothy R. Smith 32 Ethical Issues in Paediatric Traumatic Brain Injury�������������������� 327 Ahmed Ammar and Stephen Honeybul 33 Withholding and Withdrawing Treatment������������������������������������ 335 Tamra-Lee McCleary and Stephen Honeybul 34 Long-Term Outcome Following Traumatic Brain Injury������������ 345 Stephen Honeybul

Part I Scientific Background

1

Epidemiology of Traumatic Brain Injury Corrado Iaccarino, A. Gerosa, and E. Viaroli

1.1

Introduction

It is often stated in the literature that traumatic brain injury (TBI) is a silent epidemic with an estimated 64–74  million new cases presenting each year [1]. It is called silent because the impairments suffered by many TBI patients, such as memory loss, cognitive dysfunction, or behavioral disturbance, are often not visible. However, the silence is gradually being broken as the global healthcare implications for the management of TBI patients become increasingly visible. The issues that need to be considered will vary depending on the evolving patterns of injury and the local healthcare resources available [2, 3]. For example, the rapidly increasing industrialization of some low- and middle-income countries C. Iaccarino (*) Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy Neurosurgery Division, University Hospital of Modena, Modena, Italy e-mail: [email protected] A. Gerosa Neurosurgery Division, Department of Clinical Surgical Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy E. Viaroli Division of Neurosurgery, Department of Clinical Neurosciences, Addenbrooke’s Hospital, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK © Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_1

(LMICs) has led to a marked increase in motorized transportation, for both two- and four-­ wheeled vehicles. This has often not been accompanied by concomitant improvements in safety legislation, and this has led to a significant increase in the incidence of motor vehicle-related TBI, so much so that TBI is becoming one of the major causes of death and disability in many of these countries. In high-income countries (HICs), improvements in healthcare have led to considerably extended life expectancy, which has increased the risk of fall-related TBI.  In addition, in high-­ income countries (HICs), vast amounts of money are involved in organized sports such as American football, where players from a young age are encouraged to target the head in repetitive, high-­ impact collisions. It is now recognized that the long-term effects of these repetitive minor TBIs are not insignificant, and this may present substantial governance issues for some of the major sporting authorities. Finally, it is becoming apparent that military personnel returning from conflict zones such as Iraq and Afghanistan are suffering from the long-term consequences of their trauma-related brain injuries. Some of the most robust data on the epidemiology can be obtained from the Centers for Disease Control and Prevention in the USA. They report that 52,000 people die every year from TBI, 275,000 people are hospitalized, and

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C. Iaccarino et al.

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roughly 1.4  million people are seen and discharged from an emergency room for TBI. TBI is a contributing factor in 30.5% of all injury-related deaths that occur in the USA and is the leading cause of death for people under the age of 45 in the Western world [4]. The economic and social impact is considerable, with an estimate of direct medical expenditures and indirect costs (e.g., loss of productivity) attributable to TBI exceeding $60 billion in 2000 in the USA. However, notwithstanding the economic impact, the World Health Organization (WHO) estimates that almost 90% of deaths due to injuries occur in LMICs, where the 85% of the global population live. This situation will continue to represent an important global healthcare problem in the upcoming years, and in light of these findings, there is a strong need to study the epidemiology of TBI in order to plan preventive measures, allocate resources effectively to manage acute injuries and long-term rehabilitation services, and assess the short- and long-term outcomes in order to assess treatment efficacy. Despite these requirements, the reality is that the global epidemiological literature on TBI has significant limitations because: • The definition of TBI can be variable. • Classification can be inconsistent across studies. • There are limited systems in most LMICs that can prospectively and accurately track the incidence of TBI. • The incidence of TBI is highest in LMICs where resources are limited. The aim of this chapter is to assess these limitations, outline the global healthcare burden of TBI, and explore some preventive strategies.

1.2

Defining Traumatic Brain Injury

Any definition of TBI will have limitations, given that it is such a diverse and heterogeneous disease process. However, one definition that encompasses most aspects is

“an alteration of brain functioning or the emergence of evidence of brain pathology caused by an external force” [5].

This definition will cover most situations, especially in circumstances where a patient seeks medical attention or where they require hospital admission. However, there are many instances where there has been a minor impact to the head and there is no alteration in function or evidence of pathology. Currently, this is an area of intense interest because it remains to be determined when a (presumably) insignificant strike to the head, as occurs on a regular basis when heading a ball in a soccer game, becomes significant, as occurs in high velocity head-to-head collisions in an American football game. The cumulative effects of the latter type of injuries are currently under intense investigation, and there is also a growing interest in the cumulative impact of the former types of injury. These issues and the implications for sports-related injuries are discussed in more detail in Chaps. 13 and 23.

1.3

Classifying Traumatic Brain Injury

Traditionally, the severity of injury in TBI is classified as mild, moderate, or severe. This is based on clinical indicators, the most common of which are as follows: • Post-resuscitation level of consciousness • Episode and length of time of loss of consciousness • Duration of posttraumatic amnesia (PTA) The most commonly used tool for assessing conscious level is the post-resuscitation Glasgow Coma Scale (GCS), which was initially described nearly half a century ago, and there is no doubt that it is a robust assessment tool that has stood the test of time. It has also been shown to be highly effective when predicting outcome, especially in the context of severe TBI.  A score of 13–15 is considered mild, 9–12 is considered moderate, and 3–8 is considered a severe injury. However, notwithstanding its usefulness as a

1  Epidemiology of Traumatic Brain Injury

v­alidated and reliable assessment tool, it does have a number of limitations, especially when considering epidemiological studies. For severe injuries, especially in HICs, the modern-day emphasis placed on aggressive resuscitation and early endotracheal intubation can make it difficult to make a reliable assessment because a patient may already be under the influence of sedative agents prior to hospital admission. This is in no way a criticism of the accuracy of the paramedical staff assessment or indeed that of the emergency physician because in the acute setting of a severe TBI, they will understandably concentrate on the time-dependent issue of securing a patent airway and maintaining tissue perfusion. However, in these circumstances, an initial GCS may be recorded as severe when the patient has actually sustained a more moderate injury. In these circumstances, further confounders to making a reliable assessment include the following: • Alcohol intoxication • Recreational (or in some circumstances prescription) drug usage • Multiple injuries requiring prolonged resuscitation In the context of minor TBI, the prognostic value of the GCS is useful from an epidemiological basis, but from an individual clinical perspective, it may be more useful to consider other indicators when considering prognosis, such as the length of time a patient was unconscious or the length of time a patient has been in PTA.

1.4

 he Incidence of Traumatic T Brain Injury

The true incidence of TBI and its global distribution is unknown, although it has been estimated using a mathematical model [1]. There are many reasons for this, not the least of which are the issues with heterogeneous study methodology and underreporting of minor TBI; however, the overriding limitation is the lack of robust trauma registries in LMICs where up to 80% of the global burden of TBI are located.

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Most studies describe the incidence as cases per 100,000 of a population, and a systematic review of European epidemiological studies found a very wide range reported [6]. One study from a Spanish province estimated the annual average to be 91 cases per 100,000, whereas a study from Sweden estimated the annual average to be 546 per 100,000. In the USA, data from the Centers for Disease Control and Prevention (CDC) estimates the average incidence between the years 2002 and 2006 to be 576.8 per 100,00, and while the number of emergency department visits and subsequent hospitalizations has increased, the mortality rate has decreased [7]. Overall, there is little doubt that these studies underestimate the true incidence of TBI, and the wide variation in reported incidence serves to highlight the difficulty in assessing the true incidence even in HICs. One of the most robust epidemiological studies comes from a prospective population-based study conducted in the city of Hamilton in New Zealand [8]. The investigators enrolled all healthcare providers from primary healthcare to hospital and ambulance services as well as the local schools and prisons. During the period of the study, 1369 TBIs were recorded, which placed the annual incidence rate at 790 per 100,000. There is no reason to suspect that New Zealanders are more prone to TBI than any other HIC, so this data goes some way to underscore the issue of underreporting.

1.5

 he Severity of Traumatic T Brain Injury

Despite the inconsistencies regarding injury classification, it is generally estimated that by far, the most common TBIs are mild, and it has been estimated that this may represent between 70% and 90% of all TBIs. However, given the aforementioned confounder of underreporting, the figure of 95%, which was reported in the New Zealand study, may be nearer the true incidence. When considering the incidence of moderate and severe TBI, the previously mentioned confounders make a clear distinction difficult, and this is

C. Iaccarino et al.

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d­ emonstrated when utilizing hospital records to classify injury as this tends to overestimate injury severity. However, the review of European studies calculated a TBI severity ratio of 22:1.5:1 for mild, moderate, and severe injuries, respectively, and these were similar findings to the New Zealand study [5, 8]. Taken as a whole, the global incidence of TBI is thought to be rising, such that it is likely to surpass many diseases as the major cause of death and disability by the year 2020.

of 1.6:1, and the European TBI studies reported a range of 1.4:1–1.8:1. It has been noted that the European studies were biased toward more serious injuries, and the true divide may be reflected in the New Zealand studies that found a male-to-female ratio of 1.67:1. There may be a number of reasons for this disparity, such as differences between males and females in risk-taking behavior, greater exposure in males to occupational hazards, and violence-­related injuries. • Age A consistent finding in many population-­ 1.6 Financial Perspective based studies is the high rates of TBI in early childhood (age 0–4), late adolescence (age From a financial perspective, the costs of TBI are 15–19), and the elderly (age over 75). prohibitive. In the USA, the economic impact of Data from the CDC found the following head injury was estimated to be $75 billion, with rates in the USA: each individual patient costing $396,000, taking –– Early childhood—1337.5 per 100,000, preinto account the costs of treatment, rehabilitation, dominantly falls and loss of productivity [9]. –– Late adolescence—896.2 per 100,000, preThese cost estimates do not adequately dominantly MVAs and assaults account for the costs of extended rehabilitation –– Elderly—932 per 100,000, predominantly and services and supports such as informal carefalls giving that may be needed by those with long-­ The elderly account for the highest number term or lifelong disability. In addition, these of hospitalizations (339.3 per 100,000) and estimates do not take into account the value of deaths (56.6 per 100,000). lost quality of life or productivity losses for • Alcohol caregivers. There is a well-established association The methodological differences of the various between alcohol and all types of injuries. epidemiological studies combined with the variThere is a considerable range reported in the ability with which the populations are analyzed literature with figures of 56%–72% in the prevent accurate extrapolation of much of the USA down to 24%–51% in Europe. There financial data from the USA to other HICs, may be a number of reasons for this wide although the cost is presumably similar. range, not the least of which is the variation in how a blood alcohol test was actually done.

1.7

Risk Factors for TBI

There are a number of well-established risk factors for TBI, and these findings are generally consistent across most studies: • Gender Most epidemiological studies have noted that males are significantly more likely to sustain a TBI, more likely to be hospitalized, and twice as likely to sustain life-threatening injuries. US data reported a male-to-female ratio

1.8

 raumatic Brain Injury in T HICs

It is in the causes of TBI in HICs that there has been a significant change in epidemiology in recent years. In the context of severe TBI, MVAs have always contributed significantly to the global burden of disease. However, in HICs, the number of total TBI events related to MVAs has been decreasing, and the main cause of severe

1  Epidemiology of Traumatic Brain Injury

TBI is now falls in young children and in elderly patients [2, 8]. There is probably no single reason that can account for the decrease in the incidence of MVA-related TBI, and several interrelated factors may be responsible. Over recent decades, there have been considerable improvements in car safety design, and this has been combined with the development and mandatory installation of highly effective airbags. There has also been a significant preventive legislation introduced such as the following: • The compulsory wearing of seat belts, motor cycle helmets, and cycle helmets • Introduction of strict speed limits, frequently enforced by sophisticated unmanned speed cameras • Strict enforcement of drink-driving laws The reason why falls are now the most common cause of TBI in HICs probably relates to healthcare improvements and subsequent increase in life expectancy, as well as the increased risk of falls that comes with an aging population. This epidemiological shift has a major influence on the type of pathology seen by neurosurgeons. There is an absolute increase in the number of patients with contusions and hemorrhages, more frequently associated with falls, in comparison to diffuse cerebral swelling, which is more frequently associated with high-energy trauma. The high and increasing incidence of TBI-­ related emergency department visits, hospitalizations, and deaths among older adults in European countries has been confirmed in multiple epidemiological studies in individual US states and other HICs, such as the UK, Scotland, Portugal, the Netherlands, Finland, Austria, Canada, and Australia [10–17]. This changing epidemiological pattern emphasizes the need for the implementation of policies that target the elderly population, with a focus on fall prevention. Polypharmacological therapy and the use of psychotropic drugs (i.e., anticholinergics and sedatives) are common and widely

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known problems among the elderly, and they are associated with an increased risk of falls. Periodic assessment of vision, medication, and balance and of the home environment can have a substantial impact on falls, and this fall risk can be exacerbated by issues such as loneliness, depression, and subsequent use of alcohol. It would seem reasonable to target these issues in an efficient fall prevention policy in the elderly. When considering all types of TBI, data from the CDC places children aged 0–4 most at greatest risk of falls (839 per 100,000), with patients aged 75 and older in second place (599 per 100,000). The second most common cause of all types of TBI is motor vehicle accidents, followed by assault.

1.9

 raumatic Brain Injury T in LMICs

There are some key differences when considering TBI in LMICs. In LMICs, while the use of motor vehicles and motor cycles has increased, it has not been accompanied by legislation to prevent unsafe driving. Similarly, traffic safety education remains lacking in this setting. Given these problems, it is probably unsurprising that although only 54% of the world’s registered vehicles are in LMICs, approximately 90% of the deaths attributable to road traffic accidents occur in LMICs. Furthermore, because of limited reporting systems (i.e., trauma registries) in LMICs, this is likely to be an underestimation [2, 3]. A significant number of traumatic deaths and disability found in LMICs is probably due to increased risk factors, including a lack of prevention programs, low level of development of pre-­ hospital and hospital care, and the lack of rehabilitative services. This is a fundamental reason supporting the need to begin building national trauma registries. Availability of statistical information is vital to the process of applying for governmental and non-governmental funds, be it for research or quality improvement activities. The reasons behind the increasing incidence of TBI is likely multifactorial, including factors

8

such as expanding urbanization, a growing middle class, the availability of cheaper cars and motorcycles, and a growing and aging population in the absence of a mature healthcare system. Therefore, the effects of TBI are not limited to an individual’s health but are also a cause of increased socioeconomic burden. Mock et al. demonstrated that, for all persons with Injury Severity Score (ISS) greater than 9, mortality was proportional to the economic resources of the environment. Mortality rates declined from 63% in low-income settings to 55% in middle-income to 35% in high-income settings. Looking specifically at mid-range injury severity, the discrepancies become even more pronounced, with sixfold differences in mortality rates between low-income and high-income countries [18].These differences in mortality have led to the development of recommendations for trauma care guidelines according to different models of care based on local availability of resources. Unfortunately, the evidence generated from neurotrauma studies carried out in high-­ income countries does not always translate to LMICs, where the health infrastructure (including providers and facilities) is limited, creating a different context for care practice. The burden of disease is significant, and it has been estimated that between 1,730,000 and 1,965,000 lives could be saved if global trauma care were improved in LMICs [19]. In some LMICs, there are very high rates of violence-associated TBI.  In Latin America and the Caribbean, TBI following MVA is a significant healthcare problem and is the leading cause of intracranial injury; however, violence is the principal cause of trauma-related death in Brazil, Columbia, Venezuela, El Salvador, and Mexico. In Asia and the Middle East, interpretation of data can be difficult because there is no standardized methodology. A study from Yemen found that the most dominant cause of TBI was “domestic,” which included a vast array of causes including falls and violence. MVAs were the second most common cause. In Asia as a whole, the rise in MVAs is of almost epidemic proportions, with 44% of all of the world road deaths occurring in this region.

C. Iaccarino et al.

India, which is categorized as a middle-­ income country, provides a good example of the changes that have occurred over the past three decades and the impact that this has had on their healthcare demands [20–22]. There has been rapid industrialization, urbanization, and social and economic liberalization. The use of motor vehicles and motor bikes has increased dramatically with the numbers increasing from 5.3 to 59 million from 1981 to 2002, up to 253 million in 2017. It was estimated that 19 million motor bikes were sold in 2016 alone, and given the lack of infrastructure to maintain many of the roads, it is not entirely surprising that there are 140,000 estimated road deaths per year. This may be a considerable underestimation because in India, like many LMIC injuries, accidents are highly underreported due to the varied nature of hospital and police reporting systems, a mix of public and private healthcare providers, and, in certain cases, a degree of stigma around violence and dealing with government officials. It has been estimated that nearly 25% of all injuries among hospitalized patients are TBI-related and the annual death rate due to TBI is 200,000, with over 1 million survivors requiring rehabilitation. This places enormous strain on an already overstretched healthcare system. It is widely acknowledged that something needs to be done, and it was because of this that a new coalition, The Indian Traumatic Brain Injury Consortium, was formed by US and Indian neurosurgeons at a meeting in New Delhi in December, 2013. However, notwithstanding the good intentions of this organization, one of the biggest problems is knowing what it is that they are tackling. While it is widely accepted that India’s TBI crisis is, as is the case in many LMICs, worsening, there is limited robust data to quantify this increase, which make healthcare planning and resource allocation problematic. As is the case with many LMICs, mortality statistics in India have very limited information regarding the exact cause of death, unless someone dies in a hospital. The majority of available information is from hospital-based registries covering only a few hospitals with no clear catchment area. In the current healthcare environment, it is not mandatory for

1  Epidemiology of Traumatic Brain Injury

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Table 1.1  The WHO’s Global Status Report on Road Safety, published in 2015, “10 facts” [14] 10 Facts •  There are 1.3 million road traffic deaths worldwide    –  This is the leading cause of death among those aged 15–29 years    –  93% of road traffic deaths occur in LMICs, where 54% of the world’s vehicles has been registered • Vulnerable road users, such as pedestrians, cyclists, and riders, of motorized two-wheeled motor vehicles and their passengers account for half of all road traffic deaths globally, mainly in low-income countries • Controlling speed reduces road traffic injuries, but only 47 countries, representing 13% of the world’s population, have laws that meet the best practice on urban speed • Drinking alcohol and driving increases the risk of a crash, but only 34 countries have national drink-­driving laws • Wearing a good-quality helmet can reduce the risk of death from a road crash by 40%, but only 44 countries (representing 17% of the world’s population) have motorcycle helmet: laws that meet the best practice • Wearing a seat belt reduces the risk of death among front-seat passengers by 40–65%; however, among 105 countries, only 67% of the world’s population have seat belt laws • Infant seats, child seats, and booster seats can reduce child deaths by 54–80% in the event of a crash. Only 53 countries, representing 1.2 billion people, have a child restraint law • Prompt, good-quality pre-hospital care can save the lives of many people injured in road traffic crashes. Therefore, universal access to emergency services is required •  Vehicles sold in 80% of all countries worldwide fail to meet basic safety standards •  Unsafe road infrastructures increase the risk of crash

hospitals to share this information with national registries. If the management of TBI in LMICs is to improve, a more coordinated national and international approach is needed to adequately address this problem. In response to this issue, the WHO declared the Decade of Action for Road Safety 2011–2020 to increase worldwide awareness for road accident TBI and to advise and guide an efficient prevention policy. The WHO’s Global Status Report on Road Safety, published in 2015, reports a “10 facts file” showing that MVAs remain an important public health problem, especially in LMICs (Table 1.1) [23].

1.10 T  raumatic Brain Injury in the Military Over the past two decades, there has been considerable interest in TBI in the military population, predominantly in veterans of the Iraq and Afghanistan conflicts as there has been an increasing awareness of the burden of disease in many combat survivors. While those veterans with severe TBI are easy to identify, improvements in body armor and head protection have

allowed many veterans to survive previously fatal blast injuries. Many survivors have symptoms attributable to TBI; however, these are often combined with symptoms attributable to other post-­ combat conditions such as posttraumatic stress disorder. The Department of Defense (DoD), in combination with the Armed Forces Health Surveillance Center, collects data from US forces anywhere in the world and subdivides TBI into four classifications [24]: • Mild TBI or concussion –– Confused or disorientated state that lasts for less than 24 h –– Loss of consciousness for up to 30 min –– Posttraumatic amnesia lasting less than 24 h –– Normal radiological imaging • Moderate TBI –– Confused or disorientated state that lasts for more than 24 h –– Loss of consciousness for more than 30 min but less than 24 h –– Posttraumatic amnesia lasting more than 24 h but less than 7 days –– Normal or abnormal radiological imaging

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• Severe TBI –– Confused or disorientated state that lasts for more than 24 h –– Loss of consciousness for more than 24 h –– Posttraumatic amnesia lasting more than 7 days –– Normal or abnormal radiological imaging • Penetrating TBI –– Any head injury in which the dura is breached

C. Iaccarino et al.

important when considering comparative studies. The information gained can allow appropriate planning, which is required when considering issues such as the following:

• The number, type, and acuity of hospital beds that are needed to treat patients that require admission • The personnel required and their distribution across primary, secondary, and tertiary healthcare settings The DoD collects data on TBI on a year-by-­ • The number and distribution of rehabilitation year basis from 2000 to 2019, and there was a services steady increase that reflects the conflict in • Planning appropriate follow-up in the primary Afghanistan (Operation Enduring Freedom, 7th healthcare setting that can address some of the October to 31st December 2014) and the conflict long-term psychosocial issues that many in Iraq (Operation Iraq Freedom, 20th March patients with TBI encounter 2003 to 15th December 2011) [23]. The inciInformation from such studies is also useful dence of the so-called signature injury among US military personnel was 10,959 in 2000, and this when considering targeted prevention strategies rose on a consistent year-by-year basis to a peak and monitoring the effects of prevention proof 32,834  in 2011. The most common injury is grams. Examples of such programs might include concussion, which accounts for 82.5% of all inju- the following: ries, with moderate accounting for 8.1%, not classifiable 6.9%, penetrating 1.5%, and then • Monitoring the effects of compulsory seat belts and airbags in all cars for all passengers severe 1%. From 2000 to 2011, the greatest (already implemented in many HICs but increase by far occurs in the mild/concussion would be particularly useful in LMICs) group, which increased by 283% during this time period. While improvements in body armor may • Monitoring the effects of tighter speed limit restriction and drunk-driving legislation or go some way to explain this finding, another reducing the power of vehicle up to a certain age explanation could be increased awareness and better diagnosis of these conditions and the • Compulsory wearing of helmets for cyclists impact that it has on long-term outcomes for con- • Fall prevention programs in the elderly • Implementation of postnatal strategies to flict survivors. highlight parents who may need assistance to reduce falls in young children

1.11 Preventive Strategies

Population studies, such as those conducted by Feigin et al., are important for many reasons, not the least of which is to determine the real burden that TBI places on a society. They have demonstrated, probably better than any other previous epidemiological studies, that this type of study not only is feasible but also provides a useful framework for future study designs, which is

It is clear that many of these preventive strategies have been developed in HICs, and there would appear little doubt regarding their efficacy. What remains to be determined is their effectiveness in LMICs, where the burden of disease is greatest. However, given the financial costs inherent in the management of patients with TBI, even the poorest countries cannot afford not to implement some sort of preventive strategies.

1  Epidemiology of Traumatic Brain Injury

1.12 Conclusions Traumatic brain injury is a global healthcare problem that has significant socioeconomic implications for patients, their families and friends, and the community on many levels. Within HICs, it may hopefully not remain a silent epidemic as there is an increasing awareness of the burden placed on society, not only in terms of disability and dependency but also of the potential for cumulative minor TBIs to cause long-term problems. In LMICs, the effects of increase motor vehicle usage among many other contributing factors are largely unknown, and this should be the focus of future epidemiological research. Conflict of interest  Iaccarino C. is a consulent for postmarket surveillance of Finceramica S.p.A. Funding None

References 1. Dewan MC, Rattani A, Gupta S, et  al. Estimating the global incidence of traumatic brain injury. J Neurosurg. 2019;130:1080–97. 2. Rubiano AM, Carney N, Chesnut R, et  al. Global neurotrauma research challenges and opportunities. Nature. 2015;527:S193–7. 3. Roozenbeek B, Maas AI, Menon DK. Changing patterns in the epidemiology of traumatic brain injury. Nat Rev Neurol. 2013;9:231–6. 4. De Ramirez SS, Hyder AA, Herbert HK, et  al. Unintentional injuries: magnitude, prevention, and control. Annu Rev Public Health. 2012;33:175–91. 5. David K, Menon DK, Schwab K, et al. Position statement: definition of traumatic brain injury. Arch Phys Med Rehabil. 2010;91:1637–40. 6. Tagliaferri F, Compagnone C, Korsic M, et  al. A systematic review of brain injury epidemiology in Europe. Acta Neurochir. 2006;148:255–68. 7. Faul M, Xu L, Wald MM, et al. Traumatic brain injury in the united states: emergency department visits, hospitalizations and deaths 2002–2006. Available at: https://www.cdc.gov/traumaticbraininjury/pdf/blue_ book.pdf 8. Feigin VL, Theadom A, Barker-Collo S, et  al. BIONIC Study Group. Incidence of traumatic brain injury in New Zealand: a population-based study. Lancet Neurol. 2013;12:53–64.

11 9. Faul M, Rutland-Brown MM, Frankel W, et al. Using a cost-benefit analysis to estimate outcomes of a clinical treatment guideline: testing the brain trauma foundation guidelines for the treatment of severe traumatic brain injury. J Trauma. 2007;63:1271–8. 10. Hawley C, Sakr M, Scapinello S, et  al. Traumatic brain injuries in older adults—6 years of data for one UK trauma centre: retrospective analysis of prospectively collected data. Emerg Med J. 2017;34:509–16. 11. Hamill V, Barry SJE, McConnachie A, et al. Mortality from head injury over four decades in Scotland. J Neurotrauma. 2015;32:689–703. 12. Dias C, Rocha J, Pereira E, et  al. Traumatic brain injury in Portugal: trends in hospital admissions from 2000 to 2010. Acta Med Port. 2014;27:349–56. 13. Scholten AC, Haagsma JA, Panneman MJM, et  al. Traumatic brain injury in the Netherlands: incidence, costs and disability-adjusted life years. PLoS One. 2014;9:e110905. 14. Koskinen S, Alaranta H.  Traumatic brain injury in Finland 1991-2005: a nationwide register study of hospitalized and fatal TBI. Brain Inj. 2008;22:205–14. 15. Brazinova A, Mauritz W, Majdan M, et al. Fatal traumatic brain injury in older adults in Austria 1980-2012: an analysis of 33 years. Age Ageing. 2015;44:502–6. 16. Fu TS, Jing R, McFaull SR, Cusimano MD.  Recent trends in hospitalization and in-hospital mortality associated with traumatic brain injury in Canada: a nationwide, population-based study. J Trauma Acute Care Surg. 2015;79:449–54. 17. Harvey LA, Close JCT.  Traumatic brain injury in older adults: characteristics, causes and consequences. Injury. 2012;43:1821–6. 18. Mock CN, Jurkovich GJ, Nii-Amon-Kotei D, Arreola-­ Risa C, Maier RV. Trauma mortality patterns in three nations at different economic levels: implications for global trauma system development. J Trauma Inj Infect Crit Care. 1998;44:804–12. 19. Mock C, Joshipura M, Arreola-Risa C, Quansah R. An estimate of the number of lives that could be saved through improvements in trauma care globally. World J Surg. Published online; 2012. https://doi. org/10.1007/s00268-­012-­1459-­6 20. Number of vehicles in operation across India from financial year 1951 to 2017. Available at: https:// www.statista.com/statistics/664729/total-­n umber­of-­vehicles-­india 21. Massenburg BB, Veetil DK, Raykar NP, et al. A systematic review of quantitative research on traumatic brain injury in India. Neurol India. 2017;65:305–14. 22. Burton A.  A key traumatic brain injury initiative in India. Lancet Neurol. 2016;15:1011–2. 23. The WHO’s Global Status Report on Road Safety 2015. Available at: https://www.who.int/health-­topics/ road-­safety#tab=tab_1 24. Department of Defence worldwide numbers for TBI; 2019. Available at: https://dvbic.dcoe.mil/ dod-­worldwide-­numbers-­tbi#main-­content

2

Pathophysiology of Traumatic Brain Injury Katherine R. Giordano and Jonathan Lifshitz

2.1

Introduction

In broad terms, traumatic brain injury (TBI) is induced by mechanical forces applied to the head that displace the brain within the skull and disrupt neurological function. TBI can result from rotation, acceleration/deceleration of the brain, focal cavitation, blast-wave exposure, or a combination of biomechanical conditions. Following the mechanical force, pathophysiological processes are initiated, which extend the classification of TBI from an event to a complex disease [1]. Resultant clinical symptoms from the mechanical force and elements of the pathophysiology contribute to the designation of injury severity (mild, moderate, severe, debilitating, recoverable, fatal). Symptoms after TBI are highly variable even within each pathoanatomical classification of injury, such that the variability demonstrates the heterogeneity of TBI as a disease. Some of the factors that contribute to TBI heterogeneity include the magnitude of the K. R. Giordano · J. Lifshitz (*) Barrow Neurological Institute at Phoenix Children’s Hospital, Phoenix, AZ, USA Department of Child Health, University of Arizona College of Medicine – Phoenix, Phoenix, AZ, USA Phoenix VA Health Care System, Phoenix, AZ, USA e-mail: [email protected]

© Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_2

mechanical force, the location of the impact, pre-­ injury lifestyle, and genetics. However, even when all factors are considered, the complexity of the pathophysiology can make it difficult to determine which individuals recover and which may experience chronic morbidities [2]. The vast majority of TBIs are diffuse with symptoms that resolve within an acute to subacute time course (1–10 days post-injury). Persistent symptoms can lead to the diagnosis of post-concussion syndrome, which can last for months or years after the injury and is estimated to occur in about 10–15% of milder cases [3]. Common enduring symptoms of TBI can be broadly categorized as cognitive, somatic, or emotional, and the occurrence of long-term negative outcomes after TBI increases with injury severity [2, 3]. Collectively, TBI, whether focal, diffuse, and mixed focal/diffuse, is a leading cause of death and chronic disability worldwide [3]. The clinical presentation and subsequent recovery is unique to each individual who survives a TBI and ranges from minimal life disruption to prolonged intensive care and long-term dependence. However, despite a spectrum of clinical features and symptoms, the pathophysiological processes that occur after TBI are similar across most injuries and differ primarily in the magnitude and duration of the pathophysiology [3]. It is necessary to note that this is not the case

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for all acquired neurological injuries. Examples include penetrating injury and blast injury, which share many of the pathophysiological characteristics of other injury types, but additional distinct pathophysiological processes occur, such as extensive mechanical damage (penetrating injury) or blast-wave exposure (blast injury) [2]. In this chapter, we will discuss the common pathophysiology of diffuse TBI and how pathophysiological processes lead to clinical symptoms and chronic pathology.

2.2

Acute Pathophysiology

2.2.1 Consequences of Mechanical Force and Deformation Mechanical trauma occurs upon impact when blunt force or rotational and/or linear forces are irreversibly exerted onto the brain. Resultant pathophysiology based on the type, magnitude, and location of the force can lead to immediate observable clinical symptoms that are often involuntary reflexes or responses involving brainstem function, such as loss of consciousness. Loss of consciousness can occur after TBI, but is not present in all cases and not necessarily related to clinical outcomes [3]. In a porcine rotational model of mild TBI, sustained loss of consciousness (10–35 min) occurred only after axial plane rotation of the brain (transverse to the brainstem), whereas coronal plane rotation (circumferential to the brainstem) did not induce loss of consciousness, despite similar magnitude of force applied to the head [4]. Another example of an immediate observable clinical sign after TBI is the transient extension and/or flexion of the forearms, which is known as the fencing response [5]. The fencing response is used as a diagnostic tool to detect TBI predominantly in contact sports such as American football, because forces applied to the brainstem activate vestibular motor neurons [5]. The experimental findings of Browne et  al. and Hosseini and Lifshitz demonstrate immediate functional changes due to the directionality and magnitude of the mechanical forces that initiate the injury [4, 5]. There is no single

neurological test or biomarker to diagnose TBI; however, loss of consciousness and the fencing response indicate that mechanical force has been applied to the brain and disrupted neurological function. These studies are critical to our understanding of the biomechanics of TBI and establish diagnostic clinical signs of TBI. Additional transient symptoms that we speculate are direct consequences of the mechanical forces on the brainstem after TBI include immediate disorientation, dizziness, slurred speech, vomiting, and spontaneous sneezing, snoring, or crying. These symptoms are not mutually exclusive and do not occur in all cases of diffuse TBI but rather are dependent on the parameters of the initiating mechanical force.

2.2.2 Ionic and Metabolic Disruption Following the mechanical impact, acceleration and/or deceleration of the brain within the skull induces widespread damage from strain, tissue distortion, and shearing of axons. At the cellular level, ensuing mechanical-induced neuronal membrane disruption leads to an immediate efflux of potassium ions. Considerable increases in extracellular potassium evoke nonspecific neuronal depolarization and the release of glutamate neurotransmitter. Glutamate activates kainate, NMDA, and AMPA receptors to excite postsynaptic neurons. Glutamate release further exacerbates the efflux of potassium, creating a positive feedback loop of excitation in the immediate minutes following the impact. As above, the mechanical forces applied to the brainstem can release glutamate and activate neurons in the lateral vestibular nucleus to elicit the fencing response. Subsequently, activated NMDA receptors permit an influx of calcium ions to accumulate in the cell within hours of the impact and continue for 2–4 days post-injury [6]. Intracellular calcium accumulation activates calcium-­ dependent proteases, interferes with mitochondrial oxidative phosphorylation, compacts neurofilaments, and has downstream negative effects on axon function [2, 3, 6]. ATP-dependent

2  Pathophysiology of Traumatic Brain Injury

Na+/K+ pumps are activated to redistribute ions, but stored glucose is quickly consumed [7]. To restore homeostasis, glucose metabolism is increased in the brain. This hyperglycolysis increases the production of ATP but also the production of lactate, where excess lactate can further damage neuronal membranes, increase blood-brain barrier (BBB) permeability, and induce cytotoxic edema [6]. Following hyperglycolysis, the brain undergoes a prolonged period of glucose hypometabolism, which may leave the brain more vulnerable to a second injury and restrict the repair potential [6, 8]. The cellular processes initiated by the mechanical impact are a frenzy of activity to control the damage, while subsequent pathophysiological processes evolve with the TBI.

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However, axotomy does not necessarily lead to neuronal cell death but rather atrophy, recovery, and even regenerative attempts [11]. Ultimately, DAI disrupts the original neuronal circuitry within the injured brain.

2.2.4 Vascular Disruption and Dysfunction

Vascular structure and integrity are vulnerable to the mechanical forces that cause TBI.  For the most part, the extent of mechanical-induced vascular damage parallels injury severity, with evidence for hemorrhage, microhemorrhage, and hematoma, which can be detected by iron deposits and hemosiderin months later. In the more subtle situations, vascular dysfunction occurs without overt structure damage and may be a consequence of neuronal and glial pathophysiol2.2.3 Diffuse Axonal Injury ogy. After TBI, cerebral blood flow (CBF) has Diffuse axonal injury (DAI) is considered a char- been reported to be reduced to levels that qualify acteristic hallmark of diffuse TBI [9]. Mechanical as ischemic conditions [7]. Furthermore, the damage to axonal membranes leads to impaired BBB becomes disrupted and permeable as a axonal transport due to the cellular processes direct result of mechanical force or acceleration described above (increased calcium influx, mito- and or/deceleration of the brain, or subsequent to chondrial dysfunction, and neurofilament com- the pathophysiology, particularly inflammatory paction) and results in varying degrees of axonal proteins and proteases [12]. BBB permeability swelling and disconnection [6, 10]. Unmyelinated may lead to vasogenic edema and subsequent axons are especially vulnerable to injury-induced increased intracranial pressure, as well as infiltramechanical damage without the added physical tion of peripheral blood components including protection from myelin [10]. Primary axotomy, immune cells, iron, and reactive oxygen species or axon disconnection due to mechanical trauma, [6, 12]. The collection of vascular responses to begins in the immediate to acute phase post-­ TBI can compromise neuronal function and injury (5 min to 24 h) [6, 7]. Secondary axotomy, intensify pathophysiological processes. or eventual disconnection after initial axonal swelling, can also occur during the acute phase post-injury (4  h), with continued evidence for 2.2.5 Inflammation days or weeks after the injury [6]. While DAI is primarily characterized by axonal swelling and Mechanical and pathophysiological damage prodisconnection, cytoskeletal damage in axons duces inflammatory and cytotoxic molecules in without the evidence of swelling or disconnec- the injured environment. In response, glial cells tion results in additional axonal degradation [10]. become activated, inflammatory signaling propaDAI is understood to occur in most incidences of gates, and peripheral immune cells are recruited diffuse TBI, and experimental models have dem- to sites of injury, in order to mitigate the damage. onstrated that the severity of DAI pathophysiol- Glial activation encompasses astrocytes and ogy corresponds to the injury severity as microglia and directly impacts other physiologimeasured by neurological performance [3, 4, 7]. cal processes that regulate functional recovery

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after TBI. Upon activation, astrocytes undergo a hypertrophic morphological change and increase proliferation. Activated astrocytes notably form a glial scar around necrotic lesions (if present) after injury; however, glial scars are uncommon after diffuse TBI due to a lack of overt cell death. Instead, activated astrocytes predominantly support neuronal health after diffuse injury through upregulation of neurotrophic factors and reduction of excess extracellular glutamate in attempt to decrease excitotoxicity [13]. Astrogliosis is a critical pathophysiological process that reduces neuronal death after injury and promotes axonal regeneration. Nevertheless, prolonged astrogliosis may deter neural circuit function and prevent axonal regeneration. Microglia are the resident innate immune cells in the brain, and microglia activation can be triggered within minutes of the impact by mediators in the extracellular microenvironment, such as danger-associated molecular patterns (DAMPs), excess glutamate, peripheral blood components, growth factors, and cytokines [13]. Like astrocytes, activated microglia undergo morphological and functional changes. In a healthy brain environment, ramified microglia with small, round somas and long, thin, radially extended processes blanket the parenchyma. After injury, activated microglia can take on multiple morphologies with distinct hypothesized functions. Activated morphologies include a swollen soma with short, thickened processes, an amoeboid morphology with no processes, and a rod morphology with processes projecting only from the basal and apical poles of an elongated soma [14]. Activated microglia were once thought to be either anti-inflammatory or pro-inflammatory. However, activation is now understood to be a spectrum, and morphology and linked function are dependent on the surrounding extracellular environment and signaling from nearby neurons [14]. Upon activation, microglia increase proliferation, migrate to sites of injury, remove cellular debris, and promote circuit reorganization. Additionally, microglia secrete pro- and anti-­ inflammatory cytokines, chemokines, trophic factors, free radicals, and other substances to either promote or inhibit inflammation. Chronic

K. R. Giordano and J. Lifshitz

microglia activation has been shown years after TBI and may be linked to the delayed development of neurodegenerative pathology [13]. Inflammatory signaling is largely propagated by the cytokines and chemokines produced by activated microglia. In experimental and clinical studies, transient acute changes in cytokines (IL-­ 1β, TNF-α, IL-6, IL-10) have been shown in the CNS and periphery after TBI [10, 13]. In addition to promoting microglia activation and neuroinflammatory cascades, chemokine signaling recruits peripheral immune cells, predominantly neutrophils and monocytes/macrophages, to the injured brain. Depending on the extent of BBB damage and permeability from mechanical impact and other pathophysiological processes, peripheral immune cells may infiltrate the brain and carry out inflammatory functions similar to activated microglia. Beyond infiltration to the brain, TBI-induced activated immune cells can also infiltrate peripheral organs [1]. The extent to which TBI impacts function in peripheral organs, such as the liver or lungs, due to inflammation is still being explored and must be considered in a review of systems. Inflammation is a key pathophysiological process after TBI.  Inflammatory processes may be neuroprotective acutely, but prolonged inflammation can exacerbate the injury. Understanding the time course and mechanisms of the beneficial and detrimental effects of inflammation after TBI is critical to advancing care and treatment for TBI survivors.

2.2.6 Altered Neural Circuitry As acute pathophysiology resolves, recovery processes begin to restore homeostasis. Disrupted neural circuits that underlie the functional consequences and clinical symptoms of TBI undergo synaptic loss and deafferentation, initiated by axonal injury and executed by inflammatory processes. Following circuit damage and axon degeneration, neurorestoration, circuit reorganization, and synaptic pruning begin in what could be considered a recapitulation of developmental processes [5, 15]. Experimental and clinical studies demonstrate upregulated trophic and growth

2  Pathophysiology of Traumatic Brain Injury

factors acutely after TBI, which provide evidence of attempted repair and regeneration [15]. While circuit reorganization is considered a recovery process, maladaptive circuits can produce delayed symptoms and chronic morbidities, such as sensory sensitivity and cognitive impairments [8, 10]. In-depth understanding of circuit reorganization mechanisms after TBI is necessary to guide treatment and rehabilitation strategies to maximize positive functional outcome.

2.3

Chronic Pathophysiology

As mentioned throughout this chapter, pathophysiological processes can lead to persistent symptoms and chronic morbidities in TBI survivors. Additionally, chronic pathophysiology has been linked to delayed neurodegenerative pathology, which includes brain atrophy and accumulation of amyloid beta (Aβ) and/or tau protein; however, none of these studies are conclusive, given the long duration and extenuating circumstances of life. TBI survivors, particularly individuals who experienced repetitive TBI, are shown to be at higher risk to develop neurodegenerative diseases later in life, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and chronic traumatic encephalopathy (CTE). While there may be an association with TBI exposure, many factors (e.g., genetics, health history) influence which survivors may be more at risk. AD pathology is widely associated with Aβ plaques and neurofibrillary tangles in the parenchyma. Accumulation of Aβ can occur after TBI; however, Aβ accumulation does not occur after all cases of TBI [7]. While it is possible that subsequent development of AD pathology may correspond to TBI exposure, even in the absence of acute TBI-induced cognitive impairment, the exact mechanism of Aβ accumulation after TBI is unknown [1, 7]. There are multiple hypothesized pathophysiological processes that contribute to AD-related pathology. For example, acute increased levels of Aβ may be caused by the cleavage of amyloid precursor protein (APP) by γ-secretase complex and β-secretase 1 during

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impaired axonal transport [3]. However, Aβ continues to be increased even after axonal transport function is restored and APP levels return to normal [1]. Additionally, inflammation is a major pathophysiological process in both TBI and AD, where microglia activation may contribute to TBI-induced AD pathology [13]. While the link between TBI and AD pathology has been established, further mechanistic studies are needed in order to identify therapeutic targets to dissociate TBI-induced from AD pathology. CTE is a post-mortem pathological diagnosis that has gained attention in recent years. CTE is defined by aggregated hyperphosphorylated tau protein in the brain, and the mechanism responsible for TBI-induced tau accumulation is still being investigated. One hypothesis suggests that tau production is increased after TBI in order to preserve microtubule structure and function [3]. Upregulation of tau production could lead to tau accumulation, which defines CTE pathology. Alternatively, TBI-induced abnormal phosphorylation of tau leads to tau dysfunction and subsequent accumulation [3]. Many clinicians advocate that TBI is a treatable condition that does not always lead to CTE. There is a critical need for TBI-induced CTE research in order to better understand the time course and functional consequences of this chronic pathology. It is important to note that delayed neurodegenerative pathology and associated symptoms do not occur in all cases of single or repetitive TBI, and much controversy exists surrounding the underlying mechanisms of TBI-induced neurodegenerative pathophysiology and resultant functional outcome.

2.4

Conclusion

In summary, pathophysiological processes are initiated immediately after TBI and underlie the range of symptoms experienced by individuals. Pathophysiology and resultant symptoms can persist for years after the impact. In this chapter, we discussed some of the most common pathophysiology after diffuse TBI, which ­ involves every compartment of the brain and

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beyond. While discussion may have been presented in a linear manner, TBI-induced pathophysiological processes are interdependent, and these processes occur simultaneously. Kenzie et al. effectively diagrams the complexity of TBI pathophysiology and highlights the overlapping feedback loops that contribute to injury and recovery [2]. Despite decades of research on the topic of pathophysiology of TBI, many mechanisms remain poorly understood. We must continue to investigate pathophysiological processes in order to improve diagnosis and prognosis while opening avenues for therapeutic treatment options for the complexity of TBI. Financial Support No financial support has been required for this research Conflict of Interest  None declared

References 1. Masel BE, DeWitt DS.  Traumatic brain injury: a disease process, not an event. J Neurotrauma. 2010;27:1529–40. 2. Kenzie ES, Parks EL, Bigler ED, Wright DW, Lim MM, Chesnutt JC, et al. The dynamics of concussion: mapping pathophysiology, persistence, and recovery with causal-loop diagramming. Front Neurol. 2018;9:203. 3. Blennow K, Brody DL, Kochanek PM, et al. Traumatic brain injuries. Nat Rev Dis Primers. 2016;2:16084.

K. R. Giordano and J. Lifshitz 4. Browne KD, Chen XH, Meaney DF, et al. Mild traumatic brain injury and diffuse axonal injury in swine. J Neurotrauma. 2011;28:1747–55. 5. Hosseini AH, Lifshitz J. Brain injury forces of moderate magnitude elicit the fencing response. Med Sci Sports Exerc. 2009;41:1687–97. 6. Giza CC, Hovda DA. The neurometabolic cascade of concussion. J Athl Train. 2001;36:228–35. 7. Barkhoudarian G, Hovda DA, Giza CC.  The molecular pathophysiology of concussive brain injury—an update. Phys Med Rehabil Clin N Am. 2016;27:373–93. 8. Lifshitz J, Rowe RK, Griffiths DR, et al. Clinical relevance of midline fluid percussion brain injury: acute deficits, chronic morbidities and the utility of biomarkers. Brain Inj. 2016;30:1293–301. 9. Biasca N, Maxwell WL. Minor traumatic brain injury in sports: a review in order to prevent neurological sequelae. Prog Brain Res. 2007;161:263–91. 10. McGinn MJ, Povlishock JT.  Pathophysiology of traumatic brain injury. Neurosurg Clin N Am. 2016;27:397–407. 11. Lifshitz J, Kelley BJ, Povlishock JT. Perisomatic thalamic axotomy after diffuse traumatic brain injury is associated with atrophy rather than cell death. J Neuropathol Exp Neurol. 2007;66:218–29. 12. Salehi A, Zhang JH, Obenaus A.  Response of the cerebral vasculature following traumatic brain injury. J Cereb Blood Flow Metab. 2017;37:2320–39. 13. Kumar A, Loane DJ.  Neuroinflammation after traumatic brain injury: opportunities for therapeutic intervention. Brain Behav Immun. 2012;26:1191–201. 14. Ziebell JM, Adelson PD, Lifshitz J.  Microglia: dismantling and rebuilding circuits after acute neurological injury. Metab Brain Dis. 2015;30:393–400. 15. Graham DI, McIntosh TK, Maxwell WL, et al. Recent advances in neurotrauma. J Neuropathol Exp Neurol. 2000;59:641–51.

3

Mechanics of Brain Tissue Deformation and Damage Following Trauma Michael Sutcliffe and Shijia Pan

3.1

Introduction

Mathematical models of the brain, including the key biomechanical and physiological phenomena, promise to improve diagnosis and treatment of traumatic brain injury (TBI). Imaging is an important aspect of such an approach, providing a way of characterising how the brain deforms due to injury and treatment. Assessment of structural damage by neuroimaging has become routine in TBI management, with X-ray computed tomography (CT) the primary imaging modality for head injury assessment. Informal assessment of scans can provide qualitative insight into the pathology. On the other hand, midline shift provides a quantitative measure of deformation already used on a clinical setting to indicate the severity of TBI. Advances in imaging techniques provide an opportunity to better understand and characterise changes in brain condition after trauma and during treatment, in conjunction with other monitoring signals. However interpretation of such data is complex, with patient-specific factors making trends difficult to identify. It is anticipated that by combining such imaging data with mechanical

M. Sutcliffe (*) · S. Pan Cambridge University Engineering Department, Cambridge, UK e-mail: [email protected]; [email protected]

© Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_3

models, improved quantitative measures of deformation linked to disease progression and patient recovery can be developed and applied in clinical practice. However, there are considerable challenges in developing mathematical models of brain deformation and injury. Although assessment and treatment of TBI strongly rely on physical biomarkers such as blood pressure, brain deformation and intracranial pressure (ICP), there is a lack of understanding of what determines changes in these physical quantities and how they are related to the physiological state of the brain. In conjunction with modelling, experimental research underpins our understanding of the relevant processes and provides appropriate material properties and validation data. However, advances through experimental research on brain mechanics are hindered by the complexities of the system, including the need for in vivo studies with associated ethical and experimental difficulties. An alternative approach, using patient data, can provide valuable information relevant to the patient group, at the expense of the lack of control associated with a well-designed experiment. This chapter aims to review key research describing the mechanics of brain tissue behaviour following trauma, including changes both to material properties of the tissue and deformations of the brain associated with injury.

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3.2

 verview of Healthy Brain O Mechanics

This chapter focuses on biomechanical changes to the brain associated with trauma. However, to put that into context, it is important first to understand the biomechanics of healthy brain. For details of this topic the reader is referred to the excellent review by Goriely et al. [1]. This section summarises key aspects described in more detail there. A few key references are included in this section, but the reader should refer to [1] for detailed references. Mechanical modelling of the brain needs to consider both modelling of tissue materials properties and the interaction of various solid and fluid components in a macroscale approach. Outcomes of such models are the distribution of pressure, stresses and strains and associated deformations and fluid flows within the brain.

3.2.1 M  aterial Modelling of Brain Tissue Unlike traditional engineering materials, brain tissue is ultra-soft and complex in nature, making it particularly challenging to determine and characterise its mechanical properties. Flow of interstitial fluid between cells can play a role in the material behaviour. As a biological tissue, its mechanical behaviour is also affected by physiological processes over different physical and time scales. A diversity of proposed material models stems partly from the different measurement methods used and target applications, and partly from the challenges in measuring properties accurately. There are a number of testing protocols used to measure brain tissue properties. Uniaxial in  vitro testing is a commonly used method, in which the tissue specimen is loaded in tension, compression or cyclic tension-compression. Different loading times and test protocols can be used to measure the time-dependent response, including creep and relaxation tests in which stress or strain is held constant, respectively, after an initial loading period. ‘Confined’ or ‘uncon-

fined’ conditions can be used to understand better the role of interstitial fluid movement (e.g. [2]). Indentation tests provide a way of characterising brain tissue mechanical behaviour in vivo as well as in  vitro although they can be harder to interpret. Budday et al. [3] describe a comprehensive set of tests which, combined with model characterisation, provides a benchmark set of modelling data for human brain tissue. Cadaveric tissue was loaded in a range of different modes, including tension, compression and shear. The tests were complemented with imaging and histology to assess anisotropy in tissue structure. The authors noted, in agreement with many others, that the tissue shows highly time-dependent behaviour. Material properties depended on the region of the brain, but no significant anisotropy in properties was observed. The authors identified an appropriate hyper-elastic model to characterise their data for the low strain-rate regime, also assessing the viscoelastic behaviour of tissue at higher strain rates. Although a universally applicable material model is not readily available, there are reasonable material models that fit particular conditions. For short time scales (less than a few minutes) relevant to traumatic injury, a time-­ dependent viscoelastic model is required. For example Budday et al. [3] show a stress relaxation of over 80% after only 300 s, illustrating the importance of this time dependence. On time scales of the order of minutes or hours, characteristic of surgical procedures, a purely hyper-­ elastic model may be adequate, with Budday et al. showing that a simple hyper-elastic model can fit their data across a range of loading conditions. For longer-still timescales (e.g. associated with post-­trauma behaviour) it seems likely that physiological effects not currently included in these material models need to be incorporated. Interstitial fluid flow can provide time-dependent behaviour over these longer time scales. This is important when volumetric changes occur, driven by bulk flow of interstitial fluid, and in this case a poro-elastic model which incorporates such behaviour should be considered [2].

3  Mechanics of Brain Tissue Deformation and Damage Following Trauma

3.2.2 Macroscale Modelling of the Brain There are three fluid flow systems in the brain: blood in the vascular system, cerebrospinal fluid (CSF) and interstitial fluid. Together these fluid elements combine with solid tissue to determine the mechanical and deformation behaviour of the brain. The skull imposes an essentially fixed volume for its blood, CSF and tissue contents, known as the Monro–Kellie hypothesis. Some change can be accommodated by CSF movement from the cranial to lumbar space, but changes in volume of other components within the skull need to balance out, assuming that the skull is closed. The blood and CSF flows are carefully regulated to maintain effective functioning of the brain, affecting the volume of blood in the vasculature and the geometry of the CSF-filled ventricles and subarachnoid space. Interstitial fluid fills the space between cells. The amount of such fluid can increase due to cell damage, and the interstitial fluid can flow in a bulk mode through the brain. Systemic modelling of brain cerebral blood flow and cerebrospinal fluid circulations received considerable attention in the 1990s. Various hydraulic or electrical equivalent models were proposed and used to simulate responses of cerebral vascular components to physiological events. Although these models provide a valuable way to model whole-brain parameters, most of the model-derived parameters are difficult to interpret by clinicians and the models are not able to represent spatial features. The finite element (FE) method has been extensively used to model deformation of the brain. In this numerical approach, the thing being modelled is split up into small elements, each with appropriate material properties. The FE formulation allows application of boundary conditions such as changes in shape, pressure, or swelling to be modelled and the change throughout the system to be calculated. Such models can include different levels of sophistication, depending on the aims of the study. The more complex the model, the more challenging it is to identify appropriate material parameters. Factors to

21

model include anisotropic material properties, viscoelastic or poro-elastic material behaviour, generic or patient-specific geometry of the brain and skull, separate modelling of white and grey matter, inclusion of ventricles, subarachnoid space and falx cerebri. In addition changes associated with trauma or surgery need to be considered.

3.3

Microscale Tissue Damage Induced by TBI

TBI may occur when external mechanical forces are applied to the brain, either through direct impact forces, rapid accelerations and decelerations, rotational forces or penetration by a projectile. These mechanical forces, on a macroscale, result in herniation of brain structures and disruption of normal brain function. On a micro-scale, these forces directly damage the neurons, axons, dendrites and blood vessels in a focal, multifocal or diffuse pattern and set off a dynamic series of complex cellular, inflammatory, neurochemical and metabolic alterations [4]. On a longer timescale, swelling associated with cerebral oedema causes increased intracranial pressure and hence mechanical deformation of the brain tissue. Cerebral oedema is caused by fluid accumulation in the brain tissue, driven by pathological changes [5]. Vasogenic oedema is a result of disruption of the blood–brain barrier. Cytotoxic oedema results from dysfunction of ionic and osmotic flux and difficulties in maintaining cell membrane electrochemical gradients, often resulting from ischemia or hypoxia. This section presents research aiming to understand the mechanisms causing tissue damage associated with trauma or swelling and develop associated damage criteria. Advances have been made both from direct experimental observations with simple loading systems, and from combining experimental observations with modelling to infer deformations in more complex situations. The damage models have been incorporated into numerical models aiming to predict tissue damage as a result of trauma.

M. Sutcliffe and S. Pan

22

3.3.1 D  irect Observations of Tissue Damage from Experiments Experimental studies have been conducted on single axons, nerve fibres, neural cell cultures and organotypic brain slice cultures to explore the cellular mechanism of neural injury [6]. Two studies typifying this approach are described below, providing substantial evidence to characterise the effect of mechanical loading, and specifically axonal stretch, on tissue damage. Bain and Meaney describe a comprehensive set of experiments to assess the effect of strain on tissue damage [7]. Guinea pig optic nerve was stretched in vivo or in vitro to produce varying levels of damage. Different levels of strain, up to a value of 0.50, were applied at a high strain rate of 30–60 s−1. Morphological damage was assessed by histological examination to identify axonal swelling or retraction balls. Functional impairment was measured via the electrophysiological response of the retinal gan-

glion cells associated with light stimuli given to healthy and injured animals. Statistical analysis was used to identify thresholds for damage. Optimum strain thresholds were found of 0.21 and 0.18 for functional and morphological damage, respectively. In an alternative in vitro loading arrangement, Elkin and Morrison evaluated cell death in organotypic slice cultures of rat cerebral cortex [8]. Equibiaxial loading relevant to TBI was applied using a custom rig, giving strains up to 0.35 and strain rates up to 50  s−1. Propidium iodide was used to quantify cell death up to four days after mechanical loading. Figure 3.1 shows the effect of strain and strain rate on cell death rate one to four days after loading. The results showed a strain threshold for cell death of between 0.1 and 0.2 although, even at the maximum strain applied of 0.35, average cell death was below 20% indicating a rather robust cell response. A small effect of strain rate was noted, with increasing strain rate leading to increased cell death. Results were

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Fig. 3.1  The effect of strain and strain rate on cell death rate due to equibiaxial in vitro loading of organotypic slices of rat cerebral cortex. (From Stapp Car Crash. Reproduced with kind permission SAE Mobilius [8])

3  Mechanics of Brain Tissue Deformation and Damage Following Trauma

combined to give an empirical model for predicting cell death. The findings from these cortex experiments were significantly different from corresponding hippocampus results.

mesh with viscoelastic material properties, was used to assess the level of strain generated during the impact. Significant correlation was found between cell permeability damage and principal strain, as illustrated in Fig. 3.2. The finding of a correlation of membrane damage with imposed strain was supported by in vitro measurements on tissue loaded with 50 or 75% stretch. The authors noted that membrane damage has been observed post-trauma, suggesting that membrane repair could be a therapeutic target. A similar combination of in vivo testing, tissue damage characterisation and FE modelling was used by Garcia-Gonzalez et al. [10] to understand the mechanisms of damage in blast TBI. Mild blast TBI was induced in vivo in rats, with the level of trauma such that the rats showed no acute symptoms of injury. A biochemical analysis was used to assess brain oxidative stress, aiming to capture the spatial distribution of secondary injury processes post-trauma. Various tests for cognitive impairment were carried out on the animals post-injury. Regions of sustained oxidative stress were linked spatially with regions of the brain associated with cognitive impairment. An FE model, including tissue anisotropy, was used to estimate local tissue loading. It was found that axonal deformation energy rate and shear energy rate best correlated with injury in white and grey matter, respectively. A corre-

3.3.2 Inferring Tissue Damage from Experiments Combined with Modelling While the experiments described in the proceeding section provide valuable direct observations relating cell death to mechanical loading, the tissues studied and the loading situations were necessarily limited. To overcome this deficiency, a number of researchers have combined more sophisticated experiments, extracting spatially resolved biological markers of damage, with FE modelling used to infer the strain state during the impact event. A multi-faceted study by LaPlaca et  al. [9] combined experimental work with FE modelling to show that damage to the membrane and associated cell death in a rat TBI model were correlated with maximum principal strain and shear strain. Damage to the rat cortex in vivo was caused by direct cortical impact. Permeability markers were used in a histological examination to assess damage to cell membranes associated with the impact. Finite element modelling, using a high resolution

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24

sponding FE model was applied to human blast TBI, and the overall pattern of predicted tissue injury was found to correlate well with many regions known to be vulnerable to blast damage The studies described in this and the preceding section demonstrates how well-controlled experiments can be used to derive appropriate failure criteria for cell injury and death. For ethical reasons, research in this area tends to use animal brain tissue or in vitro human tissue and it is not clear how accurate injury thresholds derived in this way are for human tissue injury. Moreover the difficulties of applying a wide range of strain states and in ensuring that conditions relate to practical human trauma events limit the confidence with which the models can be relied on. Nevertheless the study of Garcia-Gonzalez et al. [10] illustrates how integration of more basic science studies with clinical observations can increase confidence in applying damage models to human brain injury.

3.3.3 Predicting and Modelling Tissue Damage The previous sections have illustrated how failure criteria can be developed from experiments to provide a way of predicting failure during impact or, potentially, subsequent evolution of the physiology. These predictive approaches require both the tissue-level predictions and head-level models of the mechanics. Currently used tissue-level models of failure are empirical, based on a rather limited set of data. It is likely that a much more complex dependence on the stress state, time, and physiological conditions is needed for accurate patient-specific predictions useful in clinical practice. An example of such an approach has been proposed by Lang et al. to model swelling [11], considering a biphasic mixture theory of swelling to study the failure of the blood–brain barrier and the development of vasogenic oedema. However considerably more work is needed before tissue damage models can provide useful predictive capability. Prediction of the overall stress state and associated damage due to trauma has been more

M. Sutcliffe and S. Pan

developed, drawing on the maturity of FE modelling in a wide range of applications. One area of difficulty arises in linking predictions of deformation to tissue injury, as there is no clear consensus on thresholds for axonal injury, which should depend on tissue type as well as the local deformation. Nevertheless such models can provide valuable insights into the mechanisms of injury and regions at risk of injury in the brain Ghahari et al. [12] illustrate how such an FE model can be used to investigate the effect of trauma details on brain injury. In their study, three different types of high-impact injury were simulated: an American football impact, a motorcycle road traffic accident, and a fall from ground level. Helmets were used in both the sports and road traffic accident cases. The impact conditions were assessed from experimental or numerical simulations of the overall impact and used in detailed FE models of the head during impact. The computational model was constructed with high fidelity, including key anatomical details such as sulci, falx and tentorium. A hyper-­viscoelastic material model was used to include the time-dependent material response relevant to the short impact time scales. Figure  3.3 illustrates results for the fall accident, plotting strain and strain rate contours in the brain and comparing the amount of highly loaded tissue in sulcal and gyral regions. Predictions of injury site were compared with assessment of neuro-­ abnormalities in MR images of TBI patients. The study concluded that the mechanical strain and strain rate were greatest in sulcal locations, which agreed well with clinical observations of chronic traumatic encephalopathy. The authors also highlighted the importance of the specifics of the impact event on the corresponding strain distribution during impact. In summary this 3D head model demonstrates the usefulness of modelling mechanical strains as a predictor in TBI. In another illustration of using FE modelling to predict brain injury, Cloots et al. [13] used a multi-scale model to predict axonal tissue damage associated with an American football injury. Again a sophisticated FE model was used to predict the brain mechanical deformation, including

3  Mechanics of Brain Tissue Deformation and Damage Following Trauma

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dicted strain and strain rates in sulcal and gyral regions of the brain. (From Brain. Reproduced with kind permission Oxford University Press [12])

anisotropy of brain tissue and viscoelastic behaviour. In this study a multi-level approach was used to link the macroscale brain deformation and the microscale tissue deformation and axonal strains. The microscale model considered a critical configuration where there was a strain concentration associated with the presence of a cell body, though similar results were expected in the vicinity of a blood vessel. This study concluded that the effect of the microstructural response was significant in influencing local strains, highlighting the need to include details of the brain architecture in such predictive models. In summary, this section has illustrated how numerical modelling can play a useful role in determining the link between the specific trauma event and brain injury although there still remain significant areas of uncertainty in the prediction of tissue damage.

3.4

Macroscale Deformation in the Brain Induced by TBI

Midline shift (MLS) is a feature evident on brain CT images, referring to the shift of brain structure from its centre line caused by brain pathologies including tumour, haematoma or unbalanced pressure. The magnitude of MLS is a relatively crude but useful indicator for the severity of TBI which is included in clinical assessment criteria such as the Marshall classification system [14]. This highlights the potential for macroscale measures of brain deformation to be used further in diagnosis and treatment of TBI. Haemorrhagic mass lesions are considered as the main cause of MLS associated with TBI.  Strong correlation has been repeatedly observed between the magnitude of midline shift and brain haemorrhagic lesion volume. For

M. Sutcliffe and S. Pan

26

example, in the multivariate study by Nelson et al [15], MLS showed a good correlation of 𝑅2 = 0.72 with the summed volume of epidural haematoma, subdural haematoma and contusion. Whole-head models of macroscale deformation need to combine models of brain tissue material behaviour, models of flow of the relevant fluid elements and a representation of the mechanical effect of the underlying pathology, for example, swelling or haematoma. This approach is illustrated by the study of Li et al., who considered the effect of gravity on fluid pressure distribution in a simulation of a TBI patient with an oedema [16]. Their FE analysis included interstitial fluid flow in the bulk tissue via a poro-elastic tissue model, along with a realistic model of CSF flow. The oedema, which was located in the posterior part of the brain, was supposed to be a source of fluid. Results showed a significant reduction in interstitial fluid pressure around the oedema by having the head in a prone position as compared with a supine position, suggesting that head position should be considered carefully in patients with such a condition. The resurgence in decompressive craniectomy (DC), a surgical operation in which part of the skull is removed to relieve excessive ICP, calls for more accurate computational models to aid surgical planning and help minimise the possibility of secondary axonal damage post-operation. Weickenmeier et  al. [17] have developed theoretical and computational models to characterise deformation in bulging brains with DC. They created a sophisticated personalised craniectomy model from magnetic resonance imaging, including key anatomical details such as the skull, skin, cortical grey matter, inner white matter, cerebellum and CSF.  To simulate the brain behaviour during the DC procedure, a prescribed expansion was applied to the white matter tissue in the left, right or both hemispheres to simulate different brain swelling scenarios. Figure  3.4 shows the effect of different skull opening positions on the amount of tissue stretch in the brain. Significant amounts of tissue deformation were predicted, both at the margin of the skull opening and deep

inside the bulge. This model could in theory be used to optimise the procedure, minimising the damage that such straining could cause to tissue during and after the DC operation. While such models provide a starting point for modelling of the effect of TBI on brain deformation, further sophistication in the modelling is required before these models can be used in clinical practice. Particular requirements include modelling of physiological processes, improvements in damage criteria, and integration with clinical data to allow parameter identification and demonstrate the validity of any predictions.

3.5

Future Directions

Although there is an increasing body of knowledge applying biomechanics to TBI, there are still major gaps limiting clinical use. Improved material models of the onset and development of tissue damage are needed to provide useful predictive tools. Challenges arise from the multi-physics and multi-scale elements required of such models, and also with effective validation. Experiments using brain organoids provide an attractive way of understanding better the physiological response over longer time periods associated with tissue injury and subsequent response, which could help develop and calibrate such models [18]. More sophisticated use of patient data also provides a pragmatic route to improvements in predictive modelling, incorporating observations of patient-specific brain injury and treatment. Models developed using physically and physiologically reasonable assumptions can be validated against the observed changes in local and global deformation, including, for example, changes in ventricle and sulci shape and midplane shift to help with validation. Advances in image analysis techniques can support such innovations. In principle machine learning provides an opportunity to incorporate large data sets, but it seems likely that a hybrid approach including physically based models will be needed, given the likely limitations in available data.

3  Mechanics of Brain Tissue Deformation and Damage Following Trauma unilateral flap

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Fig. 3.4  Predicted distribution of radial and tangential stretches associated with decompressive craniectomy operations using unilateral or frontal flap openings. From Journal of elasticity. Reproduced with kind permission Elsevier [17]

3.6

Conclusions

Biomechanics offers an opportunity to help our understanding of the effect of trauma on brain injury. However such studies need to be closely integrated with understanding of the physiological phenomena taking place, as well as being informed by clinical practice so as to provide clinically useful tools. At a microscopic level, experimental studies have shown how cells are damaged by straining, with details of membrane damage and functional impairment correlated with applied strains. By combining experimental studies of traumatic brain injury in animal models with finite element analysis of the corresponding tissue strains, it has been possible to identify tissue strain measures which correlated spatially with cell and tissue damage and cognitive impairment. Similarly FE models have been used to predict damage due to accidents or sports injuries. Macroscopic models of the head have also been used to understand the effect of gravity on interstitial fluid pressure near an oedema and how the brain deforms during the decompressive craniectomy operation.

While such studies provide valuable insights into the mechanisms of tissue damage and deformation in TBI, there are still considerable uncertainty about appropriate tissue failure criteria. Moreover there is a significant gap between such studies and person-specific predictions which could be used in clinical practice. Further work using brain organoids promises to help our understanding of the interactions between physical and physiological effects influencing tissue damage. Improvements in clinical data collection, including advances in image analysis, provide an opportunity to link scientific studies of the biomechanics of TBI with clinical observations and outcomes.

References 1. Goriely A, Geers MGD, Holzapfel GA, Jayamohan J, Jérusalem A, Sivaloganathan S, et  al. Mechanics of the brain: perspectives, challenges, and opportunities. Biomech Model Mechanobiol. 2015;14(5):931–65. 2. Franceschini G, Bigoni D, Regitnig P, Holzapfel GA.  Brain tissue deforms similarly to filled elastomers and follows consolidation theory. J Mech Phys Solids. 2006;54(12):2592–620. 3. Budday S, Sommer G, Birkl C, Langkammer C, Haybaeck J, Kohnert J, et  al. Mechanical

28 c­ haracterization of human brain tissue. Acta Biomater. 2017;48:319–40. 4. McKee A, Daneshvar D.  Chapter 4—The neuropathology of traumatic brain injury. In: Grafmen J, Salazar A, editors. Handbook of clinical neurology, traumatic brain injury Part I, vol. 127. New  York: Elsevier Inc.; 2015. p. 45–66. 5. Winkler EA, Minter D, Yue JK, Manley GT. Cerebral edema in traumatic brain injury: pathophysiology and prospective therapeutic targets. Neurosurg Clin N Am. 2016;27(4):473–88. 6. Wright RM, Ramesh KT.  An axonal strain injury criterion for traumatic brain injury. Biomech Model Mechanobiol. 2012;11(1-2):245–60. 7. Bain AC, Meaney DF.  Tissue-level thresholds for axonal damage in an experimental model of central nervous system white matter injury. J Biomech Eng. 2000;122(6):615–22. 8. Elkin BS, Morrison B.  Region-specific tolerance criteria for the living brain. Stapp Car Crash J. 2007;51:127–38. 9. LaPlaca MC, Lessing MC, Prado GR, Zhou R, Tate CC, Geddes-Klein D, et  al. Mechanoporation is a potential indicator of tissue strain and subsequent degeneration following experimental traumatic brain injury. Clin Biomech. 2018;2019(64):2–13. 10. Garcia-Gonzalez D, Race NS, Voets NL, Jenkins DR, Sotiropoulos SN, Acosta G, et  al. Cognition based bTBI mechanistic criteria: a tool for preventive and therapeutic innovations. Sci Rep. 2018;8(1):1–14. 11. Lang GE, Vella D, Waters SL, Goriely A. Mathematical modelling of blood-brain barrier failure and oedema. Math Med Biol. 2017;34(3):391–414.

M. Sutcliffe and S. Pan 12. Ghajari M, Hellyer PJ, Sharp DJ.  Computational modelling of traumatic brain injury predicts the location of chronic traumatic encephalopathy pathology. Brain. 2017;140(2):333–43. 13. Cloots RJH, Van Dommelen JAW, Kleiven S, Geers MGD.  Multi-scale mechanics of traumatic brain injury: Predicting axonal strains from head loads. Biomech Model Mechanobiol. 2013;12(1):137–50. 14. Maas AIR, Hukkelhoven CWPM, Marshall LF, Steyerberg EW.  Prediction of outcome in traumatic brain injury with computed tomographic characteristics: a comparison between the computed tomographic classification and combinations of computed tomographic predictors. Neurosurgery. 2005;57(6):1173–81. 15. Nelson DW, Nyströ H, Maccallum RM, Thornquist BR, Lilja A, Bellander BM, et al. Extended analysis of early computed tomography scans of traumatic brain injured patients and relations to outcome. J Neurotrauma. 2010;27:51–64. 16. Li X, Von Holst H, Kleiven S. Influence of gravity for optimal head positions in the treatment of head injury patients. Acta Neurochir. 2011;153(10):2057–64. 17. Weickenmeier J, Saez P, Butler CAM, Young PG, Goriely A, Kuhl E.  Bulging brains. J Elast. 2017;129(1-2):197–212. 18. Jgamadze D, Johnson VE, Wolf JA, Cullen DK, Song H, Gl M, et al. Modeling traumatic brain injury with human brain organoids. Curr Opin Biomed Eng. 2020;14:52–8.

4

Evidence Pyramid, Comparative Effectiveness Research, and Randomised Trials Kwok M. Ho

4.1

Introduction: What Constitutes ‘Evidence’?

Advances from scientific research, including the discovery of insulin, antibiotics, and all sorts of bacteria and viruses, have revolutionised medical care well before the birth of EBM. The importance of basic science in medicine cannot be understated because similar to physics, basic science has the potential to give us deterministic insights about the complexity of nature. Without thorough understanding of the mechanistic nature of a certain disease, it is hard to imagine a positive yield of any proposed untargeted therapies, let alone confirming their effectiveness in a RCT. Some clinicians also get confused between ‘evidence of absence’ (which is rare) and ‘absence of evidence’ (about whether an intervention actually works or not). There is no doubt that in practice, we cannot easily dichotomise evidence as either present or absent. Traditional evidence pyramid of EBM (Fig. 4.1) is appealing in this aspect because it ranks the strength (or validity) of evidence using a simple K. M. Ho (*) Department of Intensive Care Medicine, Medical School, University of Western Australia, Perth, Western Australia, Australia Royal Perth Hospital, Perth, Western Australia, Australia School of Veterinary & Life Sciences, Murdoch University, Perth, Western Australia, Australia e-mail: [email protected] © Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_4

scheme based on study designs. But can we also argue that such ranking system is too simplistic compared to the complexity of nature with evolving interactions between environmental, genetic, and psychosocial factors?

4.2

Background Information: Pros and Cons of Different Paradigms of Evidence

EMB was first proposed in the 1990s as a new paradigm to improve clinicians’ understanding of clinical epidemiology so that they can make better clinical decisions for their patients. EMB can be defined as the ‘process of turning clinical problems into questions and then systematically locating, appraising, and using contemporaneous research findings as the basis for clinical decisions’ [1]. Fundamental to the practice of EBM is the evidence pyramid, which ranks the validity of evidence by the study designs with systematic reviews/meta-analyses and RCTs ranked on the top, followed by cohort studies, case-control studies, and case series. Multiple minor modifications of the EBM evidence pyramid have been proposed since [2], but the hierarchical structure of the pyramid remains relatively similar—RCTs are the most valid form of evidence beyond all else. Despite the fact that EMB has been taught and practised widely by many clinicians in the last two decades, there is little high-quality evidence 29

K. M. Ho

30 Fig. 4.1 Traditional evidence-based medicine (EBM) pyramid Systematic reviews & meta-analyses

(with adequately-powered RCTs)

ity lid va Randomised controlled trials (RCTs)

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(according to the EBM’s own standards by not having double-blinded RCTs) to suggest that EBM has achieved its aim of improving patient outcomes [3]. Similar to many beliefs, there are plenty of arguments both to support and criticise EBM. The traditional evidence pyramid conveys a simple concept—RCTs trump over other study designs in guiding clinical decisions—that is easy to understand and apply. This simple concept has, however, invited some unwelcome consequences. First, it downplays the complexity of nature and the importance of using the totality of evidence, including the pivotal role of basic science in designing the RCTs [4, 5]. Many RCTs have been designed, funded, and initiated based on shaky biological rationale. When research grant and journal reviewers also believe RCTs are most influential, seasoned researchers will design and initiate RCTs, regardless of the strength of basic science foundation of the proposed interventions, which are also unfortunately more likely to be funded and published in popular clinical journals. Second, RCTs have become the main vehicle for many commercial companies to get approval for their products from the regulatory agencies as well as to convince clinicians that their products are the new ‘gold standard’ [3]. EBM has also been misused and abused by researchers who want to support their views, without caring much about the integrity, transpar-

ency, and unbiasedness of science [6]. Third, many large pragmatic RCTs fail to consider that many interventions may not have similar benefits and harms on all patients and assume the study intervention will have a one-size-fits-all effect [7]. Fourth, although the evidence pyramid is helpful in assessing the strength of interventional studies, the same hierarchical structure is not necessarily appropriate when assessing the utility of many other types of research, including pathogenetic, diagnostic, and prognostic studies when strict inclusion and exclusion criteria used in many RCTs are in fact detrimental to the validity of these types of studies. Table  4.1 summarises the strengths and weaknesses of different types of research studies and how they may complement each other to generate a totality of evidence.

4.3

Illustrative Cases: The Story of Decompressive Craniectomy

Using the terms ‘decompressive craniectomy’ and ‘animal’ to search for relevant animal studies assessing decompressive craniectomy in a PubMed database yielded 91 articles, and then the references of these articles were examined. Prior to the initiation of a multicentre human trial in 2004 assessing the benefits of bifrontal

4  Evidence Pyramid, Comparative Effectiveness Research, and Randomised Trials

31

Table 4.1  Strengths and weaknesses of different study designs Study design RCT

Strengths Not affected by known and unknown confounders and biases if:   (i) Allocation to control and intervention groups and assessment of outcomes are well concealed to the investigators  (ii) Randomisation is successful in achieving a balance in baseline characteristics between the two groups Other advantages may include a lower rate of missing data or failure to follow up compared to observational studies, especially if the latter are retrospective studies

Weaknesses   (i)  Expensive   (ii) Can have external validity problem—if the selection and exclusion criteria have excluded most patients in which the intervention is usually used for in clinical practice. The proportion of patients screened but not eligible for the trial, the baseline characteristics of the participants including any difference in observed vs. expected outcome in the control group, and whether there are interactions between severity of illness and effectiveness of the intervention are essential elements in assessing a RCT’s external validity. Hence, not the best study design for investigate predictive or prognostic research  (iii) Negative secondary outcomes due to inadequate statistical power often misinterpreted as non-inferior (or equivalent) between the two groups  (iv) Sample size often constructed based on unrealistic large effect size or high baseline risk for the control group

Cohort study

  (i) Cheaper than RCT and best suited to generate data for hypothesis testing for further confirmation or to support other types of studies  (ii) Impose no extra risk on participants other than data privacy  (iii) Suitable for predictive and prognostic research due to the use of minimal exclusion criteria   (i) Suitable for predictive and prognostic research on rare events when cohort studies are uneconomical   (i) Fundamental in generating deterministic understanding of nature

 

Case-­control study

Basic science research

(i) Prone to known and unknown confounders, particularly confounding by indication  (ii) Missing data and misclassification can be problematic especially in retrospective studies  (iii) False-positive results can also result from not recognising the collider effect

 

 

(i) Prone to recall bias and confounding, and hence, it can only be used to generate hypothesis

(i) Expensive, low yield, and takes decades of continued research to generate important understanding of nature  (ii) Even efficacious in vitro or in animals, it may not be translatable into clinical practice due to many reasons, including whether benefits exceed harms and different dose-­response relationships between animal species

K. M. Ho

32

c­ raniectomy in traumatic brain injury for diffuse brain injury without large focal lesions [8], only one animal study assessing the benefits and harms of decompressive craniectomy after focal physical injury to the brain (induced by controlled cortical impact by an impactor tip (3 mm diameter at 8 m/s velocity for 150 ms inducing 0.8 mm brain displacement)) was identified [9]. This study showed that focal craniectomy over the site of injury blunted posttraumatic intracranial pressure increase, significantly reduced secondary brain damage, and improved functional outcome after focal experimental traumatic brain injury. Surprisingly, the design of this human trial has little resemblance of this single strongly positive animal study; the rest of the story is history [10]. Decompressive craniectomy was also tested by at least four RCTs in the context of middle cerebral artery infarction. By assigning modified Rankin Scale (mRS) of 4 (moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance) as a favourable outcome [10], both the pooled analysis of three trials and the fourth trial concluded that decompressive craniectomy resulted in a significant reduction in mortality and an increase in the number of patients with a favourable outcome (or without severe disability). Because mRS of 4 has traditionally been considered as unfavourable in the stroke literature [11], perhaps the conclusions of the meta-­analysis and RCTs are far from unbiased [6].

4.4

Recent Developments: Comparative Effective Research

Comparative effectiveness research (CER) is an umbrella research term that includes pragmatic RCTs, cohort, case-control and prevalence studies, decision analyses, and systematic reviews [12, 13]. With advances in computer power, analysing big data of thousands of patients (without restrictive exclusions) with long-term follow-up

data is possible and can potentially answer many real-­world questions in real-life scenarios that are not amenable to randomisation; or at least, they can be used to improve the design and efficient execution of large RCTs, in particular non-­ inferiority, equivalence, and clustered randomisation crossover trials in comparing two active treatments [13]. As with any individual study design, choosing the important research questions, appropriateness of the data sources, and rigorous study methods remain pivotal in conducting CER [12].

4.5

Future Directions

Advances in medical science and improvements in healthcare have been built on the development of new paradigms and integration of all information to give us a comprehensive and sophisticated understanding of the nature of science. In this regard, having solid and insightful basic science background information prior to the start of any clinical research studies gives researchers a much higher ‘Bayes factor’ than would otherwise be the case for confirming a positive response to a study intervention (or to reject the null hypothesis) in a clinical study. In brief, Bayes factor can be defined as the ratio of the odds of observing two competing hypotheses after examining relevant data compared to the odds of observing those hypotheses before examining the data [14]. It is in this spirit that we should embrace basic science as a pivotal part of the totality of evidence. Although RCTs have a distinct advantage of minimising known and unknown confounding, their validity can only be fully materialised if basic science of the pathology in question, biological plausibility of the study intervention, patient-intervention interactions, and adequate sample size are all carefully considered. Science-­ based medicine (SBM) [5] is, perhaps, a more legitimate concept than EMB when we learn to accept that tackling the complex biological ecosystems requires more than knowing the study design alone. Integrating solid basic science into all

4  Evidence Pyramid, Comparative Effectiveness Research, and Randomised Trials Fig. 4.2 Integrating basic science to strengthen other study designs to achieve the totality of evidence, a paradigm similar to science-based medicine (SBM)

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Systematic reviews & meta-analyses

(with adequately-powered RCTs)

Randomised controlled trials (RCTs)

Cohort studies

Case-control studies

Case series / reports

Basic science research

domains of clinical research gives us the best chance to conduct better research and to materialise the ultimate aim of continued improvement in clinical decisions and patient outcomes advocated by EBM (Fig. 4.2).

4.6

Conclusions

We have observed an exponential growth in the number of RCTs and meta-analyses since the birth of EBM.  While clinical epidemiological skills embedded in the practice of EMB are remarkably useful, advocating RCTs without due diligence on the basic science foundation of the pathology in question and study intervention is unlikely to be helpful in achieving the aim of EBM to improve clinical decisions and patient outcomes. By integrating solid basic science into all forms of clinical research will no doubt improve both EBM and CER. Perhaps, it is time to stop arguing ‘who is better’ or ‘what design is more valid’ by accepting that the success of our clinical endeavour relies on how much we can advance the totality of evidence. Conflict of Interest  None declared Funding None

References 1. Rosenberg W, Donald A.  Evidence based medicine: an approach to clinical problem-solving. BMJ. 1995;310:1122–6. 2. Murad MH, Asi N, Alsawas M, Alahdab F. New evidence pyramid. Evid Based Med. 2016;21:125–7. 3. Every-Palmer S, Howick J.  How evidence-based medicine is failing due to biased trials and selective publication. J Eval Clin Pract. 2014;20:908–14. 4. Tobin MJ.  Counterpoint: evidence-based medicine lacks a sound scientific base. Chest. 2008;133:1071–4. 5. Gorski DH, Novella SP. Clinical trials of integrative medicine: testing whether magic works? Trends Mol Med. 2014;20:473–6. 6. Panagiotou OA, Ioannidis JP.  Primary study authors of significant studies are more likely to believe that a strong association exists in a heterogeneous meta-­ analysis compared with methodologists. J Clin Epidemiol. 2012;65:740–7. 7. Ho KM, Holley A, Lipman J.  Vena Cava filters in severely-injured patients: one size does not fit all. Anaesth Crit Care Pain Med. 2019;38:305–7. 8. Zweckberger K, Stoffel M, Baethemann A, Plesnila N.  Effect of decompression craniotomy on increase of contusion volume and functional outcome after controlled cortical impact in mice. J Neurotrauma. 2003;20:1307–14. 9. Cooper DJ, Rosenfeld JV, Murray L, et  al. the DECRA Trial Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Decompressive craniectomy in diffuse traumatic brain injury. N Engl J Med. 2011;21:1493–502.

34 10. Honeybul S, Ho KM, Gillett GR.  Long-term outcome following decompressive craniectomy: an inconvenient truth? Curr Opin Crit Care. 2018;24:97–104. 11. Honeybul S, Ho KM. The current role of decompressive craniectomy in the management of neurological emergencies. Brain Inj. 2013;27:979–91. 12. Schaumberg DA, McDonald L, Shah S, Stokes M, Nordstrom BL, Ramagopalan SV.  Evaluation of

K. M. Ho comparative effectiveness research: a practical tool. J Comp Eff Res. 2018;7:503–15. 13. Chang TI, Winkelmayer WC.  Comparative effec tiveness research: what is it and why do we need it in nephrology? Nephrol Dial Transplant. 2012;27:2156–61. 14. Baig SA.  Bayesian inference: an introduction to hypothesis testing using Bayes factors. Nicotine Tob Res. 2020;22:1244–6.

5

Big Data Collection and Traumatic Brain Injury Rianne G. F. Dolmans, Brittany M. Stopa, and Marike L. D. Broekman

5.1

Introduction

Big data (BD) is structured and unstructured data whose volume, velocity, and variety generally render traditional data processing methods insufficient. The use of BD is rapidly changing many aspects of clinical medicine, ranging from diagnosis to patient management and the working practices of physicians and surgeons alike. Neurosurgery, neurocritical care, and the care for patients with traumatic brain injury (TBI) are no exception to these changes. BD in TBI consists of a range of data, collected individually and in aggregate. There are structured, semistrucR. G. F. Dolmans Department of Neurosurgery, University Medical Center Utrecht, Utrecht, The Netherlands B. M. Stopa Computational Neuroscience Outcomes Center at Harvard, Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA, USA Virginia Tech Carilion School of Medicine, Roanoke, VA, USA M. L. D. Broekman (*) Department of Neurosurgery, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands Department of Neurosurgery, Haaglanden Medical Center, The Hague, The Netherlands Department of Neurology, Massachusetts General Hospital, Boston, MA, USA e-mail: [email protected], [email protected] © Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_5

tured, and unstructured data types, each of which must be captured and analyzed distinctly. A large amount of information is collected during the routine care of TBI patients, and this includes data such as intracranial pressure (ICP) monitoring, EEG monitoring, laboratory results, and vital signs to name a few. When this data is aggregated, it can provide an enormous amount of information about a single patient, and when it is collected systematically from all patients, it can be used for a myriad of clinical and research applications. Data points can include information regarding admission demographics, management in hospital, post-hospital disposition, and clinical outcomes. This type of data can be aggregated into national and multinational databases that can become repositories of BD, which can be used to assess the population-level impact of TBI.

5.2

What Is Big Data in TBI?

BD in TBI is generally divided into (1) patient characteristics, (2) clinical monitoring, (3) neuroimaging, (4) genomics, (5) clinical course, and (6) clinical outcomes (Table 5.1). These variables are available and clinically important at different times during the course of the disease process. As we become more adept at seeking novel ways to collect data on TBI outcomes, we find that there is unlimited potential. For example, wearable 35

R. G. F. Dolmans et al.

36 Table 5.1  Data sources for big data analysis in clinical traumatic brain injury Data category Patient characteristics

Data availability At the time of clinical encounter

Clinical monitoring

During the clinical encounter

Neuroimaging Genomics Clinical course

During the clinical encounter During the clinical encounter During the clinical encounter

Clinical outcomes

After the clinical encounter, during follow-up period

Examples of data sources Patient demographics (age, gender, race), comorbidities, medications, patient injury data (mechanism of injury, injury severity score, GCS) Vital signs (pulse, heart rate, temperature, oxygen saturation), lab values from blood, urine, CSF, specific biochemical markers, ICP monitoring, EEG monitoring, CBF monitoring CT, MRI Genetics and epigenetics Hospital length of stay, length of ventilatory support, symptoms, patient status, treatment, management strategies Functional outcomes, physical disability scores, quality of life scores, neurologic status, comorbidities, medications, e.g., wearable biosensors, digital phenotyping

Table 5.2  Principles of effective big data collection Principle Standardized

Structured

Automated

Description Data must be collected in a consistent manner across patients and across hospitals, with the same ideal data points as selected by their potential to provide clinically meaningful information in aggregate Data must be collected in a structured format, with preference for multiple-choice fields over open-text fields and for quantitative over qualitative data points Unstructured data should be reformatted using NLP and AI tools to extract structured data Big data collection must be automated to avoid issues of human error, fatigue, time and effort, and longevity of data collection

biosensors and the use of smartphones that collect minute-to-minute data from patients for digital phenotyping can be used to assess clinically relevant functional outcome scores.

5.3

Collection of Big Data

In order for the information gained from BD to be generalizable and clinically useful, there are a number of issues regarding data collection that need to be considered. In the first instance, it is critical that the information is collected in a standardized and consistent manner across individual patients and hospitals, both nationally and ideally internationally. Second, data collection should be structured. Open-text fields should be avoided in favor of multiple standardized selection options,

and ideally there should be some qualitative and quantitative assessment of data points (such as occurs when obtaining pain scores). Neurolinguistic programming (NLP) could aid in the analysis of data that cannot be otherwise structured. Third, data collection should be automated as much as possible. This is to avoid human errors related to factors, such as fatigue and limited time, and to improve longevity and sustainability of the data collection process. At the hospital level, electronic health records (EHRs) can play an important role, whereas at the national level, claims data in administrative databases could aid automatic data collection (Table  5.2). These tools have well-documented limitations, and resolving these issues enables robust patient data collection, which could fundamentally transform the use of BD in TBI [1, 2].

5  Big Data Collection and Traumatic Brain Injury

5.4

Use of Big Data in TBI

5.4.1 Classification of TBI Classification of TBI is generally based on physical mechanism (blunt, penetrating, or primary versus secondary injury), anatomical location (diffuse versus focal), symptoms and severity (Glasgow Coma Score [GCS]), or prognosis. Each of these assessments has been clinically useful; however, they all have limitations [3]. Currently, the most common classification of TBI is based on the GCS, measured at different time points [4]. The GCS classification of TBI into “mild,” “moderate,” or “severe” injury is based on a limited set of symptoms, and it does not directly capture the pathophysiological mechanisms. In addition, this classification does not take into account radiological data or clinical signs such as pupil reactivity [5]. Finally, it must be recognized that TBI is a spectrum of disease and the GCS classification does not take into account the patient heterogeneity that exists within each classification. Patient status will often change over time, and individual GCS does not make allowances for the temporality of assessment, relative to either patient deterioration or improvement. BD could potentially fill this gap and improve classification of TBI. For example, a multimodal classification system that incorporates inputs, such as anatomical location, multiple clinical assessments, intracranial pressure data, and other clinical and diagnostic data, could improve classification and prognosis. Indeed, attempts to leverage machine learning for the stratification of TBI patients have already proven useful in the prediction of TBI outcomes, and future efforts that incorporate BD will improve such models [6]. Having a more accurate classification of TBI is important for improving the clinical management and for unlocking the potential of targeted therapeutic interventions [7]. An example of a TBI database with standardized data collection is the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) database [8]. This NIH-funded database contains over 20 years of data from all

37

TBI clinical trials and epidemiologic studies and is being used for predicting TBI prognosis and mortality. It has led to the identification of data points important to TBI prognosis, such as demographics data, mechanism of injury, blood pressure on admission, laboratory parameters on admission, and CT scan characteristics. While this database includes only moderate and severe brain injury and is limited to data published from other trials rather than prospectively collected data, it is an excellent example of how multi-­ institutional data in TBI can be collected and leveraged for meaningful classification of TBI patients. Continuing upon the success of this model, others have built a predictive score for TBI classification and prognosis that incorporates multiple clinically relevant data points, such as the Gomez prognostic score [9] and the brain injury state clinical prediction model (BISCPM) score [10]. The Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-­ TBI) dataset improved upon the methodology of the IMPACT database by prospectively enrolling multicenter TBI patients and collecting clinically relevant data points [11]. This database contains demographic and social data; clinical data; hematological, biochemical, and neuroimaging data; and outcome assessments at 3 and 6 months. The data in this database is now being employed to identify predictors of TBI outcomes, which can then be used for creating an improved TBI classification and scoring system [12]. Although this database is limited to 3 clinical sites and 650 patients, it is an excellent demonstration of the feasibility of building a prospective multicenter TBI data repository and leveraging the data it contains to improve TBI outcomes. The CENTER-TBI study similarly created an even more encompassing prospective multicenter TBI database, with 80 sites, 5400 patients in the core study database, and 25,000 patients in the registry, in order to improve the current classification scheme for TBI [13]. From this repository, a new multidimensional TBI classification system has been developed, which incorporates multiple data inputs, such as imaging characteristics, demographics, clinical severity, secondary insults,

R. G. F. Dolmans et al.

38 Patient Demographics

What is Big Data in TBI?

Comorbidities

How can we use Big Data in TBI?

Medications Injury Characteristics Vital Signs

Patient Characteristics

Diagnosing TBI & Assessing Severity

Lab Values Biomarkers ICP Monitoring

Clinical Monitoring

EEG Monitoring CBF Monitoring CT

Neuroimaging

MRI

Acute TBI Management

Genetics Epigenetics

Genomics

Length of Stay Length of Ventilatory Support Associated Symptoms

Clinical Course

Chronic TBI Management

Treatment Regimen Surgical and Medical Management Functional Outcome Physical Disability Score

Clinical Outcomes

Quality of Life Score Neurologic Status

Research Applications

Injury Sequelae Wearable Biosensor Data Digital Phenotyping

Fig. 5.1  What is big data in TBI and how can we use it

and cause of injury, to cluster patients into clinically meaningful groups [14]. This use of BD will fundamentally shift the way that TBI is diagnosed, classified, and managed (Fig. 5.1).

treatments, it may be possible to develop evidence-­based management algorithms [3]. Currently, BD has been used in the management of acute TBI for the following:

5.4.2 Acute TBI Management

• ICP monitoring • IV fluids and medication adjustments • Supportive information to guide management

In neurointensive care units (NICU), there are continuous ways of monitoring vital signs as well as obtaining information regarding physiological and biochemical parameters, including but not limited to blood pressure, pulse, oxygen saturations, arterial carbon dioxide levels, ICP, brain oxygenation, and cerebral perfusion pressure, and this generates huge amounts of real-time data points. If this is combined (with neuroimaging data, blood-based biomarkers, or EEG monitoring), it could potentially be used to monitor disease progression, which may significantly improve clinical management and outcome prediction. The use of continuous real-time data points can also provide information about the dynamic process of the secondary brain injury, which could be used to guide targeted therapy. By combining data obtained from individual

5.4.3 ICP Monitoring Continuous measurement of intracranial pressure is an important clinical tool in the management of traumatic brain injury, and by analyzing the data with NLP or AI, it may be possible to design an early warning system to detect subtle changes in patients’ vital signs, which can predict rises in ICP and enable staff to proactively intervene [3]. To date, only mean ICP is used in the clinic setting; however, ICP waveforms contain potentially useful information for predicting cerebrovascular and intracranial instability [14]. An example of the potential benefits of this approach is the morphological clustering and analysis of ICP pulse (MOCAIP) algorithm. This

5  Big Data Collection and Traumatic Brain Injury

algorithm is designed to precisely detect and measure non-artifactual ICP peaks, thereby creating data about the slope and waveform of each ICP oscillation [14]. This algorithm could be used to analyze the ICP data and provide an indication of disease progression.

5.4.4 I ntravenous (IV) Fluids and Medication Adjustments In TBI patients, it is of utmost importance to maintain an adequate brain oxygen level to avoid hypoxia and cerebral ischemia and the associated secondary brain injury. IV fluid adjustments as well as medication adjustments in the management of TBI are largely dependent on MAP and ICP to optimize cerebral perfusion pressure (CPP) and cerebral blood flow (CBF). With more accurate measurement of ICP using BD analysis as described above, it will be possible to make faster adjustments using hyperosmolar saline or mannitol as well as 0.9% normal saline (NS) or colloids or any other relevant medication such as pain medication and anticonvulsant therapy.

5.4.5 Supportive Information to Guide Management In the context of intractable intracranial hypertension, the clinical decision to surgically decompress or to continue with medical management is complex and remains largely unresolved. There is little doubt that a decompressive craniectomy can reduce the intracranial pressure and reduce mortality; however, there are a number of ethical issues that require consideration [15]. It may be possible to apply BD analysis to guide clinical decision-making by incorporating individual patient characteristics such as the following: • Patient age • Primary intracranial injury severity –– Initial GCS –– Pupil reactivity • Presence of intracranial lesions such as:

39

–– Petechial hemorrhage’s –– Contusions –– Midline –– Basal cistern status –– Hydrocephalus • ICP level, stability, and response to treatment Where ambiguity in surgical decision-making continues to exist, such as the optimal timing and size of the craniectomy, an algorithm informed by BD could possibly provide valuable information for the clinical team. Such an algorithm has yet to be developed, but this is an example of the gap in clinical knowledge that BD could help resolve (Fig. 5.1).

5.4.6 Management of Chronic TBI BD could also provide information that may be useful on the long-term management of patients recovering from a TBI. This is important because there are often difficulties encountered regarding the following: • Tracking patient symptoms outside of the hospital setting • Heterogeneity of recovery and hence support requirements • Limited guidelines for managing the needs of these patients (especially when compared with guidelines for acute care) [16] Some of the ways in which BD may be useful include the following: • Extraction and quantification of data from existing sources • Increasing the frequency and length of follow­up data collection • Creation of prediction models for recovery and development of long-term sequelae such as headache, fatigue, memory impairment, and depression Extraction and quantification of data from existing sources depends on streams of data collected from patients during admission and fol-

40

low-­ up. For example, the streams collected during admission include GCS, age, pupillary diameter and light reflex, hypotension, and CT scan features as early indicators of prognosis in the context of severe TBI.  However, they may also include radiological findings, hematological and biochemical results, and clinic assessments at follow-up visits. This information can be used not only to monitor a patient’s status and progress, but by analyzing it in aggregate, it may also be possible to improve the accuracy of prediction models. This data may also include assessments that are collected but not necessarily quantified or commonly included in prediction models, such as physiotherapy, occupational therapy, speech therapy, and rehabilitation assessments. These detailed clinical assessments are often included in a patient’s record in narrative format. Without converting this information into quantifiable data, it has limited potential for broader applications. For such data, a NLP tool could be employed to mine for relevant data without increasing the burden for clinicians. Such tools are increasingly used and have proven very helpful in extracting meaningful data from unstructured free-text medical notes [17]. Increasing the frequency and duration of follow-­up data collection is important for getting a clear picture of the patient’s status and progress but is currently challenging due to the time and resource constraints needed to collect such data. This is a particular challenge in the context of patients with mild TBI and concussion, as these patients often have less engagement with the healthcare system and there may be limited information available because there is less data that can be (automatically) extracted from the EHR. For longitudinal data collection, there are smart device wearables, smartphone applications, and smartphone meta-data that have the potential to provide clinically useful information. Wearable devices include applications such as the Apple Watch and Fitbit, which collect data on the wearer’s vital signs and activity in real time. These rich streams of real-time data can be incorporated into recovery prediction algorithms or chronic TBI management algorithms, which can

R. G. F. Dolmans et al.

be housed in either the EHR or a chronic management platform, which gathers multiple data streams. Smartphone applications that collect data on patients reported outcomes have been developed for various conditions including rheumatoid arthritis, atopic dermatitis, and cancer. As patient-reported outcomes gain greater importance in clinical management, the demand for applications like this is likely to increase. Until now the market for TBI smartphone applications has been mainly limited to sports-related concussion [18]. However, there is little doubt that the use of these applications would be useful for monitoring progress and improving management of patients recovering from moderate and severe TBI. Standardizing the use of such data collection platforms would allow for more frequent assessments by gathering meaningful data such as the following: • Distance and frequency of travel from hospital rehabilitation, home, or work • Frequency, nature, and duration of calls made and received • Screen time duration and content Analysis of the data may provide meaningful insight into the subtle recovery of a patient, especially when considered in combination with other data streams. Incorporating these patient-­centered assessment tools would improve chronic TBI management by increasing frequency of assessment, increasing data types collected, and increasing the potential duration of patient data collection. This would potentially be helpful for monitoring a patient’s symptoms and the impact that this has on their recovery, as well as tracking the development of comorbidities and sequelae. There would also be potential for monitoring the effects of repeated head injuries, as occurs in a number of sporting events such as boxing, American football, rugby, and ice hockey. The next step in the evolution of these devices is the development and introduction of prediction models for long-term recovery and the development of the aforementioned sequelae. Such models, either built in the EHR or as a separate

5  Big Data Collection and Traumatic Brain Injury

chronic TBI management platform, would receive data from the patient, which in turn would provide valuable information to healthcare professionals. Prediction models using BD expand upon the previous prediction models by incorporating data of more volume, velocity, and variety than has previously been feasible. Additionally, a greater inclusion of patients and hospitals will not limit the model to a single institution or set of trial sites. However, despite their potential, the early efforts to leverage ML for TBI outcome prediction have been thus far limited to mortality prediction [19]. The development of more advanced models will incorporate various data sources across the timeline of a patient’s disease, from preexisting medical history to the hospital course and hospital data, the follow-up data, and patient-centered tracking data. The output of such models will be twofold. Firstly, it can provide education to patients about the nature and severity of their condition and expected course of recovery, and it can alert them to circumstances where medical help is required. Secondly, it can provide predictive and prognostic value to clinicians by incorporating more data that facilitates an individualized management plan. Up to now, attempts at developing these models have been hindered by difficulties integrating medical record data with consumer-facing devices. However, adopting this type of approach is undoubtedly the future of BD in TBI management, as the pressure to better characterize and manage TBI patients mounts and the need for better clinical guidelines drives the need for BD solutions (Fig. 5.1).

5.4.7 Research Applications The collection and use of BD is highly likely to change the management of TBI, but it is also likely to change the way in which research is conducted. Not only can previously published data be mined at much greater speed and accuracy, but the data streams described above can change how

41

TBI research is performed. With more (seemingly unlimited) data available, research efforts that aim to improve treatment of TBI patients will benefit, and the development of algorithms will change how clinical trials are conducted. Basic science can benefit from the implementation of BD as well. For example, standardized collection of continuously monitored data points from experimental animal studies may contribute to the optimal use of resources by providing reliable baseline information that negates the need for repeated experiments. Improved or increased access to preclinical data, ideally shared between labs, could also speed up current research efforts. Combining preclinical and clinical data sources could aid in many aspects of TBI research that will hopefully lead to the development of novel treatment strategies and ultimately transform TBI research and care (Fig. 5.1).

5.5

Strengths and Limitations

The different categories of BD relevant for TBI are not perfect as each category has strengths and weaknesses (Table  5.3). Patient characteristics reflect the actual medical records and scoring system. Even though they are widely used, this information is not always electronically available or available in a timely manner. In addition, it is often a mixture of structured and unstructured data, making efficient analysis challenging. Clinical monitoring generates huge amounts of standardized and structured (near) real-time data that contains information about the primary and secondary injury process, which can be used to guide therapy. However, patient comorbidities as well as the presence of other life-threatening injuries can affect the data and its interpretation. There is also the possibility of confounding due to variability in data collection, storage, and retrieval due to differences in monitoring devices (e.g., ICP monitors or brain tissue oxygenation monitors), and there is variability in the degree to which certain clinical monitoring data is available. Neuroimaging is routinely used in most trauma centers and contains rich data sources;

R. G. F. Dolmans et al.

42

Table 5.3  Strengths and limitations of data sources for big data analysis in clinical traumatic brain injury Data source Patient characteristics

Clinical monitoring

Neuroimaging Genomics Clinical course Clinical outcomes

Strengths Diverse data reflecting the actual medical records, previous conditions, etc., injury severity scores are widely used and standardized Standardized outputs, structured data, (near) real-time data flow, biomarkers can potentially inform about the secondary injury process, can guide therapy Routine technology and consistency of CT and MRI, rich data sources Structured data Diverse data reflecting the actual clinical course Multiple time points enable monitoring of disease progression, assessing treatment efficacy

however, the data can be unstructured, and this can make it difficult to analyze consistently. Genomics has the potential to guide personalized TBI strategies; however, this is currently very expensive and therefore not widely used. Finally, clinical outcomes allow clinicians to monitor disease progression and assess treatment efficacy; however, this is not universally performed and is a mixture of structured and unstructured data. Nevertheless, despite these imperfections, BD has a lot of potential to help optimize acute and chronic management of TBI as well as to facilitate further research.

5.6

Future Directions

As the role of big data in TBI is crystallizing, it is becoming increasingly clear that the future of TBI management will undoubtedly involve collection and use of BD. The evolution of medicine is the evolution of data, from its early origins based on intuition to our increasing dependency on data and evidence-based medicine. We are now entering the next phase of medicine and data, wherein the data available to us as clinicians and researchers is expanding ever-more rapidly. The potential for this data to help our patients is currently limited only by our imagination, and investing in BD approaches will hopefully trans-

Limitations Not always available electronically or in a timely manner, mixture of structured and unstructured data, scores are subjective Comorbidities (polytrauma) can affect data, data quality is uneven, variability in data types, variability among users, no verified biomarker, assays are not widely used, multiple types of sensors Unstructured data, data quality is uneven, variability in data types, user-specific Not widely performed, expensive Not standardized, mixture of structured and unstructured data Not universally performed, mixture of structured and unstructured data, expensive, needs dedicated staff

form TBI care and research to ultimately improve patients’ outcomes.Conflicts of InterestThe authors report no conflicts of interest.

References 1. Fragidis LL, Chatzoglou PD.  Implementation of a nationwide electronic health record (EHR). Int J Health Care Qual Assur. 2018;31:116–30. 2. Huie JR, Almeida CA, Ferguson AR. Neurotrauma as a big-data problem. Curr Opin Neurol. 2018;31:702–8. 3. Hawryluk GW, Manley GT.  Classification of traumatic brain injury: past, present, and future. Handb Clin Neurol. 2015;127:15–21. 4. Saika A, Bansal S, Philip M, et al. Prognostic value of FOUR and GCS scores in determining mortality in patients with traumatic brain injury. Acta Neurochir. 2015;157:1323–8. 5. Brennan PM, Murray GD, Teasdale GM. Simplifying the use of prognostic information in traumatic brain injury. Part 1: The GCS-Pupils score: an extended index of clinical severity. J Neurosurg. 2018;128:1612–20. 6. Raj R, Luostarinen T, Pursiainen E, et  al. Machine learning-based dynamic mortality prediction after traumatic brain injury. Sci Rep. 2019;9:17672. 7. Saatman KE, Duhaime AC, Bullock R, et  al. Classification of traumatic brain injury for targeted therapies. J Neurotrauma. 2008;25:719–38. 8. Marmarou A, Lu J, Butcher I, et al. IMPACT database of traumatic brain injury: design and description. J Neurotrauma. 2007;24:239–50. 9. Gomez PA, de-la-Cruz J, Lora D, et al. Validation of a prognostic score for early mortality in severe head injury cases. J Neurosurg. 2014;121:1314–22.

5  Big Data Collection and Traumatic Brain Injury 10. Li X, Lu C, Wang J, et al. Establishment and validation of a model for brain injury state evaluation and prognosis prediction. Chin J Traumatol. 2020;23:284–9. 11. Yue JK, Vassar MJ, Lingsma HF, et al. Transforming research and clinical knowledge in traumatic brain injury pilot: multicenter implementation of the common data elements for traumatic brain injury. J Neurotrauma. 2013;30:1831–44. 12. Madhok DY, Yue JK, Sun X, et al. Clinical predictors of 3- and 6-month outcome for mild traumatic brain injury patients with a negative head ct scan in the emergency department: a TRACK-TBI pilot study. Brain Sci. 2020;10:269. 13. Maas AI, Menon DK, Steyerberg EW, et  al. Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-­ TBI): a prospective longitudinal observational study. Neurosurgery. 2015;76:67–80. 14. Hu X, Xu P, Scalzo F, et al. Morphological clustering and analysis of continuous intracranial pressure. IEEE Trans Biomed Eng. 2009;56:696–705.

43 15. Honeybul S, Ho KM, Gillett GR. Long-term outcome following decompressive craniectomy: an inconvenient truth? Curr Opin Crit Care. 2018;24:97–104. 16. Malec JF, Hammond FM, Flanagan S, et  al. Recommendations from the 2013 Galveston Brain Injury Conference for implementation of a chronic care model in brain injury. J Head Trauma Rehabil. 2013;28:476–83. 17. Sheikhalishahi S, Miotto R, Dudley JT, et al. Natural language processing of clinical notes on chronic diseases: systematic review. JMIR Med Inform. 2109;e12239:7. 18. Christopher E, Alsaffarini KW, Jamjoom AA. Mobile health for traumatic brain injury: a systematic review of the literature and mobile application market. Cureus. 2019;e5120:11. 19. Rau CS, Kuo PJ, Chien PC, et al. Mortality prediction in patients with isolated moderate and severe traumatic brain injury using machine learning models. PLoS One. 2018;13:e0207192.

Part II Current Clinical Practice

6

Prehospital and Emergency Department Management of TBI David J. Barton and Francis X. Guyette

6.1

Introduction

Traumatic brain injury (TBI) is one of the leading causes of death globally, affecting more than 10 million people per year [1]. It is a contributing factor in more than 1/3 of trauma deaths and is a leading cause of death in individuals less than 45  years old, resulting in a tremendous societal loss. Mortality from traumatic brain injury disproportionately affects patients in rural areas and those from low- and middle-income countries [1]. While the primary insult of traumatic brain injury is often difficult to mitigate, much of the disability associated with traumatic brain injury is due to secondary insults. Emergent management of secondary injury, particularly minimizing early exposure to hypoxemia, hypotension, and hyperventilation during prehospital and emergency care, may lead to improved outcomes in patients suffering from TBI [2].

6.2

Background Information and Pathophysiology

Menon has described traumatic brain injury as “an alteration in brain function or other evidence of brain pathology caused by an external force” D. J. Barton · F. X. Guyette (*) Department of Emergency Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_6

[3]. Traumatic brain injury can be divided into primary brain injury, which may include focal tissue destruction, disruption of axons, and hemorrhages, and secondary injury, which may include ischemia, edema, oxidative stress, or inflammatory cascades resulting in cell death [4]. Secondary injury may be worsened by impaired autoregulation, which can lead to decreased cerebral blood flow and failure to meet the metabolic demands of the tissues [5]. Decreasing cerebral blood flow worsens the insult of traumatic brain injury by contributing to tissue hypoxia and ischemia. The traumatized brain may also be at higher risk of seizures, further increasing the metabolic demands of tissue compromised by hemorrhage or contusion [1]. Successful emergent treatment of traumatic brain injury requires the prevention of hypoxemia, hypotension, and hyper- and hypocarbia and maintenance of cerebral perfusion pressure through the identification and management of intracranial hypertension and prevention and management of seizures [5]. Outcomes in patients with TBI are the product of the complex interaction between primary and secondary injuries and the management that begins immediately after the traumatic event [2]. Illustrative Case An unhelmeted 45-year-old male operator of an all-terrain vehicle drove over an embankment and struck a tree. He was found unconscious with an abrasion over his face, periorbital ecchymosis, 47

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and blood from his nose and mouth. He underwent spinal motion restriction (SMR) and was placed on high-flow oxygen, and IV access was obtained. The prehospital providers found the patient to have a heart rate of 51, a blood pressure of 151/99 mmHg, oxygen saturation of 93%, and a GCS of 3. He was tachypneic at a rate of 32. The patient had IV fluids administered to ensure adequate perfusion and supplemental oxygen to avoid hypoxia. He underwent a rapid sequence induction with 0.3 mg per kilogram of etomidate and 1 mg per kilogram of rocuronium. His airway was secured without hypoxia or hypotension. He was placed on a mechanical ventilator adjusted to target an EtCO2 of 35–45. His head of bed was elevated to 30  degrees while maintaining SMR. He was kept warm to prevent hypothermia. Despite these interventions, he was noted to have persistent bradycardia, hypertension, and anisocoria with his right pupil dilated to 7  mm. The crew consulted with a medical oversight physician and administered 1  gm/kg of mannitol. Mannitol was administered on route to a trauma center where the trauma and neurosurgical services received prearrival notification. Following a secondary trauma survey, the patient was taken for a CT scan of the brain, which showed patchy traumatic subarachnoid hemorrhage and bifrontal contusions. He was administered levetiracetam for seizure prophylaxis and admitted to the neurotrauma ICU for close monitoring. Over the following 2  weeks, his clinical condition improved, and he was discharged to a rehabilitation facility 2 weeks later.

6.3

Current Evidence and Contemporary Practice

The Brain Trauma Foundation has developed evidence-based guidelines for the emergent management of patients with traumatic brain injury. Specific recommendations for prehospital and emergency management were published in 2007 and updated in 2016. In 2019, Spaite et al. demonstrated that adherence to the Brain Trauma Foundation guidelines was associated with improved survival in patients with severe TBI

[6]. Unfortunately, the implementation of these recommendations is very limited, and even the assessment of traumatic brain injury in the prehospital and emergency environment is highly variable [7]. One of the key principles in the Brain Trauma Foundation guidelines is assessment of the patient with traumatic brain injury. Patient assessment in the prehospital environment is limited by the available diagnostic resources, and advanced intracranial monitoring may not be available in the emergency department [8]. In all cases, assessment may also be impaired by intoxication, sedation, and endotracheal intubation [5]. The patient should first be assessed with a Glasgow Coma Score (GCS) and pupillary response to evaluate the severity of injury. In addition, the patient’s vital signs should be monitored to assess for hypoxemia, hypotension, and hypocarbia. The GCS should be reassessed prior to and following any intervention or change in status [7]. Data regarding the patient’s injury severity, vital signs, mechanism of injury, injury type, history, and comorbidities should be used to determine the need for emergent interventions and patient care resources [1]. Patients suspected of having severe brain injury require special attention to prevent secondary injury from hypoxia (SaO2 > 90%) and hypotension (SBP 2 mm or bilateral mydriasis • New focal motor deficit • Herniation syndrome (e.g., Cushing’s triad) Timing for CT scanning: • CT scan as soon as possible after TBI injury • If the initial CT scan is obtained at ≤4 h after injury, obtain a follow-up CT scan within the subsequent 12 h • CT scan at 24 h after injury • CT scan at 72 h after injury • As needed based on the patients clinical condition: –– Neuroworsening –– To assist in decision making –– Other clinical situations The Classification of CT scan findings: • CT scans should each be individually be classified according to the Marshall Score Evacuated Mass Lesion Classification Innovation: For the purposes of further understanding decision making following surgical evacuation of mass lesions, any CT performed in a patient following such surgery will be classified according to the non-surgical component of the Marshall score (DI 1–IV). An additional interesting proposal from this protocol is a series of heat maps related to when to decrease the intensity of therapy based on medical exam and CT imaging in the first week of patient management in an ICU. As we present in our illustrative case, in areas where advanced neuromonitoring is not present, there is no specific guide regarding when to start

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decreasing sedation or other acute therapies such as muscle paralysis or osmotherapy. The proposed heat map divides the clinical evaluation based on motor score of the GCS and pupil reactivity (normal or abnormal) combined with the Marshall score of the CT scan, 24, 48 and 72 h after the injury. If the GCS is low or pupils are abnormal, they do not recommend cessation of sedation, especially if the CT Marshall score is high (>3). This recommendation remains mostly during the first 48 h and then if there are improvements in GCS or pupil reactivity or if the Marshal score decreases (1 and 7 days 24 h), posttraumatic amnesia (0–1 day, >1  day and 7  days), and Glasgow Coma Scale (GCS) score (3–8, 9–12, or 13–15). Table  11.1 shows the classification scheme for the severity of TBI used in the DoD/VA CPG for concussion/mild TBI. Because the determination of TBI severity is dependent upon several clinical factors, a patient may meet criteria for more than one class of severity. In these cases, the most severe classification of TBI for which the patient meets criteria is selected [11].

11.3.2 Roles of Care Military medical care for service members injured in combat is organized and stratified into four roles of care based on proximity to injury, medical unit mobility, and medical capabilities. Role 1 refers to military unit-level care and represents the first medical care that military personnel receive, including not only routine sick call and care of minor injuries but also immediate life-saving measures and initial stabilization in preparation for evacuation to higher roles of care. Role 2 facilities are mobile units that offer advanced trauma and intensive care capabilities, as well as basic X-ray, laboratory, and dental services. These mobile medical units are capable of performing damage control surgery and postoperative stabilization before transfer to higher role care. This Forward Surgical Team (FST) or Role 2-plus unit performs life-saving general trauma surgery and in some cases orthopedic surgery.

11  Military Management of Traumatic Brain Injury

Role 2 units do not have neurosurgeons. Role 3 medical care is provided at permanent or semi-­ permanent facilities capable of providing both initial resuscitative care and emergency specialty care, including orthopedic surgery, urology, thoracic surgery, otolaryngology, ophthalmic surgery, and neurosurgery. CT imaging is available at Role 3 locations. Lastly, Role 4 hospitals are medical treatment facilities (MTFs) providing definitive general, specialty, and subspecialty care, both in the United States and at select international locations. In general, care begins at Role 1, with transfer to progressively higher roles of care as appropriate. In some cases, it may be appropriate to bypass a lower role of care, such as a patient with severe or penetrating TBI with acute neurosurgical needs being evacuated directly to a Role 3 facility from Role 1 care. The rapid evacuation of injured personnel to higher echelons or levels of care, once they are stabilized, is an important component of a highly functioning military trauma system. Continued expert medical care during evacuation is also crucial. Frequent reassessment, treatment of missed injuries, further stabilization, and in many cases further surgery improve overall outcomes for severely injured personnel. Civilian trauma systems have adopted many of the military medical “lessons learned” during OIF and OEF.

11.3.3 Severe and Penetrating TBI The care of patients with severe and penetrating TBI in the forward-deployed setting is complicated by a number of factors, including the relative lack of specialty care, limited resources, high likelihood of significant concomitant injuries, and logistical challenges in their transport to definitive care. Accordingly, treatment in the immediate postinjury setting is most often delivered by nonspecialized medical practitioners and consists primarily of stabilization according to the Advanced Trauma Life Support (ATLS) and Joint Trauma System (JTS) resuscitative principles and preparation for evacuation to Role 3 facilities. Their care in this setting, as well as upon arrival to Role 3 care, is informed by the

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JTS CPG for Neurosurgery and Severe Head Injury [13]. Updated every 2  years, this CPG provides guidance regarding eligibility for care, as well as recommendations for the acute and surgical care of patients with severe TBI. Coalition service members with symptomatic mild TBI persisting for more than 24 h are considered eligible for further workup and possible neurosurgical evaluation at a Role 3 facility. All coalition patients with moderate to severe or penetrating TBI are evacuated to Role 3 hospitals for imaging and neurosurgical evaluation and treatment. The host nation’s patients with moderate and severe TBI may be evaluated and treated at Role 3 centers on a case-by-case basis [13]. The initial management of severe TBI patients injured in conflict centers around the treatment of life-threatening injuries and resuscitation according to ATLS protocols. The airway should be secured, and the patient should be oxygenated to maintain an SpO2 greater than 93% and a PaO2 greater than 80 mmHg. While brief hyperventilation may be used as a temporizing strategy in the context of suspected impending herniation, sustained hyperventilation is not beneficial; thus, ventilation to a goal PaCO2 of 35–40  mmHg is recommended. As hypotension is highly associated with mortality in TBI, patients should be resuscitated as necessary with crystalloids or blood products to maintain a systolic blood pressure of at least 100 mmHg for patients between the ages of 50 and 69 and at least 110 mmHg for patients between the ages of 15 and 49, or over the age of 69 [13]. The neurological exam should be reassessed regularly and at a minimum should include the patient’s GCS, pupillary reactivity, and any focal neurologic signs. Maintenance of serum glucose below 180  mg/dL (while avoiding hypoglycemia) is recommended. In open fractures and penetrating TBI (or for any patient in the preoperative setting), prophylactic antibiotics are appropriate. The antibiotic of choice is typically either cefazolin or clindamycin, with the optional addition of metronidazole in cases with gross contamination. In cases of known or suspected intracranial hypertension, empiric hyperosmotic therapy

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should be initiated, with either hypertonic saline infusion to a sodium goal of 150–160 mEq/L or mannitol [13]. The guidelines for ICP monitoring in the deployed setting are adopted from the Brain Trauma Foundation (BTF) Guidelines for the Management of Severe Traumatic Brain Injury [14]. Intracranial pressure monitoring is considered in all salvageable patients meeting the clinical definition of severe TBI who have either an abnormal head CT or a normal CT with at least two of the following: age older than 40, motor posturing, or hypotension with systolic blood pressure less than 90  mmHg. Providers may place either an external ventricular drain (EVD) or a parenchymal ICP monitor, with the goal to maintain ICP less than 22 mmHg, with a cerebral perfusion pressure between 60 and 70 mmHg [13]. The operative indications for hematoma evacuation are similarly derived from the BTF guidelines and are dependent upon hemorrhage thickness and/or volume, degree of midline shift, and clinical status [14]. Posterior fossa mass lesions with neurological symptoms should be operated on expeditiously. Debridement of devitalized brain tissue and superficial bone fragments may be undertaken during surgery, though routine exploration for foreign bodies is not recommended. Surgical decompression with a large frontotemporoparietal craniectomy is strongly recommended for all salvageable patients with penetrating TBI, as the kinematics of combat trauma are different compared with civilian trauma. Higher muzzle velocities of military firearms result in greater cavitation and devitalization of brain tissue, and blasts may result in complex injuries as a result of several mechanisms. Gross brain swelling and intracranial hypertension are typical of blast injury or penetrating missile injury. This is life-threatening if not relieved. Additionally, the opportunity for interventions for elevated ICP is limited during patient transport; thus, aggressive early decompression with placement of an ICP monitor allows for streamlined ICP management en route [13]. The size of the frontotemporoparietal crani-

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ectomy should be at least 14 cm anteroposterior and 12  cm superoinferior [9]. The basal dura should be repaired if it is lacerated. This can usually be achieved with a pericranial vascularized flap. Prevention of CSF leak is vital in preventing secondary infection. The use of tensor fascia lata is an alternative. It is important to avoid using metallic implants such as titanium mesh for the repair of the skull base. The convexity dura usually requires expansion by duroplasty. Onlay graft with DuraGen is an alternative. The scalp is closed in a water-tight fashion. Complex trauma involving the eyes, orbits, air sinuses, nose, mouth, throat, and neck is common in blast injury and requires coordinated multidisciplinary management from the outset. For military personnel, the craniectomy bone flap is discarded in any case of penetrating TBI, or in any blunt TBI case with significant comminution, or where sterile abdominal subcutaneous placement is not feasible. These patients may undergo subsequent cranioplasty with a custom implant. The host nation’s patients represent a unique challenge with regard to reconstruction; as there is limited opportunity for follow-up care, they may be difficult to locate or contact, and custom alloplastic implants may be difficult to procure. Options in these cases include replacement of the bone in situ, replacement with elevation of the flap, or a hinge craniectomy, which involves partial fixation of the bone flap to accommodate cerebral swelling [13]. A consideration unique to neurosurgical care in the deployed setting pertains to aeromedical transport. Such patient movement is generally performed over long distances, without access to specialty care. Particularly for extended air evacuations, it is recommended that patients have functioning ICP monitors in place, and if a patient’s ICPs are sufficiently high that he or she is considered unstable for transport, it may be more appropriate for them to be observed in theater. The effect of increasing altitude on pneumocephalus should also be considered, as these air collections may expand during flight and increase ICP [13]. Patients with catastrophic, nonsurvivable TBIs are treated according to the JTS CPG for

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Table 11.2  I/E/D Checklist for evaluation of service members exposed to potentially concussive events. Adapted from DoD Policy Guidance for Management of Mild Traumatic Brain Injury/Concussion in the Deployed Setting [12] Injury Evaluation

Distance

Physical damage to the body or body part of a service member? H—Headaches and/or vomiting? E—Ear ringing? A—Amnesia, altered consciousness, and/or loss of consciousness? D—Double vision and/or dizziness? S—Something feels wrong or is not right? Was the service member within 50 meters of the blast? Record the distance from the blast.

Catastrophic Non-Survivable Brain Injury, with a goal of achieving hemodynamic stability whenever possible to permit evacuation to Role 4 facilities for eventual reunion with families and participation in organ donation. This CPG provides exhaustive recommendations for the management of catastrophic TBI-related complications. In cases where a patient cannot be stabilized for evacuation to a Role 4 facility, or where battlefield provisions preclude safe evacuation, providers may choose to cease resuscitative efforts [15]. Upon arrival at a Role 4 facility, repeat imaging is obtained to confirm stability of findings on previous imaging, and a baseline neurological exam is obtained with sedation held. Particularly in cases of penetrating TBI, a DSA is obtained as soon as possible to evaluate for and treat traumatic vascular injuries. Delayed cerebral vasospasm may also occur following blast injury and requires regular monitoring and active management [16, 17]. Following recovery from the acute posttraumatic period and several months of extensive neurocognitive rehabilitation, patients usually return to WRNMMC for cranioplasty with a custom synthetic titanium implant.

11.3.4 Mild TBI Care for service members in the deployed setting with mild TBI is guided by DoD instruction. The initial care of these patients is largely algorithmic and is centered around identifying service members at risk for mild TBI.  DoD Instruction 6490.11 mandates a post-event rest period and

Yes/No Yes/No

Yes/No/Not applicable

evaluation for all personnel who are involved in vehicle blasts, collisions, or rollovers, are within 50 meters of a blast, have sustained a direct blow to the head with a witnessed LOC, or have been exposed to more than one blast event. This directive applies even to service members without apparent injury [12]. Service members meeting the above criteria are assessed with the Injury/Evaluation/Distance checklist (Table 11.2) as soon as possible following the event and are referred for medical evaluation, particularly if they answer “Yes” to any of the questions in the checklist. The patient’s command is responsible for submitting a report within 24  h to the Joint Trauma Analysis and Prevention of Injury in Combat (JTAPIC) Program Office [12]. The initial rest period is 24 h, beginning at the time of the potentially concussive event. There is limited command discretion regarding this requirement; however, any departure from the 24-h rest period is required to be documented in the report to the JTAPIC. For a first concussive event, the patient may return to duty if medically cleared after the 24-h rest period. Personnel sustaining a second event within one 12-month period are required to have an additional 7 days from resolution of symptoms before returning to duty. Recurrent concussions or events (defined as three or more within a 12-month period) incur longer delays and more intensive medical evaluation before return to duty is considered [12]. The medical evaluation of service members involved in potentially concussive events includes the use of the MACE (https://dvbic.dcoe.mil/system/files/resources/MACE2.pdf) as soon as pos-

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sible after the event. Patients who suffer recurrent concussion or exposure to potentially concussive events should undergo a subsequent comprehensive neurological exam, which may include neuroimaging, neuropsychological evaluation, and a functional assessment. At the conclusion of this assessment, the treating medical professional will make decisions regarding subsequent management and duty status. At any point, patients with concerning or progressive symptoms, whether on initial evaluation or comprehensive examination, should be evacuated as necessary for specialist care at a higher level [12]. For personnel not on a deployed status, the care of patients with suspected mild TBI is delivered according to the DoD/VA CPG for the Management of Concussion/Mild Traumatic Brain Injury. Care of these patients begins at 1  week postinjury and involves identifying any symptoms or associated conditions that warrant a higher level of care, such as alterations in conscious level, declining neurological exam, progressive neurological deficits, visual deficits, seizures, slurred speech, behavioral changes, etc. This also represents an opportunity to identify patients with more severe TBI that may have been missed or misclassified. Patients who are symptom-free are reassured and provided with educational resources, with follow-up as indicated. Patients with persistent symptoms are further evaluated for comorbid neurological and psychological conditions, and medical providers are advised to establish an ongoing therapeutic alliance, establish expectations for symptoms resolution, and reassess at regular intervals, with the involvement of a TBI specialist as necessary [11].

11.4 Future Directions Despite intensive efforts at developing improved protective equipment, more sensitive and specific screening techniques, and intensive prevention programs, mild TBI remains a significant problem among members of the US military. The DoD and VA enjoy robust partnerships with research organizations that are currently engaged

in the search for reliable biomarkers for mild TBI, as well as a fuller understanding of the full spectrum of neurocognitive effects of isolated and recurrent mild TBI. The DoD has also coordinated with sports organizations such as the NFL and the NCAA in developing strategies for long-term follow-up of patients with mild TBI, particularly recurrent subconcussive injuries, as well as banking of tissue specimens to look for the pathological hallmarks of conditions such as chronic traumatic encephalopathy (CTE) [1]. Long-term outcomes for patients with severe and penetrating TBI are currently under investigation, and many service members who sustained penetrating head injuries in OIF and OEF are currently undergoing intensive neurocognitive and neuropsychological evaluation to better understand the long-term effects of these often devastating injuries.

11.5 Conclusions The care of TBI sustained in battle has evolved over several millennia, from the earliest evidence of trephination in the skulls of ancient indigenous Peruvians to the current approach of aggressive decompression and aeromedical evacuation for severe and penetrating TBI.  Rapid stabilization and evacuation from the point of injury on the battlefield to higher levels of multidisciplinary specialist care, including neurosurgery, is a feature of the modern military trauma system. This protocolized hierarchy of care has improved outcomes for service members with these serious injuries. Additionally, recent decades have seen a growing recognition of mild TBI as a serious health issue with effects that may persist long after the time of injury. The recognition of the significant health implications of all forms of TBI has prompted the development of a more comprehensive approach for screening, diagnosing, and treating mild TBI, with a priority on preserving neurocognitive function and returning an injured service member safely to duty. It is hoped that a better understanding and knowledge of the principles of TBI management will build on these

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developments and that research into the long-­ 9. Bell RS, Mossop CM, Dirks MS, et al. Early decompressive craniectomy for severe penetrating and term neurocognitive effects of TBI will allow us closed head injury during wartime. Neurosurg Focus. to better predict and support recovery. 2010;28:E1.

References 1. Helmick KM, Spells CA, Malik SZ, et al. Traumatic brain injury in the US military: epidemiology and key clinical and research programs. Brain Imaging Behav. 2015;9:358–66. 2. Defense and Veterans Brain Injury Center. DoD worldwide numbers for TBI. Available from: https:// dvbic.dcoe.mil/sites/default/files/tbi-­n umbers/ DVBIC_WorldwideTotal_2000-­2019_Q3.pdf 3. Dowdy J, Pait TG. The influence of war on the development of neurosurgery. J Neurosurg. 2013;120:237–43. 4. Agarwalla PK, Dunn GP, Laws ER.  An historical context of modern principles in the management of intracranial injury from projectiles. Neurosurg Focus. 2010;28:E23. 5. Cushing H. A study of a series of wounds involving the brain and its enveloping structures. Br J Surg. 1917;5:558–684. 6. Cushing H.  Organization and activities of the Neurological Service, American Expeditionary Forces. In: Weed FW, McAfee L, editors. The Medical Department of the United States Army in the World War. Washington, DC: Government Printing Office; 1927. p. 749–58. 7. Walker P, Bozzay J, Bell R, et  al. Traumatic brain injury in combat casualties. Curr Trauma Reports. 2018;4:149–59. 8. Aarabi B.  Traumatic aneurysms of brain due to high velocity missile head wounds. Neurosurgery. 1988;22:1056–63.

10. Ling GSF, Ecklund JM. Severe TBI in military: medical and surgical interventions. In: Wang KKW, editor. Neurotrauma: a comprehensive textbook on traumatic brain injury and spinal cord injury. New York: Oxford University Press; 2019. p. 13–20. 11. Management of Concussion—Mild Traumatic Brain Injury Working Group. DoD/VA Clinical Practice Guideline for the Management of Concussion— Mild Traumatic Brain Injury. Version 2.0 [Internet]. Washington, DC: Department of Defense and Department of Veterans Affairs; 2016. Available at: https://www.healthquality.va.gov/guidelines/Rehab/ mtbi/mTBICPGFullCPG50821816.pdf 12. Department of Defense. DoD policy guidance for management of mild traumatic brain injury/concussion in the deployed setting (DODI 6490.11); 2019. 13. McCafferty R, Neal C, Marshall S, et al. Joint trauma system clinical practice guideline: neurosurgery and severe head injury (CPG ID:30); 2017. 14. Carney N, Totten AM, O’Reilly C, et  al. Guidelines for the management of severe traumatic brain injury, fourth edition. Neurosurgery. 2016;80:6–15. 15. Neal C, Bell RS, Carmichael JJ, et  al. Joint trauma system clinical practice guideline: catastrophic and non-survivable brain injury (CPG ID:13); 2017. 16. Armonda RA, Bell RS, Vo AH, et  al. Wartime traumatic cerebral vasospasm: recent review of combat casualties. Neurosurgery. 2006;59:1215–25. 17. Bell RS, Ecker RD, Severson MA, et al. The evolution of the treatment of traumatic cerebrovascular injury during wartime. Neurosurg Focus. 2010;28:E5.

Contemporary Management of Paediatric Head Injuries

12

Snigdha Saha and Stephen Honeybul

12.1 Introduction Traumatic brain injury (TBI) remains the leading cause of mortality in children all over the world, which presents a bimodal peak. It is higher in infants and toddlers where non-accidental injury (NAI) or abusive head injury (AHI) is most common. This decreases in the school-age group, where falls and sporting injuries predominate, and rises again in the adolescent age group, where MVA and assault are frequently the cause [1]. NAI with its delayed presentation, potential for missed diagnosis, repeat insults and MVAs accounts for the most severe injuries and outcomes. Like adults, paediatric head injuries can be classified, according to the Paediatric Glasgow Coma Scale at presentation, into mild (14–15), moderate (9–13) and severe (3–8) head injury. This widely used scale has a modified verbal score for children and nonverbal score for infants. Overall, mild head injuries are most common,

S. Saha (*) Department of Neurosurgery, Perth Childrens Hospital and Sir Charles Gairdner Hospital, Perth, Western Australia, Australia e-mail: [email protected]

accounting for 80–90% of those who present to hospital. Concussion is a subset of mild head injury, which involves transient neurological impairment, attributable to impaired function without underlying structural injury, and resolves without medical intervention. It is common with injury related to sports and falls, and this has significant implications when considering return to play, especially in contact sports where there is the possibility of further injury. Patient management is influenced by a number of factors that are unique to the paediatric population: • Age-related differences in anatomy and pathophysiological response to injury • The ability to obtain an accurate history from caregivers who in certain instances may be perpetrators of the injury • Difficulty in the clinical assessment of young children • The need to consider the effects of radiation to the developing brain when requesting imaging • Surgical considerations such as blood loss and temperature regulation that require greater attention to detail when compared with the adult population

S. Honeybul Department of Neurosurgery, Sir Charles Gairdner and Royal Perth Hospitals, Perth, WA, Australia © Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_12

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12.2 Anatomical and Pathophysiological Differences in Children Relevant to TBI Brain and spine undergo rapid development during the first decade of life, and this is especially the case in the first 2 years of life where there is a rapid growth in head circumference. The fontanels are open in the first year of life, and the open cranial sutures allow bony plates to float apart, and this provides partial protection from raised intracranial pressure [ICP]. The skull is initially thin and pliable, and this provides limited protection to the brain, making growing skull fractures and ping-pong fractures unique to this age group. The head is larger and heavier relative to body size and is poorly supported by weak neck muscles and ligaments. The facet joints are flat, and the intervertebral discs have high water content, and this places the vertebral bodies at a higher risk of dislocation when compared to adults. These factors contribute to children with a TBI being more likely to have concurrent spine injuries, especially at the craniovertebral junction. In these circumstances, MRI plays an important role in investigating these patients especially when considering the difficulties that can arise when making a clinical assessment. Other issues that need to be considered in the context of paediatric TBI are as follows: • Children have smaller airways, making them more susceptible to airway obstruction. • Chest and abdominal organs are poorly protected. • Long bones are weaker, making chest wall injuries, visceral injuries and long bone fractures more common in polytrauma. • Children are more prone to hypothermia due to their large surface area compared to their weight. The response of the central nervous system to trauma also had some characteristics that are unique to the paediatric population: • Cerebral metabolism undergoes rapid changes with cortical development, synaptogenesis

• • •

•

•

•

and myelination, followed by changes in cerebral blood flow. The ICP is lower in children. Cerebral metabolic rate is higher. Blood pressure varies with age, and this has implications regarding optimal cerebral perfusion pressure (CPP) (hence, adult neuromonitoring threshold values are not necessarily applicable to children [2]). They have an exaggerated response to changes in CO2, making them more susceptible to changes in ventilator parameters and more susceptible to hyperaemia or cerebral ischaemia [3]. Up to one third of children with TBI demonstrate loss of cerebral autoregulation, which can result in ischaemia, hyperaemia and raised ICP, all of which can contribute to a poor outcome. Delayed rises in ICP can occur in severe TBI injury due to inflammatory and cellular cascades.

Finally, management of haemorrhage presents unique challenges. The total blood volume in children is lower than adults, and whilst they can compensate for up to 25% of the total volume of blood loss, they then have a sudden circulatory collapse. It is therefore important to be cognizant of clinical signs such as mottled skin, hypothermia, lethargy, metabolic acidosis, reduced palpable pulses and increased capillary refill time, all of which are predictive of cardiovascular instability. A scalp laceration in a neonate weighing 3–4  kg (total blood volume of 85  mL/kg) can cause significant blood loss, unlike adults where head trauma is not usually the cause of major heamorrhage. Therefore, at every step of surgical intervention, close attention to haemostasis is imperative, especially in infants and young children.

12.3 Characteristics of Primary TBI in Children Primary TBI in children includes skull fractures, intracranial haematomas, traumatic subarachnoid haemorrhage, intraventricular haemorrhage,

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d­ iffuse axonal injury and vascular injuries, such as dissections and pseudoaneurysms.

12.3.1 Skull Fractures These can be classified into linear, displaced, depressed and comminuted. Linear skull fractures are common and must be differentiated from normal suture lines on imaging. Diastatic fractures occur when a fracture line crosses patent sutures, resulting in their widening. Hospitalisation is not required in children who have a normal neurological examination and no intracranial bleed on CT imaging. Indications for surgical intervention include the following: • Fractures that are significantly depressed. • Fractures where there is a breach of the dura. • There is involvement of the posterior wall of the frontal sinus. • There is a CSF leak. • There is involvement of a foreign body. • There is an underlying haematoma. The frontal sinuses aerate after 3 years of age, and hence, most frontal fractures can be treated conservatively in younger children. Ping-pong fractures are unique to newborns and young infants because the skull is relatively soft and resilient and is able to indent without a break in the bone. It is so called due to its similarity to indentation produced on a ping-pong ball. These fractures have been described in birth injuries and accidental and non-accidental injuries. They are seldom associated with an intracranial injury, and in most cases, they can be treated conservatively. They often reduce spontaneously due to brain growth and remodelling of skull. Those that don’t reduce can be treated surgically by placing a burr hole next to the fracture and sliding an instrument under the bone to elevate the fracture. Growing skull fractures are uncommon but unique to infants and children up to age 3. These occur when a linear fracture is associated with an underlying dural breach. With brain growth and CSF pulsations, the dural and bone edges are pushed further apart, resulting in brain herniating

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into the defect, forming a pulsatile swelling. Surgical correction involves craniotomy to expose the dural defect (which is usually larger than the overlying bony defect) and repair of the defect with or without a graft, followed by repair of bony defect using a split-thickness calvarial graft or bone chips.

12.3.2 Intracranial Haematomas These include the following: • • • •

Extradural haematoma (EDH) Subdural haematoma (SDH) Intracerebral haemorrhage (ICH) Traumatic subarachnoid and intraventricular haemorrhage (SAH and IVH)

EDH is less common in infants as the dura is adherent firmly to the inner surface of the skull, especially along functional suture lines. Furthermore, the middle meningeal artery has yet to be incorporated into the bone of the inner aspect of the skull, making it less likely to get damaged during trauma. The cause of an EDH in infants is more likely to be a venous injury or a fracture haematoma. An acute SDH is usually the result of a direct external force, causing vascular rupture, and rotational acceleration due to sudden deceleration such as when the skull collides with a stationary object. NAI or AHT is the most common cause of acute SDH in infants and younger children. They often present with haematomas of different ages, which are indicative of repeated injuries. Conditions such as cerebral atrophy, external hydrocephalus and over-shunting in children with large ventricles predispose to the formation of SDH after minor trauma due to avulsion of delicate unsupported bridging veins within enlarged subdural spaces. Cerebral contusions are common in the frontal and temporal region due to skull base irregularities. They usually involve grey matter and occur near the area of impact. With large intracerebral haematomas, it is important to rule out an underlying vascular malformation, such as an arteriovenous malformation or cavernoma, especially when the history of trauma is inconclusive.

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SAH and IVH are more commonly seen in more severe TBI. SAH results from microvascular rupture within the subarachnoid space on the brain surface or from redistribution of blood from traumatic ICH and IVH. IVH can be caused by intracerebral haematomas extending into the ventricles, from subependymal bleeds or from redistribution of blood from SAH, and may be associated with DAI.  This can lead to posttraumatic hydrocephalus due to arachnoid granulation fibrosis.

12.3.3 Diffuse Axonal Injury (DAI) This is the most severe form of injury with shearing of axons and blood vessels of the basal ganglia, corpus callosum, subcortical white matter and internal capsule. The pathophysiological changes are better characterised by MRI imaging rather than CT scans, especially in cases where CT findings are relatively unremarkable, but the patient remains comatose or exhibits poor prognostic features, such as decorticate or decerebrate posturing.

12.4 Secondary TBI in Children Children are more prone to develop diffuse cerebral swelling (DCS) as a complication of TBI. There are several factors that contribute to this, including the following: • Less CSF available for displacement • Greater propensity to lose cerebral autoregulation • Greater propensity to develop hyperaemia, ischaemia and severe raised ICP Infants and younger children are more likely to become hypotensive due to their smaller blood volume, which can lead to compromised CBF and the development of cerebral ischaemia. CT findings of diffuse cerebral swelling include extensive areas of hypodensity with effacement of the cerebral sulci and obliteration of the basal cisterns, leading to the so-called Big Black Brain [4].

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There are certain aspects of TBI in the paediatric population that require special consideration.

12.5 Non-Accidental Injury (NAI) NAI is common and can lead to devastating injuries with high mortality and morbidity. It can lead to severe long-term consequences in previously healthy children and in an age group that is vulnerable and entirely dependent on caregivers for their well-being. It is more common in males and peaks between the ages of 3 and 6 months. NAI perpetrators are more likely to be caregivers who are younger, less educated, single and male, and they are more likely to come from dysfunction families with a history of psychiatry illness and substance abuse. These individuals can sometimes be identified during prenatal consultations, and in these circumstances, measures should be put in place such that they can be monitored after the discharge of their newborn into the community and, where necessary, they can be provided with targeted preventive measures [5]. It is important for paediatric neurosurgeons to suspect NAI in cases where the history does not necessarily collaborate with the extent or pattern of injuries found either clinically or radiologically. In these circumstances, it is important to: • Look for other associated injuries, such as long bone fractures and spine injuries. • Involve ophthalmology early to perform the relevant examination. • Obtain relevant imaging. • Involve child protection services. Characteristic features of NAI include subdural haematomas of different ages, areas of cerebral oedema and ischaemia of varying severity, retinal haemorrhages and retinal detachment. The cerebral ischaemia that occurs in more severe cases is the most common cause of death in this group of patients. It can result from raised ICP, low CPP, apnoea due to initial loss of consciousness, spinal cord insult or seizures [6]. Retinal haemorrhages are an important hallmark in NAI, but they can also occur in acciden-

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tal TBI and following an aneurysmal subarachnoid haemorrhage. These tend to clear in a weeks’ time, and mild cases may be missed if the fundoscopy examination is delayed, emphasising the importance of getting early and repeated imaging of the fundus by an experienced ophthalmologist. Retinal detachment can also occur, and in the most severe cases, this may lead to visual deficits and blindness. Subdural haematomas seen in NAI can be acute, subacute or chronic. The chronic SDH tend to be bilateral, consisting of haemorrhagic CSF, which becomes more like CSF with time. Ex vacuo CSF collection can be seen in children weeks to months after severe NAI, with underlying atrophy of the brain. These children may need repeated evacuation of subdural collections or a subdural-peritoneal shunt. Skeletal survey X-rays are useful when investigating suspected cases of NAI as they can provide evidence of healed fractures, indicating multiple episodes of trauma. It is becoming increasingly apparent that spine injuries are a frequent result of NAI. Autopsy studies have shown that NAI is often associated with high cervical cord contusions and subdural haematomas in the spine. Whilst CT scanning remains the imaging modality of choice for the initial evaluation and management of patients with a suspected NAI, MRI is more sensitive for the diagnosis, characterisation and prognostication of brain and spinal injuries, and this is usually obtained once the child is stable.

12.6 Birth Injuries The most common birth injuries are subgaleal haematomas and cephalohaematomas. Subgaleal haematomas are usually associated with linear skull fractures, which lead to bleeding into the loose connective tissue of the scalp. Because these infants have such a small blood volume and the subgaleal haematomas can be quite large, blood transfusion is sometimes required. Cephalohaematoma is a subperiosteal haematoma limited by the suture lines because the periosteum is densely adherent to the sutures. Most

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reabsorb; however, some may calcify. Aspiration of these haematomas is not recommended due to the risk of infection, and some babies may develop jaundice as the blood gets reabsorbed. Rarely depressed skull fractures can lead to laceration of the underlying dura and brain during instrumental delivery; however, most of these can be managed conservatively. Illustrative Cases Case No. 1 An 8-year-old girl presented to the emergency department drowsy, with multiple episodes of vomiting, unable to talk and unable to walk independently. She was accompanied by her grandmother who did not speak English. She was admitted under general paediatrics with a provisional diagnosis of gastroenteritis and possible meningoencephalitis. During the next 3 days, her clinical condition progressively deteriorated. Following a tonic clonic seizure, she became unresponsive, and her left pupil became fixed and dilated. A CT head showed a large left-sided EDH, with midline shift and uncal herniation (Fig. 12.1). The child was intubated and urgently transferred to a tertiary hospital with neurosurgical facilities. On rechecking the clinical history with her parents, it turns out that she had had a fall and hit her head on the corner of a glass coffee table 24  h prior to her initial presentation. Closer examination revealed a small scalp bruise in the left temporal area at the area of impact. She subsequently had an emergency evacuation of the EDH and went on to make a full neurological recovery. This case highlights the importance of history taking and clinical examination; the missed diagnosis could have had a disastrous outcome. Case No. 2 An 11-month-old girl presented to the hospital having had a seizure. A CT head scan revealed a right-sided subdural haematoma with mild mass effect (Fig. 12.2). She was transferred to a ­tertiary centre where she remained well with a GCS of 15 and no neurological deficits. She was referred to the paediatricians for further assessment, and clinical examination revealed bilateral bruising of both buttocks and vaginal tearing.

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Fig. 12.1  Large left EDH, with midline shift and uncal herniation. Arrow points to small temporal fracture, at the area of impact, underlying the focal scalp bruising

Fig. 12.2  Initial CT head, and MRI 3  days after NAI demonstrating right convexity SDH and large spinal epidural haemorrhage from C7 to T11, displacing cord ante-

riorly (above). Follow-up MRI after 10  days showing resolution of intracranial and intraspinal haemorrhages (below)

Ophthalmology assessment showed bilateral retinal haemorrhages and right-sided subhyaloid haemorrhage. Skeletal survey confirmed a bucket handle fracture of the distal metaphysis of the right fibula, which required casting. A diagnosis of NAI was established, and her case was referred to the local child protection services. Her head injury was treated conservatively. Subsequent MRI scan of her brain and spine confirmed stable appearance of the subdu-

ral haematoma and a large spinal epidural haemorrhage from C7 to T11, displacing the cord anteriorly without cord signal changes. This was managed conservatively in view of the normal neurological examination. Follow-up MRI head and spine (Fig. 12.2) showed resolution of both haemorrhages. Following surgery for her urogenital injuries, she was discharged under the care of the Department of Child Protection where she remains with a special guardianship order in

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place up to the age of 18 years. She was followed up by the paediatric rehabilitation and early childhood intervention units where she received treatment for speech delay and emotional dysregulation. This case highlights the importance of multidisciplinary care in the management of young children presenting with NAI and the role of MRI brain and spine in screening for occult injuries. Case No. 3 A 1-month old baby girl presented to the emergency department having had a seizure following a fall from a changing table. On clinical examination, she was generally floppy with unequal pupils and a tense anterior fontanelle. A CT scan of the brain revealed extensive traumatic SAH, some scattered subdural haemorrhages and extensive bilateral supratentorial hypodensities with sparing of the cerebellum, thalamus and basal ganglia (Fig. 12.3). She was intubated and transferred to the paediatric intensive care unit where she was evaluated for other injuries. A subsequent MRI scan of the brain and spine showed global cortical restricted diffusion with sparing of deep grey matter, brainstem and cerebellum. Layered intraspinal haemorrhage was seen within the spinal canal from T9 to S1, displacing the cauda equina nerve roots anteriorly. Based on these findings, a diagnosis of NAI with severe head injury was made, and there followed extensive discussion between intensive care, neu-

rosurgery, neurology and the child protection services. It was established that there was a history of maternal drug abuse that may have contributed to the child’s fall, due to neglect. Over the following weeks, there were further discussions with the family regarding goals of care and prognosis. She was eventually extubated and was able to maintain her airway and tolerate feeds. She continues to live but is severely disabled and is being followed up by palliative care. Her mother is receiving ongoing therapy for substance abuse. This case highlights the impact that a single episode of neglect can have on vulnerable patients. Case No. 4 A 3.5-kg baby boy was delivered via an emergency lower segment caesarean section for obstructed labour and foetal bradycardia. APGARs [appearance (skin colour), pulse (heart rate), grimace response (reflexes), activity (muscle tone) and respiration (breathing rate and effort)] were 3 initially and subsequently improved to 8. The baby had progressive swelling of the scalp, which was presumed to be due to a subgaleal haematoma. Twelve hours later, the baby had seizures and was transferred to tertiary neonatal intensive care unit (NICU). Upon arrival, he was lethargic and hypotonic with midpoint, nonreactive pupils. His haemoglobin had dropped from

Fig. 12.3  Severe head injury from NAI. CT head demonstrating extensive hypodensities ‘Black Brain’, SAH and temporal contusions. MRI brain and spine the same day shows global cortical restricted diffusion with sparing of

the deep grey matter, brainstem and cerebellum and layered intraspinal haemorrhage from T9 to S1, displacing cauda equine nerve roots

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120 g/dL at birth to 80 g/dL; however, the coagulation profile was normal. Urgent MRI scan of the brain revealed bilateral extra-­axial haematomas with severe mass effect, midline shift and extensive watershed territory diffusion restriction (Fig. 12.4). The boy was immediately taken to theatre for evacuation of the haematomas. Surgery required meticulous attention to haemostasis at every stage. Blood transfusion was commenced at the start of the procedure and had to be continued throughout the case. The anaesthetist ensured that the baby remained relatively haemodynamically stable by constantly replacing ongoing blood and coagulation factor losses. Overall, the boy received one unit of blood which was supplemented with fresh frozen plasma and cryoprecipitate based on the hospital’s massive transfusion protocol. Despite these measures, there were episodes of transient hypotension during surgery, highlighting the risk of haemodynamic instability in this age group. The boy made a good recovery and was discharged from the hospital with a normal neurological examination. This case highlights the need to pre-empt catastrophic blood loss in neonates, given the potential for haemodynamic instability and secondary brain injury in this group of patients.

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12.7 Management of Traumatic Brain Injury The immediate management of paediatric traumatic brain injury is similar to adults in that there is much emphasis placed on the evaluation and stabilisation of the airway with cervical spine precautions, breathing and circulation prior to any detailed neurological assessment. Thereafter, full exposure is required to assess for any other injuries, and great care must be taken not to focus purely on the TBI at the expense of missing injuries that may lead to occult blood loss. The primary survey includes a head-to-toe examination, looking for scalp lacerations and depressed skull fractures that may be hidden by hair. The presence of the so-called Raccoon eyes refers to a condition where there are bruises around both eyes. These bruises look like the dark patches around the eyes of raccoons and are indicative of an anterior skull base fracture. Similarly, Battle’s sign (named after Dr. William Henry Battle) is defined as bruising over the mastoid process, and this is suggestive of a more posterior skull base fracture. These findings in themselves are not concerning, but they may alert the clinician to a more serious underlying

Fig. 12.4  MRI head showing bilateral extra-axial haematomas with severe mass effect, midline shift and extensive watershed territories with diffusion restriction related to traumatic birth injury

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injury, especially if the patient is clinically well. In neonates, serial palpation of the anterior fontanelle and noting any progressive separation of cranial sutures can provide useful information regarding the presence or development of raised ICP. In the context of polytrauma, it is important to look for evidence of chest and abdominal injuries as well as fractures of long bones. This is especially important in patients with severe traumatic brain injury, where more than a third of children will have associated systemic injuries which need to be addressed. These patients may remain heavily sedated for many days, and missing other injuries can be highly problematic. A delay in diagnosing long bone fractures may delay treatment and predispose to the development of a later functional impairment. Likewise, failure to diagnose a solid organ injury, such as liver laceration, may lead to occult haemorrhage with subsequent haemodynamic instability, which may compromise cerebral perfusion. These examples serve to emphasise that management of TBI is not focused solely on the brain but on the injured patient with TBI. Following initial resuscitation and stabilisation, a detailed history of events is required. This includes but is not limited to the following: • Post-resuscitation paediatric GCS (prognostically important) • Mechanism of injury • Length of time of loss of consciousness • Vomiting • Seizures • Comorbidities (medications, bleeding disorders, past medical history) • History of previous trauma The later point is critical when considering NAI, and it is important to note any inconsistency in the history and subsequent injury pattern, which may raise suspicions. If a NAI is considered likely, then the child will require skeletal survey X-rays, an ophthalmology assessment and referral to the appropriate child protection agency.

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12.7.1 Mild TBI Children with mild TBI, defined as a GCS of 14–15, represent the most common group of patients that presentation to the ED. There are numerous causes of TBI in children, ranging from a simple fall to more potentially serious mechanisms, such as motor vehicle accidents (MVA). Consideration of the mechanism is important not only to ensure consistency, as previously mentioned, but also when considering the possibility of other injuries of which the child may not necessarily complain. A good example would be the need to exclude an abdominal injury from a poorly positioned seatbelt in a child who has sustained a TBI in an MVA. In most cases of minor TBI, children can be observed in the ED or as an inpatient for 6–24 h and then discharged home. Certain clinical signs and symptoms may indicate the need for longer observation. These include the following: • • • • •

A history of LOC Vomiting Seizures Ongoing ear, nose or throat bleeding An inconsistency in the history that may suggest a NAI • High-risk medical comorbidities • Signs suggestive of a skull base fracture • Any neurological deficits Following discharge, parents are advised to represent to the ED if they have concerns or if there is any clinical deterioration. In general, this group of patients does not need to have a CT head unless they deteriorate clinically during the period of observation. This is important not only when considering resource allocation but also because of the cumulative age-related lifetime risk of cancer that comes with exposure to ionising radiation. For example, a recent study found that the projected lifetime attributable risk of leukaemia was highest for head scans among children younger than 10 years of age and decreased with age from 1.9 cases per 10 000 scans for children younger than 5 years of age to 0.5 cases per 10 000 scans for children 10–14 years of age [7].

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There are several clinical decision rules such as PECARN, CATCH and CHALICE, and these can be used to determine the need for CT imaging in children with TBI. In a prospective observational study of children with TBI who presented to the ED across ten Australian and New Zealand hospitals, these three clinical decision rules were found to have high sensitivities when used as designed, and each had a negative predictive value of higher than 99% [8].

12.7.2 Moderate and Severe TBI The management of children with moderate and severe TBI should be based on the Brain Trauma Foundation Guidelines. This was first published in 2003 and was subsequently updated in 2012 and 2019. The third update incorporated 48 new studies and 22 recommendations, 9 of which were new or revised; however, the overall quality of evidence remains weak. There are: • No level I recommendation • 3 level II recommendations • 19 level III recommendations [9] In a similar fashion to the medical management of adult TBI outlined in Chap. 8, a tier-­ based approach is increasingly being used in paediatric TBI. Patients with moderate injuries will usually require regular observation in order to assess their progress and determine which patients deteriorate and require more intensive support. For those patients who are more severely injured, a period of sedation and ventilation will allow full-control cerebral perfusion and prevent agitation and distress due to pain and confusion. Sedating children with TBI will also facilitate ICP monitoring. This will determine those patients who develop progressive cerebral swelling, which will not only preclude early weaning but also guide therapeutic intervention. It will also highlight those patients who develop surgical lesions, such as evolving intracranial haematomas or progressive posttraumatic hydrocephalus.

In general, an ICP target of 20 mmHg is used; however, it must be remembered that this is only a level III recommendation, as is a target CPP of 40 mmHg.

12.7.2.1 Initial Management of Paediatric Patients in the ICU For those patients who require ventilatory support, initial measures should include the following: • Adequate sedation and controlled ventilation with a view to maintaining normal physiological levels of oxygen and carbon dioxide (PaC02 levels 4.7–5.5 kPA). • Adequate analgesia to treat pain and avoid tracheal tube discomfort. • Avoid hyperthermia (fever) and aim for normothermia. This initial management can be considered a Tier ‘0’ therapy, and the aim is to establish a stable, neuroprotective physiological baseline. When these measures fail to control the ICP below the designated threshold, Tier 1 measures are introduced [10].

12.7.3 Tier 1 Commencing Tier 1 therapy will initially involve relatively simple measures, such as raising the head of the bed to 30° and avoiding compression of the neck by removing either soft or hard collars, which are unnecessary if the head is supported in the neutral position by bolsters. Increasing the level of sedation may lower cerebral metabolism and minimize responses to nursing interventions such as changes in position or endotracheal suction. Subclinical seizure activity can lead to intracranial hypertension, and there are level III recommendations that include the use of levetiracetam or phenytoin for seizure prophylaxis. Hyperventilation remains a Tier 2 therapy; however, maintaining the PaCO2 at the lower end

12  Contemporary Management of Paediatric Head Injuries

of the normal range may be considered within Tier 1. Finally, there are level II recommendations that support the use of hypertonic saline boluses for ICP control. If the ICP continues to rise despite these therapies, it may be necessary to escalate medical therapy to Tier 2; however, simple surgical measures such as insertion of an EVD may be considered. In addition, repeat imaging may be considered to rule out surgical lesions such as the development or expansion of intracranial haematomas. In these circumstances, CT head should be performed with the minimal amount of radiation that can accurately characterise the brain injury.

12.7.4 Tier 2 Tier 2 therapies are introduced when the ICP fails to respond to Tier 1 therapies, and they may be introduced in any order with no particular rank. They are usually introduced sequentially so that the ICP response can be assessed. Whilst prophylactic hyperventilation is not recommended, there are level III recommendations for the mild hyperventilation (PaCO2 4.3–4.6  kPA/32–35  mmHg) in refractory intracranial hypertension. In these circumstances, it is recommended that this should be combined with invasive brain oxygenation monitoring to ensure oxygenation is not compromised. There are also level III recommendations for the use of additional sedatives and neuromuscular blockage in these circumstances. If these measures fail to control the ICP, it may be necessary to Tier 3 therapies and further imaging to exclude surgical lesions may need to be considered again.

12.7.5 Tier 3 Therapies Intracranial hypertension that does not respond to Tiers 1 and 2 must be considered intractable and life-threatening; however, the use of Tier 3 therapies must be judicious because they have the potential for significant morbidity.

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12.7.5.1 Hypothermia The use of prophylactic hypothermia (32–33 °C) as a neuroprotective agent is no longer recommended; however, in the context of intractable intracranial hypertension, there are level III recommendations that support its use. The recommendations also acknowledged that there are safety concerns regarding the use of hypothermia and advise that rewarming is slow (0.5–1  °C every 12–24  h) and drug levels of medications such as phenytoin are monitored to avoid toxicity. 12.7.5.2 Barbiturate Coma Barbiturate coma has been used for many years to control refractory ICP; however, its use is contentious. They cause profound dose-dependent cardiovascular suppression, leading to significant episodes of hypotension, and patients frequently require significant inotropic support. They are also associated with significantly increased risk of infection, immune suppression and hepatic and renal dysfunction, and their prolonged half-­ life makes clinical assessment difficult after their use is discontinued. There are level III recommendations for the use of barbiturates in haemodynamically stable patients, and it is recommended that continuous arterial blood pressure monitoring and cardiovascular support are provided in order to maintain adequate cerebral perfusion. 12.7.5.3 Decompressive Craniectomy The use of secondary decompressive craniectomy in the context of intractable intracranial hypertension has been a source of considerable debate. Many of the clinical and ethical issues as they pertain to the adult population are dealt with elsewhere in this book; however, it is now evident that surgical intervention can reduce mortality. It is also evident that surgical decompression will not reverse the effects of the pathology that precipitated the neurological crisis (whether it be trauma, stroke, subarachnoid haemorrhage or infection), and many survivors will be left with severe disability. These issues have not been sufficiently investigated in the context of paediatric

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TBI, and the ethical issues are discussed in detail in Chap. 33. Currently, the use of decompressive craniectomy should be reserved as a salvage intervention in circumstances where it is considered that the child will otherwise not survive. Whilst there have been a number of retrospective studies that have demonstrated good outcomes in some survivors, this is by no means always the case and the issue of publication bias must always be considered [11]. For the use of decompressive craniectomy to continue, prospective long-term outcome studies which include cognitive assessment are required.

which may be lifesaving but is certainly nonrestorative. Performing randomised controlled trials for therapies such as hypothermia, barbiturates and decompressive craniectomy may be problematic in the paediatric population; however, the use of long-term observational studies, combined with detailed registries, may form the basis on which comparative effectiveness studies may be based, and this may provide useful evidence to inform practice. This can be combined with advances in neurocritical care and the implementation of paediatric neurocritical care programmes that has already been shown to decrease mortality [12].

12.8 Future Directions

12.9 Conclusions

When considering children with mild head injury or concussions with normal imaging, there is no doubt that many go on to make a full long-term recovery. However, it is becoming increasingly apparent that there can be long-term side effects especially in the context of repeated minor trauma as can occur in sports such as soccer, where heading a football is an integral part of the game. Concerns regarding the impact that this can have on the developing brain have led to certain sporting organisations to ban this practice, and it will be interesting to note whether this is extended to other contact sports such as American football and rugby, where impacts can be frequent and severe, and these issues are covered in more detail in Chap. 23. There has been already been extensive research into this area in adults addressing cognitive, behavioural and psychological sequelae of TBI, and these issues require ongoing attention in children. When considering more severe TBI in the paediatric population, it is becoming increasingly clear that outcomes are better in children managed in specialised paediatric centres with access to comprehensive multidisciplinary rehabilitation services. It is also apparent that there are significant limitations when taking evidence obtained from studies in the adult population and extrapolating that to the paediatric population. This is especially pertinent for aggressive surgical intervention such as a decompressive craniectomy,

Paediatric head injury is a spectrum including concussion, sports-related injuries, birth-related injuries and non-accidental and accidental TBI.  Optimal care of children requires a thorough understanding of underlying anatomical, pathophysiological differences in children and appreciation of the underlying mechanisms of injury. A multidisciplinary approach in evaluation and management is essential to obtain optimal results. Conflict of Interest  None declared. Funding None.

References 1. Centers for Disease Control and Prevention. WISCARS.  Leading causes of Death Reports, National and Regional, 1999–2013; 2015. Available at: http://webappa.cdc.gov/cgi-­bin/broker.exe. Access 2015.9.22 2. Figaiji AA. Anatomical and physiological differences between children and adults relevant to traumatic brain injury and the implications for clinical assessment and care. Front Neurol. 2017;8:685. 3. Philip S, Udomphorn Y, Kirkham F, et  al. Cerebrovascular pathophysiology in pediatric traumatic brain injury. J Trauma. 2009;67(2 Suppl):S128–34. 4. Takashi A, Yokota H, Morita A.  Pediatric traumatic brain injury: characteristic features, diagno-

12  Contemporary Management of Paediatric Head Injuries sis, and management. Neurol Med Chir (Tokyo). 2017;57:82–93. 5. Ninomiya T, Hashimoto H, Tani H, Mori K. Effects of primary prevention of child abuse that begins during pregnancy and immediately after childbirth. J Med Invest. 2017;64:153–9. 6. Vinchon M.  Shaken baby syndrome: what certainty do we have? Childs Nerv Syst. 2017;33:1727–33. 7. Miglioretti DL, Johnson E, William A, et al. The use of computed tomography in pediatrics and the associated radiation exposure and estimated cancer risk. JAMA Pediatr. 2013;167:700–7. 8. Babl FE, Borland ML, Phillips N, et al. Accuracy of PECARN, CATCH and CHALICE head injury decision rules in children: a prospective cohort study. Lancet. 2017;389:2393–402. 9. Kochanek PM, Tasker RC, Carney N, et al. Guidelines for the management of pediatric severe traumatic brain

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injury, third edition: update of the brain trauma foundation guidelines, executive summary. Neurosurgery. 2019;84:1169–78. 10. Bowers C, Riva-Cambrin J, Hertzler D, et  al. Risk factors and rates of bone flap resorption in pediatric patients after decompressive craniectomy for traumatic brain injury. J Neurosurg Pediatr. 2013;11:526–32. 11. Jagannathan J, Okonkwo D, Dumont A, et  al. Outcome following decompressive craniectomy in children with severe traumatic brain injury: a 10-year single-center experience with long-term follow up. J Neurosurg. 2007;106(4 Suppl):268–75. 12. Pineda JA, Leonard JR, Mazotas IG, et al. Effect of implementation of a paediatric neurocritical care programme on outcomes after severe traumatic brain injury: a retrospective cohort study. Lancet Neurol. 2013;12:45–52.

Sports-Related Traumatic Brain Injury

13

Niklas Marklund

13.1 Introduction The Olympic motto is faster, higher, and stronger (in Latin Citius, Altius, Fortius). The continuously rising speed of increasingly stronger and faster athletes in modern sports leads to heightened risks for sports-related injuries. In recent years, the incidence of head injuries, not least in contact sports such as boxing, mixed martial arts, rugby, soccer, American football, ice hockey, and others, is rising. When the impact is sufficiently strong, a sports-related concussion (SRC) may occur. SRCs account for approximately 5–9% of all sports injuries. There has been a gradual change in the definition of an SRC over the years, although according to the most recent definition put forth by the Concussion in Sports Study Group, a SRC is a mild traumatic brain injury (mTBI) that is induced by biomechanical forces [1]. Importantly, an impact that occurs elsewhere on the body may also induce a SRC if the force is transmitted to the head. Rapid head rotation is the predominant biomechanical feature associated with an SRC, and as discussed in the following paragraphs of this chapter, injury to the white matter and/or energy metabolic disturbances may N. Marklund (*) Department of Clinical Sciences Lund, Neurosurgery, Lund University, Skåne University Hospital, Lund, Sweden e-mail: [email protected] © Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_13

be the most important underlying pathophysiological mechanism. At time of an SRC, a range of clinical signs and symptoms may be observed, although loss of consciousness and amnesia, while common, are not mandatory for the diagnosis. It is now established that some symptoms may evolve hours after the initial injury, and this is why repeated assessments are needed. The vast majority of SRCs occur in young, healthy, and highly motivated athletes. Following the injury, resolution of symptoms often follows a sequential course, and 85–90% of athletes recover completely within 10 days. Female athletes appear to have a higher risk of sustaining a SRC in sports, in which the rules are the same as in males (such as soccer and basketball). A small subset of athletes develop prolonged symptoms that may last for many months or even years after the injury, and it is being increasingly recognized that the long-term prognosis is closely related to the duration of symptoms [2]. High initial symptom load following an SRC is one risk factor for developing persistent post-concussion symptoms, and in most reports, female athletes fare worse and have a longer recovery time. Historically, SRC was considered a self-­ limiting and benign disorder; however, it is now established that multiple SRCs are associated with adverse health outcomes and certain neurodegenerative disorders. Repeated SRCs are increasingly linked to depression, mild cognitive impairment, premature onset of Alzheimer’s 137

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d­isease, Parkinson’s disease, and perhaps the feared entity of chronic traumatic encephalopathy (CTE). There is an immense research effort directed toward the understanding, prevention, diagnosis, and treatment of SRC, but currently available return-to-play strategies and neurorehabilitatory efforts seem insufficient in ameliorating the devastating and long-lasting consequences that are commonly associated with SRC.  The present chapter aims to address the current and evolving management and understanding of SRC.

13.2 Background Information and History While a sports-related concussion is now defined as a mild traumatic brain injury (mTBI), this has not always been the case. The term “concussion” was coined many centuries ago to describe a state of abnormal brain physiology or function. In the twentieth century, the term “punch drunk” was used by the lay community to describe retired boxers who presented with gait and neuropsychiatric disturbances. Work by Martland (1928) and later Millspaugh (1937) established the term dementia pugilistica (boxer’s dementia), but it was not until the 1970s that the first neuropathological case series of former boxers were published. While the terminology has been revised during subsequent years, the term “chronic traumatic encephalopathy” (CTE) is now used to describe the features associated with repetitive head trauma and multiple concussive or subconcussive events. It is now known that this entity is not unique to boxing, and it was Dr. Omalu and co-workers who in 2005 demonstrated early evidence of this condition on a retired American football player at autopsy. Evidence of this condition has subsequently been observed in many other high-impact sports, such as ice hockey, wrestling, and soccer. During recent years, there has been increasing concerns of the potential health hazards associated with SRCs, and the protocols for managing the concussed athletes have been refined accord-

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ingly. However, it is becoming increasingly apparent that many athletes suffer from both short- and long-term symptoms that may interfere with education, work, and daily life as well as lead to a reduced quality of life. There have been tremendous efforts during the last decades to reduce the overall impact of SRC among the sports communities. While a definition of concussion was established by the Committee to Study Head Injury Nomenclature in 1966, these criteria were difficult to measure and included subjective grading systems [3]. Beginning in 2001  in Vienna, consensus statement conferences of concussion in sports have been held at regular intervals, and the most recent congress was hosted in Berlin in 2016, and the upcoming sixth congress is planned for Paris in 2022. During these congresses, the definition of concussion has been clarified, guidelines for early management and return-to-play strategies have been put forth, and the scientific basis for concussion prevention and treatment has been thoroughly reviewed [1]. Illustrative Cases Numerous depictions of spectacular knockouts in boxing and mixed martial arts, typically when the athlete is subjected to a blow or kick to the head that produces rapid unconsciousness, are easily found online. Sadly, numerous lives have been lost from these knockouts, and this is not limited to boxing. These tragic deaths have occurred not only in professional men’s boxing but also following women’s boxing and following amateur bouts. Perhaps surprisingly, most boxing deaths have occurred in the lower weight classes and are usually caused by acute subdural hematomas, although contusions and intracerebral hematomas have also been described [4]. Several sporting icons who have suffered from the consequences of SRCs have also been displayed in the media. Of many examples, ice hockey player Bob Probert (portrayed in Tough Guy: The Bob Probert Story) suffered numerous head injuries as a hockey player and fighter in the rink and sustained a high number of SRCs as well as numerous subconcussive head impacts.

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Following his premature death, the tau aggregations associated with CTE were found at autopsy. A key factor in the early management of SRC is immediate removal from play; however, it is obvious that the pressure on players and coaches to continue playing early after an SRC makes this rule difficult to implement. During the two most recent soccer FIFA World Cups, perhaps the most televised events in the world, there were several SRCs, two of which deserve comment. In the final of 2014, a German defender clearly attained an  SRC (according to media reports, he ran to the referee after the impact and asked if he was indeed playing in the final, indicating amnesia and cognitive impairment) but was allowed to continue playing until half time. In 2018, in the game against Iran, a Moroccan player sustained an obvious SRC, after which a member of the medical team slapped him on the cheeks, splashed water on him, and then let him back on the pitch. These events illustrate the difficulties in implementing strict SRC management protocols. Furthermore,  athletes tend to underreport symptoms at time of a SRC and may continue to play, not uncommonly due to expectations of others [5]. Ideally, the team physician should have the final say regarding the decision to remove an individual from the field of play even if there is opposition from the team coach, the athlete, or others involved in the event. Along these lines, new concussion management procedures were introduced following the men’s soccer World Cup in 2014 by the Union of European Football Associations (UEFA), which allows the referee to stop the game for up to 3 min for SRC assessment.

13.3 Management and Long-Term Consequences of SRC There are numerous steps in the management of a SRC, ranging from recognition of the condition to the assessment of the risks of long-term consequences.

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13.3.1 SRC Recognition and Diagnosis The diagnosis of SRC is based on clinical judgment by a trained medical professional, and currently there is neither a biomarker nor any other diagnostic aid that can categorically establish the  diagnosis of an SRC.  Following the initial impact or rapid head rotation, there may be a transient disturbance of CNS function. The medical staff should know the normal behavior of the team players and should have a high degree of suspicion of an SRC. The diagnosis is not always obvious, and some key features are shown in Table 13.1. Video analysis of the event may aid in the diagnosis where key findings are no attempts to resist the fall after the impact, seizures or tonic posturing, and the athlete showing a “blank stare”. It is important to note that symptoms may evolve during the first hours following an SRC, and repeated evaluations may be necessary [6]. The Sports Concussion Assessment Tool 5th Edition (SCAT5) is a well-established instrument used for sideline assessment by medically trained individuals (Table 13.2). The decision to remove the player from play should be made from the clinical signs and symptoms described previously, and merely the suspicion of an SRC should be sufficient. Of note, the complete SCAT5 can take a minimum of 15 min to complete. It is also important to note that the SCAT5 cannot be used solely to diagnose or exclude an SRC, since an athlete may have sustained an SRC despite minimal findTable 13.1  Key signs of SRC at the time of impact Clinical sign • Unconsciousness •  Abnormal behavior/confusion • Disorientation •  Poor balance •  Motor impairment •  Lying still •  Difficulties getting up •  Grabs the head •  Blank stare •  Significant facial injury/fracture

140 Table 13.2  Key points of the SCAT-5  and Maddocks questionnaire for cognitive evaluation Assessments Immediate on field assessment  •  Taking note of red flags  •  Checking for observable signs of concussion  •  Memory assessment using Maddocks questionnaire    –  At what venue are we today?    –  Which half is it?    –  Who scored last in this match?    –  Who did you play last week?    –  Did your team win the last game?  •  Examining the level of consciousness using the Glasgow Coma Scale  •  Cervical spine assessment Off-field assessment – preferably carried out in a clinical setting  •  Comprehensive history  •  Symptom evaluation  •  Cognitive screen  •  Measure of concentration  •  Neurological screen  •  Delayed recall

ings on the assessment. The SCAT5 can be used from 13 years of age, and there is also a pediatric SCAT that can be used from 5 to 12 years of age [7]. The detailed SCAT5 includes a symptom evaluation score, based on the original description of Lovell and colleagues, which lists 22 symptoms (severity range from 0 to 6) to be evaluated by the player and allows for the calculation of a symptom severity score (SSS, the sum of all symptom severity scorings with a range from 0 to 132) and the number of symptoms (NOS; ranging from 0 to 22) to be used in the follow-up of the concussed athlete. The King-Devick (K-D) test of rapid number naming and the Immediate Post-Concussion and Cognitive Testing (ImPACT) are other tests shown to be sensitive for the evaluation of SRC at the sideline. The K-D test evaluates saccadic eye movements and should be used at baseline and at the sideline at time of SRC and is fast to administer, The ImPACT test, a computerized test of cognitive abilities, is FDA-approved for concussion management. Athletes are tested in the preseason, and postinjury scores can be compared to aid concussion diagnosis.

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For the lay person without medical training, the Concussion Recognition Tool (CRT), as introduced by the Concussion in Sport Group in 2005, can aid in recognizing the signs and symptoms of SRC and guide when to remove an athlete from play and to seek medical attention. Typically, unless some red flag criteria are present, the yield of conventional neuroimaging (CT, MRI) is very low and should not be routinely recommended. The use of biomarkers is a rapidly evolving field [8], where neurofilament light (NF-L) may hold particular promise for the detection of any underlying and progressive white matter pathology. At present, no biomarker is rapid or sensitive enough for guiding acute clinical decisions at the time of a SRC.

13.3.2 Early Removal from Play and Graduated Return-to-Play (or School) Protocol As stated by the soccer (football) association in the UK (the FA), the main line of thinking is “if in doubt, sit them out.” The meaning of this statement is that when suspected, or diagnosed, an athlete with an SRC should not be allowed to return to play before medically assessed and potentially cleared. The rationale for this strategy is threefold: • The risk of severe traumatic brain injury requiring emergent medical assistance. There are several warning signs (red flags) that can be used as guidance as to when the athlete and medical staff should seek urgent  medical attention (Table  13.3). There are numerous examples of severe TBI and spinal and spinal cord injuries occurring during sports that subsequently require emergent neurosurgical treatment, and these red flags have often been observed at the time of the injury. • The second-impact syndrome. This term was coined in 1984 by Saunders and Harbaugh, who described a 19-year old athlete who had an SRC and suddenly died 4 days later, having attained another head impact while still symptomatic from the first injury. This controver-

13  Sports-Related Traumatic Brain Injury Table 13.3  Red flags used in the diagnosis of PCS athletes that when present mandate referral for medical evaluation Red flags •  Neck pain/tenderness •  Vomiting (>1) •  Severe of increasing headache •  Weakness/burning in arms or legs •  Double vision •  Loss of consciousness • Seizures •  Deteriorating level of consciousness •  Increasing restlessness (indicating raised intracranial pressure)

sial and exceedingly rare entity is characterized by sudden death of an athlete, typically from massive uncontrolled brain swelling, following minor head trauma occurring shortly after sustaining a previous SRC and still being symptomatic. While uncommon (and it is debated if the syndrome even exists), the consequences of sudden impact syndrome are devastating, which contributes to the recommendation of removal from play acutely following an SRC. • Brain vulnerability. Animal experiments have unequivocally established that an SRC induces metabolic and vascular changes in the brain and elicits a period of brain vulnerability. During this vulnerable phase, an additional impact results in exacerbation of the initial injury, and an additional head impact and symptom-­ provoking activities must be avoided at all costs. This is the main reason for implementing the graduated return-to-play protocol in sports. After an SRC has been diagnosed and the player has been removed from play, the graduated (the term graded is also used) return-to-play protocol is initiated. This includes a period, typically 24–48 h, of brain rest. The previously recommended “dark room” policy has been abandoned, and now this period should include avoidance of activities that provoke symptoms. Thus, the athlete should not practice or go to school/work during these initial 1–2  days. Moreover, alcohol, recreational drugs, and driving should be avoided. When the player is

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symptom-­free, a gradual increase in sports activity then ensues in 24 h steps, and unless the player experience additional symptoms, full-contact practice is allowed 6–7  days following the SRC. If each step has been cleared without additional symptoms, match play is then allowed. It must be noted that there are numerous reports showing that the neurobiological recovery typically is longer than the clinical recovery, suggesting that the vulnerable time period may be longer than previously expected. In children, similar as  in adults, a gradual symptom-limited sports activity should be encouraged, and, importantly, return to school should come before return to sports. In addition, schools should  implement concussion policies that include educational support for the recovering child.

13.3.3 Concussion Recovery and the “Post-Concussion Syndrome” Using these return-to-play strategies, uneventful recovery is observed in approximately 85–90% of concussed athletes. Normal recovery time is 2 weeks for adults and 4 weeks for children and adolescents; however, the trajectory for recovery may vary [9]. Some athletes develop prolonged symptoms, called “post-concussion syndrome” (PCS). This is a controversial entity and is poorly defined, although it can be regarded as a constellation of symptoms that commonly include headache, dizziness, fatigue, and anxiety. Cognitive impairment is usually of key importance for the PCS athlete. The mechanisms resulting in PCS have not been established; however, it may be related to impaired cerebral blood flow. Indeed, even after a single SRC, cerebral blood flow (CBF) may be decreased for many months postinjury, and CBF changes may correlate with the persisting symptom load. If CBF normalizes, so may the associated symptoms. Altered cerebrovascular reactivity and chronic CBF reductions have also been observed in retired rSRC athletes, and it is important to note that non-injured, healthy females have a higher CBF than males,

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emphasizing the need for sex-specific compari- bias, there is a general consensus that repeated sons. These potential CBF changes may be SRCs (rSRC) result in an increased risk of develrelated to persisting energy metabolic brain alter- oping a number of brain-related disorders. ations, the details of which will require additional These included depression, mild cognitive evaluations. impairment, Parkinson’s disease, Alzheimer’s One of the problems with managing patients disease (AD), and CTE.  On neuroimaging, athwith PCS is that there is no consensus on a pre- letes with rSRC demonstrate cortical thinning cise definition. The term persisting post-­ and hippocampal atrophy. Importantly, previous concussive symptoms (PPCS) has been suggested participation in sports is good for the general as an alternative to PCS.  The Diagnostic and health of the individual, and there is no, contrary Statistical Manual of Mental Disorders 5th to some previous reports, increased risk for suiEdition (DSM-5) no longer defines PCS as a dis- cide [11]. Recently, a large retrospective epidetinct entity and instead focuses on mTBI as a miologic analysis confirmed that mortality from cause of cognitive impairment. In the ICD-10 as several common diseases was lower among > well as the DSM IV, PCS was defined as three or 7000 former Scottish professional soccer players. more post-concussive symptoms lasting for However, they suffered significantly more from 3  months or longer. The longer the duration of neurodegenerative disorders and received a PCS, the worse the prognosis, and overall, PCS is higher number of prescriptions for dementia-­ associated with a poor quality of life [2]. related medications [12]. While the increased Notwithstanding these difficulties in a precise risk of AD and Parkinson’s disease is shown in definition, management of athletes with symp- many (although not all) reports investigating athtoms of PCS/PPCS should be multidisciplinary letes who have sustained rSRC, CTE may reprein order to address varying emotional, physical, sent a distinct disease entity in itself. and behavioral problems [10]. This will include Athletes suffering from CTE commonly disbut is not limited to the following: play clinical features that include psychosocial problems, depression, anxiety, and anger. • Rehabilitation medicine Importantly, the vast majority of confirmed CTE • Vestibular and oculomotor rehabilitation cases are male, and the condition is most com• Physiotherapy monly observed in elderly, retired athletes who • Occupational therapy have sustained rSRC.  A number of reports have • Psychology described the postmortem features consistent with • Sports medicine CTE, and these are characterized by irregular aggregation of phosphorylated tau (p-tau) protein There are a number of pharmacological options at the depths of cortical sulci. The accumulation that aim to provide symptom relief, and these of abnormal p-tau is observed in neurons and include analgesics for headache, sleep inducers, astroglia around small blood vessels [13]. While antidepressants, and migraine relief medications. the pathophysiology of CTE is at large unknown, In addition, amantadine has been tested in a num- it may be related to neuroinflammation and axober of studies, and there is some evidence sug- nal pathology. Importantly, the pathological feagesting that it may provide symptom relief and tures of CTE may not be unique to rSRC and may improve cognitive function, although further not necessarily be progressive with time [14]. work is required to clearly establish efficacy. While the knowledge base continues to accumulate, there remain numerous unanswered questions with regard to CTE [14]. For example:

13.3.4 Long-Term Consequences

While many of the underlying studies have a rather low evidence level with significant limitations and

• What athlete is at risk? • How high is the incidence, and what are the covariate factors contributing to the disorder?

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• Are there sex differences? • Is there a link between the p-tau aggregations and the clinical symptoms? • Over what time period does this condition develop and can it be prevented?

13.4 Future Directions Currently, the pathophysiology underlying the short- and long-term consequences of SRC are largely unknown, and no specific treatments are available. The term “SRC” probably represents a profound oversimplification of what is likely to be a very heterogeneous disorder. Recently, an attempt to classify SRC into five different predominant concussion subtypes was made: These suggested subtypes were as follows, depending on the dominating symptoms: • • • • •

Cognitive Oculomotor Headache/migraine Vestibular Anxiety/mood

In addition, two concussion-associated conditions (sleep disturbance and cervical strain) were suggested [15]. There is little doubt that this type of classification is clinically useful especially from a research perspective; however, given that SRC can produce such a wide variety of different symptoms, clinical presentations, and recovery patterns, a more individualized approach to treatment and rehabilitation continues to be required.

13.4.1 Controversies While the broad definition of SRC has been generally accepted, there is still debate with regards to the lowest threshold of  symptoms that are required to confirm a definitive diagnosis. In addition, the long-term effects of subconcussive head impact, such as those occurring from heading a soccer ball (impacts not reaching the criteria for an SRC), are being increasingly

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discussed. Specifically, how many of these subconcussive  impacts can be tolerated and what their long-term consequences  are, especially in children and adolescents where there is potential to affect the developing brain, is highly controversial. In light of these concerns, the practice of young children heading a soccer ball has recently been discouraged in many countries, and this practice has now been adopted by the Fédération Internationale de Football Association (FIFA). Future research is needed to define what subconcussive impacts really are and how many of such impacts can be safely tolerated. In many sports, there are sex differences in concussion susceptibility, where women have been more prone to attain SRCs in sports where the rules are the same for both sexes. Furthermore, the SRC recovery is often longer in female athletes, and while the precise reasons for this are unknown, it may be related to differences in neck strength, which in turn leads to increased head rotation/acceleration upon impact. The sex differences in SRC pathophysiology, and potentially SRC management, should be a topic for future studies; however, it should also be noted that CTE has not, to date, been diagnosed in female rSRC athletes.

13.4.2 Prevention Obviously, prevention is key in SRC management. While helmets are crucial in preventing head impacts in several sports, they do not in themselves prevent head rotation, which reduces their potential for reducing SRC incidence. In an attempt to address this limitation, recently developed helmets have incorporated an inner shell that allows for rotation of the helmet layers, thereby potentially absorbing some of the rotational forces and  be beneficial in reducing the head rotation at impact. Another technological advance can be seen in ice hockey, where changing the plexiglass surrounding the rink into a less rigid one was associated with reduced SRC incidence and severity. However, notwithstanding these technological innovations, the most important preventive mea-

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sures must surely come from an increased awareness of the importance of SRC as a long-term health concern, and everyone involved in sport at every level must be appropriately educated. Rule changes and harsh penalties, including suspension from play of those athletes guilty of careless behavior resulting in a SRC of the opponent, are also needed. In light of these health concerns, sporting associations will probably come under increasing pressure to modify the rule of the sports over which they have governance in order to reduce the incidence and severity of head trauma.

13.4.3 Fluid Biomarkers Notwithstanding that a diagnosis of a SRC is based on clinical criteria, the use of a rapid, sideline biomarker would potentially improve diagnostic accuracy and reliability. Several biomarker candidates have been evaluated, and for mTBI in the emergency room, the FDA has approved the use of the combination GFAP (glial fibrillary acidic protein) and UCHL-1 (ubiquitin C-terminal hydrolase). Furthermore, tau and cytoskeletal protein spectrin N-terminal fragment have been evaluated, and they show some promise for providing guidance as to when an athlete is cleared to return to play. Early but not late increases in S100B levels have also been observed in blood. While not used for acute SRC diagnosis, NF-L levels show much promise in indicating large axon/white matter injury and may develop into a very useful biomarker in the follow-up of SRCs.

term consequences, although this needs further evaluation.

13.4.5 Neuroimaging 13.4.5.1 Magnetic Resonance Imaging (MRI) The head rotation at the time of head impact can induce axonal strain, which results in white matter injury. This may be one of the mechanisms that lead to some of the long-term sequelae of SRC.  Increasingly, improved MRI technology can be used to demonstrate subtle white matter abnormalities on diffusion tensor imaging (DTI), and functional MRI can demonstrate areas of potential white matter pathway disconnection. Furthermore, differences in brain energy metabolism have been observed using MR spectroscopy. Increasingly refined MRI studies, including higher field strengths, will possibly reveal white matter and axonal abnormalities disproportionate to the age of the concussed athletes. In view of the importance of the white matter for cognitive processing, further research using enhanced MR spectroscopy protocols or refined DTI protocols may potentially improve the understanding of the pathophysiology of SRC. In addition, longitudinal neuroimaging studies could potentially quantify ongoing atrophy of white matter tracts and other regions of the brain, which may be used to counsel athletes regarding issues such as retirement from sports.

13.4.5.2 Positron Emission Tomography Aggregation of p-tau is a hallmark finding of 13.4.4 Acute Treatment CTE; however, currently this is a postmortem finding and provides limited information regardAt present, there are only management protocols ing initiation and progression of the disease proand symptomatic treatment of SRC-associated cess. In vivo  evaluations would be far more symptoms, such as headache. Since most SRCs clinically useful, and it is in this regard that occur at increased brain and body temperatures, recently developed PET tau tracers are being some studies have found that rapid head cooling investigated. These tracers include THK5317, may result in a shorter duration of symptoms. In Flortaucipir (AV1451), PBB3, FDDNP, and a addition, there may be a role for early anti-­ number of others. In a previous study, a inflammatory treatment in mTBI, which may ­39-year-­old athlete, who had sustained 22 verimitigate some of the SRC symptoms  and long-­ fied concussions and who had clinical features of

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CTE, was subjected to tau PET imaging using the [18F]T807/AV1451 tracer. Increased uptake of the tracer was observed in subcortical white matter regions, and some years later, CTE was diagnosed by postmortem examination. In Alzheimer’s disease, PET using the radioligand 18F-flortaucipir could detect paired helical tau deposition; however, its ability to detect tau deposition in CTE has yet to be determined and remains a source of ongoing investigation [16]. It must be noted that currently there is no perfect tau tracer and further work is needed to establish the sensitivity and specificity of the various tracers available. It must also be remembered that PET is an expensive method that exposes the athlete of ionizing radiation. However, if it can be used as an in vivo evaluation of SRC and development of CTE, it would have huge potential to identify those athletes most at risk and on whom recommendations may be made regarding ongoing participation in contact sports. PET can also be used for the study of neuroinflammation/ microglial activation and beta-­ amyloid (Aβ) deposits, increasing the possibility of studying the association between white matter injury (on MRI), neuroinflammation, and neurodegeneration and how these factors contribute to post-concussion symptoms and the cognitive impairment commonly observed in rSRC athletes.

13.4.6 When Should a Career Be Terminated? In this chapter, the consequences of repeated SRC have been discussed. It may seem surprising that there are no strict guidelines for determining, or even recommending, when an athlete should terminate their career due to the effects of SRC.  Thus, the question of how many SRCs are too many have not been answered. In view of the emerging evidence of a poor quality of life, reduced capacity for work, and the potential risk for neurodegeneration and dementias, this is a topic that will be addressed in future consensus conferences. At present, a strategy of

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“common sense” or severity of symptoms is commonly used, but in view of the limited evidence or defined criteria, this is likely insufficient for preventing long-term brain health problems in athletes with SRC.

13.5 Conclusions A concussion typically results in a short-lived disturbance of brain function that causes various symptoms and clinical signs. Typically, symptoms are lasting a few weeks although in some cases these can be more persistent and can delay return to work, school, and sport in which the injury was sustained. Despite being defined as a “mild’ head injury, an SRC is not a benign condition and should be managed by removing the athlete from play and then initiating a graduated return-to-play protocol. While most athletes recovery completely from a single SRC, all efforts should be made to prevent the athlete from additional impacts in view of the brain vulnerability in the early stages of recovery. There is evidence accumulating that repeated SRCs are associated with a number of neurodegenerative disorders; further work is required in order to develop better diagnostic tools, advance neuroimaging, and investigate the role of biomarkers. There is no doubt that sport provides an avenue of great enjoyment and employment for millions of participants. Overall, participation in sports has great health benefits. There is however an increased awareness of the long-term risks of SRCs. In light of the recent findings, it may be that certain governing bodies will need to modify some of their rules and regulations in order to minimize these risks and ensure continued safe participation of athletes at all levels. Conflict of Interest  The author is scientific advisor for PolarCool, Inc. developing a device for rapid head-neck cooling following an SRC. 

Funding  The author is supported by  The Swedish Research Council for Sport Science.

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N. Marklund 9. Kamins J, Bigler E, Covassin T, et  al. What is the physiological time to recovery after concussion? A systematic review. Br J Sports Med. 2017;51:935–40. 10. Kapadia M, Scheid A, Fine E, et  al. Review of the management of pediatric post-concussion syndrome-a multi-disciplinary, individualized approach. Curr Rev Musculoskelet Med. 2019;12:57–66. 11. Manley G, Gardner AJ, Schneider KJ, et  al. A systematic review of potential long-term effects of sport-­ related concussion. Br J Sports Med. 2017;51:969–77. 12. Mackay DF, Russell ER, Stewart K, et  al. Neurodegenerative disease mortality among former professional soccer players. N Engl J Med. 2019;381:1801–8. 13. McKee AC, Cairns NJ, Dickson DW, et al. The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol. 2016;131:75–86. 14. Iverson GL, Gardner AJ, Shultz SR, et  al. Chronic traumatic encephalopathy neuropathology might not be inexorably progressive or unique to repetitive neurotrauma. Brain. 2019;142:3672–93. 15. Lumba-Brown A, Teramoto M, Bloom OJ, et  al. Concussion guidelines step 2: evidence for subtype classification. Neurosurgery. 2020;86:2–13. 16. Stern RA, Adler CH, Chen K, et  al. Tau positron-­ emission tomography in former National Football League players. N Engl J Med. 2019;380:1716–25.

Rehabilitation After Traumatic Brain Injury

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H. Mee, L. M. Li, and F. Anwar

14.1 Introduction Rehabilitation is the process of facilitating the recovery of patients following any injury or insult, with traumatic brain injury (TBI) patients often having some of the most complex needs. It aims to maximise the quality of life, improve functional outcome where able and ensure maximal participation in activities of daily living, work and leisure [1]. There is such heterogeneity in the deficits and outcomes for patients following a traumatic brain injury (TBI) that it is important to start the process of rehabilitation by understanding the patient’s individual needs. A multitude of assessments helps determine the nature of the physical, cognitive, emotional and behavioural impairments and their potential functional consequences. Goal setting process is then undertaken by the multidisciplinary team (MDT) identifying short-term and long-term goals based on, if possible, the patient’s wishes. Rehabilitation following a TBI is complex and takes place in a variety of inpatient and outpatient settings, depending on the patient’s needs, H. Mee (*) · F. Anwar Department of Rehabilitation Medicine, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK e-mail: [email protected] L. M. Li Department of Neurology, Charing Cross Hospital, London, UK © Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_14

impairments, comorbidities, injury severity and pathophysiological effects, resulting from the injury. A multidisciplinary team of rehabilitation professionals must assess the needs of the patients while they are in acute settings as patients with similar injuries often have significant differences in their presentation.  The resultant neurological damage to the brain following a TBI can be either transient or permanent, producing heterogeneity of clinical features. The severity of a survivable TBI varies and ranges from mild through to severe, and which may result in a prolonged disorder of consciousness (PDoC) state (Fig. 14.1) [2]. Even patients on the mild TBI spectrum can have lasting serious sequelae  impacting their quality of life and functional independance.

14.1.1 Historical Perspective of TBI Rehabilitation Historically, persons with disabilities have been viewed differently within a society. The first real development in the field of rehabilitation was after World War I, which produced a large number of injured soldiers with very limited structured support; this led to the creation of various policies around the rehabilitation of military personnel. Rehabilitation medicine (physical medicine and rehabilitation) was recognised as a medical speciality in the United States after World War II. Dr. Howard Kessler 147

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Mild TBI /Concussion

Severe TBI

Moderate TBI

Criteria

Criteria

Criteria

Initial Glasgow Coma Scale of 13-15

Initial Glasgow Coma Scale of 9-12

Initial Glasgow Coma Scale of 1-9

Loss of consciousness up to 30 minutes

Loss of consciousness from 30 minutes to 24 hours

Loss of consciousness of more than 24 hours

Antegrade/Retrograde amnesia not greater than 24 hours

Antegrade amnesia between 1-7 days

Antegrade amnesia of more than 7 days

Un-survivable TBI/ Death

Adapted from Management of Conscious/mTBI Working Group (1)

Fig. 14.1  Spectrum of injury severity

first i­ ntroduced the concept of a comprehensive multidisciplinary approach to the disability with an emphasis on medical, social, psychological and vocational aspects [3]. Since then, rehabilitation medicine has developed into a speciality providing cost-effective treatment for people with complex disabilities.

14.2 Classification of Disability and Health The International Classification of Functioning, Disability and Health (ICF), adapted by the World Health Organization (WHO) in 2001, is a biopsychosocial model which provides a framework for rehabilitation providers to recognise the medical and nonmedical needs of a patient acknowledging the role of personal factors, environmental factors and other associated health conditions. The World Health Assembly also passed a resolution on “Disability—including prevention, management and rehabilitation” in 2005 [1]. The  ICF is structured into six components:  Health condition, body functions, body structures, activities and participation, environmental factors and personal factors (Fig. 14.2) all linked to and from each other, demonstarting the importance one particular component has on another. The  ICF framework is an aid for rehabilitation practitioners to ensure consideration all

domains along with the  involvment of patients and their families in assessment and service planning [4]. It is now routinely used in rehabilitation settings to manage rehabilitation goal planning, facilitate multidisciplinary working, improve communication with patients and families and provide a common language not only between the rehabilitation professionals but also with the social care providers and other agencies.

14.3 Rehabilitation Pathways and Services Rehabilitation following traumatic brain injury depends on the severity of the injury and the complexity of the impairments that it produces. It is important to identify those patients who have complex rehabilitation needs, so that a referral to an appropriate service is made in a timely manner from the acute hospital. In the United Kingdom (UK) the Patient Categorisation Tool (PCAT), which was initially developed as a checklist to assist in identifying patients with complex needs, has been further developed as an ordinal scale to identify category A, B or C/D rehabilitation needs (where category A means more complex needs) [5]. The tool is now most widely used by rehabilitation medicine specialists to guide patients to various levels of rehabilitation services within the  UK.  The National Health Services England (NHSE)

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Health Condition

Body Functions and Structures

Activities

Environmental Factors

Participation

Personal Factors

Fig. 14.2  The international classification of functioning, disability and health

s­ervice specification categorizes the specialist rehabilitation services into three levels, from Level 1 to Level 3 [6], where a Level 1 unit mostly takes patients with category A needs. Inpatient rehabilitation is required for patients with more severe injuries who have a prolonged disorder of consciousness, severe neurological disability, moderate to severe cognitive impairment and neurobehavioural problems. The emphasis of inpatient rehabilitation is wide ranging with patient focused structured programmes key. Some  areas of focus include the management of physical disability,  promotion of errorless learning, retraining in the activities of daily living, cognitive therapies, behaviour monitoring and modification, speech and swallowing therapies, monitoring of mood, pharmacological interventions and  trials, providing a structured environment for therapies, assessing for assistive technology and preparing for complex discharges into the community. Community rehabilitation is suitable for patients who do not necessarily require an inpatient setting but would still benefit from rehabilitation services. These include patients who  are discharged directly from the acute hospitals or from the inpatient rehabilitation units. Community rehabilitation is a vital part of the rehabilitation pathway,  and  is based around the concept that, if appropiate, skills are most likely to be adopted and learn't when taught

in the environment where they are to be used. Environmental manipulations and assistive technologies may be needed to aid in a patients progress towards functional independance in the community. These may all result in empowerment, self-determination and self-respect, which are essential aspects of rehabilitation [7]. Community rehabilitation, in many cases, bridges the gap between inpatient rehabilitation and living independently in the community. Apart from providing rehabilitation therapies, it also involves providing support, education and counselling for both the patients and their families.

14.3.1 Rehabilitation Prescriptions A rehabilitation prescription is a detailed summary of a patient’s journey through the major trauma pathway. It aids in the ongoing transition of care from acute to the rehabilitation services and outlines the rehabilitation needs of the patients at the time of discharge from the major trauma centre. The use of a rehabilitation prescription across the United Kingdom in major trauma patients was first recommended by the Clinical Advisory Group on Major Trauma services [8]. The recent guidance for the rehabilitation prescription was issued by the Trauma Audit and Research Network (TARN)

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Ongoing rehabilitation needs

A management list for each injuries

Services the patient referred to

A list of relevant injuries

A contact number for advice Actions for GP and patients

A section for patient to record comments

Patients demographics

Fig. 14.3  The eight-core items for rehabilitation prescription 2019

in 2019 [9]. The guidance states that a rehabilitation prescription should be completed (by a healthcare professional after multidisciplinary team assessment) for all major trauma patients who need rehabilitation at discharge, and the first rehabilitation assessment should take place within 48–72  hrs of admission to the major trauma centre. Throughout the patients’ journey, the rehabilitation prescription is updated by all the healthcare professionals and signed off by a consultant in rehabilitation medicine or their deputy. The completed rehabilitation prescription is given to the patients on discharge, sent to the general practitioner or shared with the other services where the patients would receive post-acute rehabilitation. The eightcore items for the rehabilitation prescription (as recommended by the TARN) are shown in Fig. 14.3.

14.4 The Multidisciplinary Approach Following a TBI, patients present with a multitude of physical, cognitive, functional and psychological needs. A multidisciplinary team (MDT) approach  is critical to any successful rehabilitation programme and relies on coherent and effective team working, with no one clinical

discipline able to meet all of the patient’s needs. Nurses, rehabilitation practitioners, physiotherapists, occupational therapists, speech and language therapists, neuropsychologists, neuropsychiatrists, dieticians, pharmacists, social workers and rehabilitation physicians generally make up the core of any MDT. However, the precise composition of the team will vary according to the clinical need and nature of any individual service. It is important to be able to ask for the advice and assistance of other teams outside the core MDT, and this is termed interdisciplinary team working. There are acute, post-acute and community components to a rehabilitation programme, and although the core principles of each MDT discipline apply at any stage, each phase requires a different team focus.

14.4.1 Physiotherapy Physiotherapy facilitates in the re-education of a patient’s movement, mobility and balance, aiming to maximise limb function wherever possible. In the acute setting and following trauma, focusing on chest function and oxygenation is critical. This is done through attention to positioning, chest physiotherapy, manual chest techniques of sputum expectoration and regular suctioning with pre- and post-treatment hyper-

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oxygenation. Spasticity is another key consideration across all phases of rehabilitation. It is common following TBI and if not managed effectively can have detrimental effects on a patient’s limb function. Long periods of immobility may lead to fixed deformities, which further limit the functional recovery of the patient; therefore, active and passive stretching of muscles is key in preventing contracture formation. Prolonged stretching of muscles is achieved by casting or splinting to reduce spasticity. Further control of spasticity can be achieved by the use of oral antispasmodic agents, botulinum toxin or phenol nerve blocks in the acute stage and intrathecal phenol or baclofen pump insertion in the post-acute stage. In the longer term, a physiotherapist will continue to focus on physical activity to prevent other comorbidities and aiding in the management of other TBI-­ related issues, such as fatigue and low mood.

14.4.2 Occupational Therapy Occupational therapists aim to enable people to achieve health, well-being and life satisfaction. Key considerations are to promote independence in activities of daily living by facilitating higher cognitive and executive function retraining, fatigue management, supporting home adaptions and environment organisation, vocational training and return to work. In the acute phase, the focus is to reduce the effect of any impairment, focusing on functional performance and improving independence in as many daily activities as possible, trying to prevent complications and therefore maximising long-term function. Initial cognitive assessments allow for an understanding of the level of engagement and awareness expected by any given patient and allow for tailoring of individual treatment programmes using restorative or adaptation techniques to introduce appropriate activities at the right time, optimising functional capacity. Occupational therapists play a critical role in transitioning patients from the hospital to community settings, with the aim, if possible, of eventual independent living and regaining a role in society.

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14.4.3 Speech and Language Therapy In the acute phase following TBI, the focus primarily lies in the assessment and management of swallowing difficulties. The type of trauma, reduced consciousness and the use of a tracheostomy can all lead to dysphagia, and patients are at an increased risk of aspiration. Therefore, early assessment of swallowing is crucial in order to establish an appropriate route of feeding and manage weight loss, malnutrition and medication delivery appropriately. Ongoing evaluation of a patient’s swallow is often required, but communication then also becomes an important consideration. Following TBI, it is common for both verbal and nonverbal communication to be affected. In many cases, this is due to the linguistic process of language disorder, but also frequently there is a cognitive element to the communication disorder. Cognitive deficits, such as executive dysfunction, attention deficits and impaired concentration, can all result in communication and language difficulties. The role of the speech and language therapist is to help identify these and employ techniques aimed at minimising the effects of these wherever possible. In many cases, adaptive techniques can be found and implemented to help patients compensate, and while deficits will often improve, in cases of severe TBI, this is not always the case. In these circumstances, adaptive aids can often be beneficial.

14.4.4 Neuropsychology Acute neuropsychological input aims at dealing with a large variety of behavioural and psychological issues caused by a traumatic brain injury. Cognitive and neuropsychological rehabilitation is pivotal at this stage of recovery. A patient post-­TBI may suffer from impairments of memory, attention, executive dysfunction, language or perception. Poor function in daily living may arise due to a combination of factors, including specific deficits within a cogni-

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tive domain, low mood, apathy and external factors. The “frontal lobe paradox” reflects the observation that patients can perform well on routine screening, but major problems emerge once in the community as a result of failing to engage with therapy or perform necessary tasks [10]. Detailed neuropsychology assessment can help in differentiating the specific problems leading to poor cognitive function after TBI and thus guide rehabilitation goals and strategies. Behavioural management programmes tailored to the individual are a key initial step and are critical in helping health professionals ensure that the patient’s environment is modified as much as possible to aid recovery and provide an optimal environment for rehabilitation. Cognitive insufficiency is prevalent and can be long lasting following TBI, and different cognitive rehabilitation techniques and training models are implemented by the neuropsychology team [11]. Providing support and education for the patients’ families allows for longer-term planning to help the often difficult transition into the community, ensuring a better understanding of behaviours that could be expected, hopefully enabling optimal coping strategies for families to allow and maximise the function of the patient.

14.4.5 Rehabilitation Medicine Physicians A rehabilitation physicians role is to over-see a patients rehabilitation programme  and help to  coordinate the multidisciplinary team. Their role is to be able to oversee the road ahead for the patients’ long-term recovery and rehabilitation, from confirming the diagnosis and prognosis, through treating, managing and preventing complications and side effects, to liaising with third-­ party organisations, providing information and support to the patient and their families and contributing to life decisions. Professional relationships are often built up over many years, from acute admission to long-term disability management in the community.

14.4.6 Goal Setting What defines an integrated programme most clearly is the operation of a patient-centred goal-­ setting system. This means that goals for the rehabilitation programme are set collectively by the team, in conjunction with the patient and/or his or her advocate, rather than by individual disciplines in isolation. While some goals may require input from only one discipline, for many goals, the interventions of several team members will be necessary. Goals should be specific, measurable, achievable and relevant with the period for achievement clearly identified. The majority of the goals are written at the activities/participation level of the ICF framework. Goal Attainment Scaling (GAS) is now commonly used in the rehabilitation settings to document the extent to which the individual goals are achieved during the course of the rehabilitation programme [12].

Illustrative Case 1: Acute Rehabilitation

A 45-year-old female was admitted to the hospital after being hit by a car travelling at 30 miles per hour. At the scene, her GCS was 13/15, and she was intubated secondary to agitation. The patient was transferred to the major trauma centre where imaging demonstrated a TBI, with traumatic subarachnoid haemorrhage, bitemporal and right cerebellar contusion and a complex skull base fracture. Initial neurological critical care clinical pathways were followed, and after a week, the patient was transferred to the rapid access acute rehabilitation ward. Ongoing medical and surgical reviews continued with assessments of nutrition and hydration requirements. Physiotherapy assessments, including tonal management, were started, and assessments of posttraumatic amnesia (PTA) using the Galveston Orientation and Amnesia Test (GOAT) completed. The period of PTA lasted 3 weeks, which correlates with a “very severe” injury [13]

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before emergence allowed for detailed neurocognitive testing to start. The patient was found to lack the mental capacity to make decisions around her health and rehabilitation needs. Family involvement at this time is critically important if possible, both for the psychological well-being of the patient and for engagement in the longer-term planning of rehabilitation needs. A best interest meeting was arranged with the family and MDT, and they were referred to a local cognitive Level 2 rehabilitation unit for ongoing cognitive rehabilitation under Deprivation of Liberty Safeguarding (DoLS). This case demonstrates the need for acute early rehabilitation in the context of traumatic brain injury. It allows for early transfer of patients from the acute setting to a rehabilitation environment, where a full MDT assessment can be started alongside any ongoing medical or surgical issues. Not all rehabilitation needs can be met in this environment, and another crucial role of the MDT is to sign-post ongoing rehabilitation needs and ensure the patient is referred and transferred to appropriate services, where the longer-term care rehabilitation needs of an individual patient can hopefully be met.

14.4.7 Brain Injury and the Mental Capacity Act Mental capacity is the ability of any one individual to make decisions, and this can be compromised following a brain injury of any aetiology. It is important to remember that capacity is not a blanket term. An individual should be assessed for capacity for a specific decision, as quite often capacity may be lacking for some decisions but not for others. There are many reasons why a person’s mental capacity may be lacking following TBI, but regular, documented reassessment is necessary especially in

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the first part of a patient’s recovery, where the clinical picture of their brain injury can change on a day-to-day basis. The Mental Capacity Act 2005 provides a statutory framework to empower and protect vulnerable people who are not able to make their own decisions [14]. Assessment of capacity stems from five core principles: 1. Assume a person has capacity unless proved otherwise. 2. Do not treat as incapable of making a decision unless all practicable steps have been tried to help them. 3. A person should not be treated as incapable of making a decision because their decision may seem unwise. 4. Always do things or take decisions for people without capacity in their best interests. 5. Before doing something to someone or making a decision on their behalf, consider whether the outcome could be achieved in a less restrictive way. Often in a rehabilitation or other healthcare setting, if a patient is found to lack capacity, then a Deprivation of Liberty Safeguarding (DoLS) is applied for through the local authority. A DoLS is an amendment to the Mental Capacity Act 2005 [14]. It ensures that people who cannot consent to their care arrangements in a hospital or care environment are protected if those arrangements deprive them of their liberty. Arrangements of the DOLS are assessed regularly to ensure the care provided is within the person’s best interests. Difficulties can arise in circumstances where a patient with TBI is unaware of their cognitive or physical disabilities because of reduced insight. Close team working with both the neuropsychiatric team and neuropsychologists is necessary to ensure the correct clinical path is taken, the patients’ best interests are met, they remain safe and the most suitable rehabilitation setting is found for them. Close liaison with family members and other professional teams is often necessary to ensure a satisfactory outcome.

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14.4.8 Cognitive Impairment and Recovery After Traumatic Brain Injury Traumatic brain injury of any severity is liable to produce a variety of cognitive impairments with varying intensity. Even a mild cognitive impairment can lead to severely disabling effects on the individual as well as on the families and caregivers. Cognitive deficits produce a wide variety of effects, impacting an individual’s activities of daily living, hobbies, social interactions in the community, vocational activities and family life. In moderate to severe TBI, the incidence of long-­term cognitive impairment is around 65% [15], which can greatly impact a patients long-term functional independance [16]. The nature of the cognitive impairments depends on the particular areas of the brain that have been injured. There tends to be a relationship between injury severity and cognitive deficits with a longer duration of unconsciousness and a longer period of posttraumatic amnesia being associated with more severe cognitive impairments [17, 18]. Also, more often than not, substantial cognitive symptoms can occur in the absence of significant objective cognitive deficit in many mild cases, and this may reflect the complex interactions of premorbid function between mood, cognitive deficits and external factors in determining post-­TBI cognitive recovery. Mild to moderate TBI often leads to impairments in memory, attention, executive processing and speed of processing. In moderate to severe TBI, in addition to the above, other prevalent cognitive deficits are communication impairments, impairments in visuospatial processing and lack of awareness of the deficit. Most of the cognitive impairments after mild to moderate TBI recover within 3–6  months after the injury [19]. In the moderate to severe TBI group, the steep trajectory of cognitive recovery continues up to 12 months, followed by a gradual cognitive recovery that has been reported even 5 years after the injury [20]. Cognitive rehabilitation after TBI helps to aid new learning and development of compensatory strategies over time. There is a subset of patients with mild to moderate TBI where the cognitive impairments do not improve, causing significant life-long disability.

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Illustrative Case 2: Charitable Organisations in TBI

A 22-year-old man sustained a severe traumatic brain injury in a road traffic collision. The patient had a rapid physical recovery and was able to leave the hospital after less than a fortnight. However, he continued to experience multiple symptoms, ranging from headache and fatigue to low mood and irritability. Although he had taken some weeks off work, he found returning to work and trying to resume his usual social activities difficult. His own and family’s sense of bewilderment and frustration increased as they had equated hospital discharge with being back to “the old me”. No one has told them to expect a long recovery, lasting months and accompanied by ongoing difficulties. His sense of isolation was compounded by the feeling that his colleagues and friends did not understand why, when he did not have any visible physical injuries, he still found himself struggling. Through looking online, his mother came across Headway, a brain injury charity with franchises throughout the United Kingdom, providing a range of services for survivors of brain injury. Their local Headway group ran regular peer support groups, which were often facilitated by a retired nurse, who used to work in the local tertiary neurosciences centre and was familiar with all the problems faced by those living with TBI and their families. He started going to these peer support group meetings with his local Headway branch, often accompanied by members of his family. He recalls the relief he felt when he met other people living with the effects of TBI and understood that he was not abnormal or alone in experiencing ongoing effects months after discharge. His mother found conversations with other family members to be similarly helpful. Volunteers with his local Headway group were able to help sign-post G and his family to information

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about brain injury, provide advice on how to manage specific symptoms and help them get in touch with local community services. Over time, he found that the local Headway group provided a community of people who understood what they were going through, reducing their feelings of isolation. He is now many years after his head injury; he is working full time and living with his long-term girlfriend. He no longer attends his local Headway group regularly for his own sake but has continued his involvement by raising money for their activities, and his mother spent several years on the committee. Local third sector organisations, particularly those providing peer support groups and sign-posting services, can be an invaluable adjunct for patients with TBI and their families. These local organisations can step in, support patients in the community and reduce their sense of isolation and bewilderment. In some areas, these organisations may have direct links with NHS services and receive referrals from them. When asked about the early years after his TBI, he says simply that the local Headway group “saved my sanity”.

14.4.9 Vocational Rehabilitation After Brain Injury Vocational rehabilitation is defined as “whatever helps someone with a health problem stay at, return to or remain in work” [21]. As TBI often  hits people at the heart of their working lives, returning to work is an important goal for both the patients and their families. Furthermore, return to work is also associated with improved quality of life and less use of health resources [22]. The reported rate of return to work after brain injury is variable. Shames and colleagues in 2007 reported that 13–70% of patients returned to work between 6  weeks and 7  years after the injury [23]. A systematic review of return to work

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after acquired brain injury included 49 studies and concluded that about 40% of the people with traumatic or nontraumatic brain injury were able to return to work after 1 or 2 years [24]. The rehabilitation services within the National Health Services (NHS), UK, are provided by the clinical neuropsychologist, neuro-occupational therapist and consultant in rehabilitation medicine, who provide advice about a return to work after TBI, help liaise with the occupational health services or provide information for the employers regarding impairments and advise them of any adaptations required for a smooth return to work (Table 14.1). Although multidisciplinary teams help patients with traumatic brain injuries to return to meaningful employment, there are no guidelines or specific interventions that help to guide this process. A systematic review carried out by Donker-Cools in 2016 looked at various interventions for traumatic and nontraumatic brain injury and found that the most effective returnto-­work interventions for patients with brain injury were a combination of work-directed interventions (like adaptations of the working tasks), coaching/education and/or skills trainTable 14.1 Vocational post-TBI

rehabilitation

Evaluate/Engage Identify the barriers to work Evaluate the working tasks

Implement Vocational counselling Coping strategies

Evaluate the working hours

Individual goals

Evaluate the working environment Engage the employer

Access to other support services Education on TBI Training of social skills Cognitive skills training Work hardening

interventions

Consider alternative Assess skills and aptitude Engage employer for alternative work Refer to a disability employment advisor Refer to other statutory agencies for support

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ing [25]. For a vocational rehabilitation programme to be successful, all these interventions are tailored towards the individual patient, keeping in mind the psychosocial factors and the impact of fatigue and cognition on workrelated tasks.

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related to improved brain network functional connectivity. Noninvasive stimulation techniques, such as transcranial direct current stimulation (tDCS), are also attractive, as their use is not as clinically complicated and burdened by the safety concerns associated with DBS.  There is evidence from a small RCT supporting the efficacy of anodal 14.5 Emerging Trends tDCS to the left dorsolateral prefrontal cortex with an improved level of consciousness in a in Rehabilitation small population of both traumatic and nontrau14.5.1 Deep Brain Stimulation matic causes of MCS or vegetative state [33]. It should be noted that DBS has ongoing use Severe TBI, where the patient remains in a mini- and variable evidence for several psychiatric mally conscious state (MCS), is thought to repre- problems, such as depression, which are fresent a state of widespread loss of connectivity quently seen as sequelae of TBI [34, 35]. There is throughout the brain. This loss of connectivity currently no clear consensus on the most useful prevents patients who may still experience an stimulation target or parameters. element of awareness, that is, “covert consciousThe challenges with using either DBS or tDCS ness”, from manifesting purposeful or goal-­ for severe TBI are similar to that of determining directed motor activity. This has been termed the most effective stimulation parameters and the “cognitive motor dissociation” [26]. Several patient characteristics that most suggest a patient innovative studies have demonstrated that while is likely to respond. The latter is particularly perlarge-scale brain networks that support normal tinent for the use of DBS for TBI, given the goal-directed behaviour can be preserved in this already important challenge that patient and state, there is a disruption in standard brain net- injury heterogeneity poses for investigating interwork connectivity patterns [27–30]. This mecha- ventions. For example, a clinical study using nism is thought to also apply to other causes of tDCS suggests that clinical responsiveness is MCS. The theory behind using deep brain stimu- associated with preserved grey matter volume lation (DBS) in this group of patients is that DBS and metabolism at the site of stimulation and in may improve the connectivity of these preserved the thalamus [36]. Modelling studies may prove brain networks, thereby enabling the “covert con- useful, as they can systematically test a large sciousness” to become more overt meaningful number of stimulation targets and parameters. behaviour. In 2007, the first case of bilateral medial thalamic DBS increasing purposeful behaviour was 14.5.2 Augmented Reality reported [31]. Since then, a handful of other studies have investigated DBS for severe TBI, Augmented reality (AR) is an emerging technolcovering ten separate patients [32]. The studies ogy that is being increasingly utilised in the rehahave all targeted the thalamus, intending to bilitation of patients. It is a variation of virtual improve thalamocortical and brain network con- reality (VR), in which it allows the user to experinectivity, but the stimulation parameters have ence their reality in real time rather than always varied substantially. It is impossible to conclude having a synthetic feature as in VR. Over the past that DBS will deliver on the promise of a 20 years, these technologies have been researched Lazarus-type raising for severe TBI patients with to enhance a patient’s rehabilitation journey by these small numbers. Additionally, none of these improving motor control, supporting motivation studies used concurrent physiological measures and aiding with treatment options, such as analto investigate whether any recovery was indeed gesic effects [37]. AR is a technology that allows

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the user to extend their reality using digital information and thus gives an ability to experience how any disability may feel in the real world [38]. There is promise regarding clinical use; however, significant barriers have been found when it comes to patient set up in a home-based environment, and there are often significant differences between therapist and patient reporting on regime adherence [37]. These technological advancements should be seen as additional tools to aid the patient recovery, but for maximal benefit, they need to be incorporated into a varied, MDT-led rehabilitation programme.

requiring varying levels of support and intervention The process starts soon after the head injury, with differing skill sets required for each of the stages of a patient’s recovery and rehabilitation. It is a collaborative process, in which the patient and their family members and friends work with a multidisciplinary team to maximise the patient’s ability and opportunity to participate in activities of everyday life that are valued by an individual.

14.5.3 Brain-Computer Interface

References

A brain-computer interface (BCI) is both a hardware and software communications system that permits cerebral activity to control computers or external devices [39]. It is an innovation that is not new to researchers but is now just starting to influence rehabilitation practises. BCI systems can be used for both motor and sensory modalities. A motor system records neural activity associated with the user’s thoughts, perceptions and motor intent. They then decode brain signals and turn them into commands for an output device and finally perform the user’s intended action through whichever output device has been chosen. Sensory systems transduce environmental stimuli into neural signals interpretable by the central nervous system [40]. Both types of systems, whether working separately or in tangent, have the potential to reduce disability by aiding a user to interact with the environment.

1. Stucki G, Cieza A, Melvin J.  The international classification of functioning, disability and health (ICF): a unifying model for the conceptual description of the rehabilitation strategy. J Rehabil Med. 2007;39:279–85. 2. Cifu D, Hurley R, Peterson M, et al. VA/DoD clinical practice guideline for management of concussion/mild traumatic brain injury. J Rehabil Res Dev. 2009;46:CP1–68. 3. Teasdale G, Zitnay G. History of acute care and rehabilitation of head injury. In: Zasler ND, Katz DL, Zafonte RD, Arciniegas DB, Bullock MR, Kreutzer JS, editors; 2012. 4. Madden RH, Bundy A.  The ICF has made a difference to functioning and disability measurement and statistics. Disabil Rehabil. 2018;41:1450–62. 5. Turner-Stokes L, Krägeloh CU, Siegert RJ.  The patient categorisation tool: psychometric evaluation of a tool to measure complexity of needs for rehabilitation in a large multicentre dataset from the United Kingdom. Disabil Rehabil. 2018;41:1101–9. 6. Board NC, editor. NHS standard contract for specialised rehabilitation for patients with highly complex needs; 2013. 7. Willer B, Corrigan JD. Whatever it takes: a model for community-based services. Brain Inj. 1994;8:647–59. 8. Regional Networks for Major Trauma NHS Clinical Advisory Groups Report; n.d. 9. Major trauma rehabilitation prescription 2019 TARN data entry guidance document; 2018. 10. Worthington A.  Decision making and mental capacity: resolving the Frontal Paradox. Neuropsychologist. 2019:7. 11. Barman A, Chatterjee A, Bhide R. Cognitive impairment and rehabilitation strategies after traumatic brain injury. Indian J Psychol Med. 2016;38:172–81. 12. Turner-Stokes L, Williams H, Sephton K, et  al. Engaging the hearts and minds of clinicians in out-

14.6 Conclusion There is such heterogeneity in the deficits and outcomes of TBI patients that the rehabilitation of such is only possible with a cohesive multidisciplinary team approach in providing individualised programmes based on individual need. This process spans across both the acute and chronic phases of rehabilitation as the chronicity of a patients deficits and needs will change therefore

Conflict of Interest  None declared.

Funding  None.

158 come measurement—the UK rehabilitation outcomes collaborative approach. Disabil Rehabil. 2012;34:1871–9. 13. Nakase-Richardson R, Sepehri A, Sherer M, et  al. Classification schema of posttraumatic amnesia duration-based injury severity relative to 1-year outcome: analysis of individuals with moderate and severe traumatic brain injury. Arch Phys Med Rehabil. 2009;90:17–9. 14. Affairs D for C. Mental Capacity Act 2005—Code of Practice. In: Department for Constitutional Affairs; 2005. 15. Rabinowitz AR, Levin HS. Cognitive Sequelae of Traumatic Brain Injury. Psychiat Clin N Am. 2014;37(1):1–11. 16. Whiteneck GG, Gerhart KA, Cusick CP. Identifying environmental factors that influence the outcomes of people with traumatic brain injury. J Head Trauma Rehabil. 2004;19:191–204. 17. Dikmen SS, Machamer JE, Winn HR, et  al. Neuropsychological outcome at 1-year post head injury. Neuropsychology. 1995;9:80–90. 18. Spitz G, Mahmooei BH, Ross P, et al. Characterizing early and late return to work after traumatic brain injury. J Neurotrauma. 2019;36:2533–40. 19. Schretlen DJ, Shapiro AM. A quantitative review of the effects of traumatic brain injury on cognitive functioning. Int Rev Psychiatry. 2003;15:341–9. 20. NIH Consensus Development Panel on Rehabilitation of Persons With Traumatic Brain Injury. Rehabilitation of persons with traumatic brain injury. JAMA. 1999;282:974–83. 21. Waddell G, Burton AK, Kendell NAS.  Vocational rehabilitation. What works, for whom, and when? Vocational Rehabilitation Task Force Group and Industrial Injuries Advisory Council; 2008. Available at: https://assets.publishing.service. gov.uk/government/uploads/system/uploads/ attachment_data/file/209474/hwwb-­v ocational-­ rehabilitation.pdf 22. Wehman P, Targett P, West M, et al. Productive work and employment for persons with traumatic brain injury: what have we learned after 20 years? J Head Trauma Rehabil. 2005;20:115–27. 23. Shames J, Treger I, Ring H, et al. Return to work following traumatic brain injury: trends and challenges. Disabil Rehabil. 2007;29:1387–95. 24. van Velzen JM, van Bennekom CAM, Edelaar MJA, et  al. How many people return to work after acquired brain injury? A systematic review. Brain Inj. 2009;23:473–88. 25. Donker-Cools BHPM, Daams JG, Wind H, et  al. Effective return-to-work interventions after acquired brain injury: a systematic review. Brain Inj. 2015;30:113–31.

H. Mee et al. 26. Schiff ND.  Cognitive motor dissociation following severe brain injuries. JAMA Neurol. 2015;72:1413. 27. Schiff ND, Rodriguez-Moreno D, Kamal A, et al. fMRI reveals large-scale network activation in minimally conscious patients. Neurology. 2005;64:514–23. 28. Threlkeld ZD, Bodien YG, Rosenthal ES, et  al. Functional networks reemerge during recovery of consciousness after acute severe traumatic brain injury. Cortex J Devoted Study Nerv Syst Behav. 2018;106:299–308. 29. Perri CD, Bahri MA, Amico E, et  al. Neural correlates of consciousness in patients who have emerged from a minimally conscious state: a cross-­ sectional multimodal imaging study. Lancet Neurol. 2016;15:830–42. 30. Fernández-Espejo D, Rossit S, Owen AMA.  Thalamocortical mechanism for the absence of overt motor behavior in covertly aware patients. JAMA Neurol. 2015;72:1442. 31. Schiff ND, Giacino JT, Kalmar K, et al. Behavioural improvements with thalamic stimulation after severe traumatic brain injury. Nature. 2007;448:600–3. 32. Haddad AR, Lythe V, Green AL.  Deep brain stimulation for recovery of consciousness in minimally conscious patients after traumatic brain injury: a systematic review. Neuromodulation. 2019;22:373–9. 33. Thibaut A, Bruno M-A, Ledoux D, et  al. tDCS in patients with disorders of consciousness: Sham-­ controlled randomized double-blind study. Neurology. 2014;82:1112–8. 34. Dandekar MP, Fenoy AJ, Carvalho AF, et  al. Deep brain stimulation for treatment-resistant depression: an integrative review of preclinical and clinical findings and translational implications. Mol Psychiatry. 2018;23:1094–112. 35. Drobisz D, Damborská A.  Deep brain stimulation targets for treating depression. Behav Brain Res. 2018;359:266–73. 36. Deco G, Cruzat J, Cabral J, et al. Awakening: predicting external stimulation to force transitions between different brain states. Proc Natl Acad Sci U S A. 2019;116:18088–97. 37. Williams RM, Alikhademi K, Drobina E, et  al. Augmented reality for rehabilitative therapy: patient experiences and practitioner perspectives. Proc Hum Factors Ergonomics Soc Annu Meet. 2019;63:748–52. 38. Eckert M, Volmerg JS, Friedrich CM.  Augmented reality in medicine: systematic and bibliographic review. JMIR Mhealth Uhealth. 2019;e10967:7. 39. Nicolas-Alonso LF, Gomez-Gil J.  Brain computer interfaces, a review. Sensors Basel Switz. 2012;12:1211–79. 40. Bockbrader MA, Francisco G, Lee R, et  al. Brain computer interfaces in rehabilitation medicine. PM&R. 2018;10:S233–43.

Part III Evidence

Predicting Outcome Following Traumatic Brain Injury

15

Kwok M. Ho

15.1 Introduction Evolution has equipped us an ability to pursue food source and safety in the presence of uncertainty about the likely yields from such efforts [1]. One of these tools is heuristic reasoning which is similar to a common concept called ‘gut feeling’. Heuristics operate seamlessly at a subconscious level, allowing us to make quick decisions on how we should respond when faced with potential dangers and what action will most likely make us better or worse off in the end. Although this cognitive ability offers us a distinct survival advantage when we face situations associated with small degree of uncertainty and ambiguity, heuristics is no longer efficient or could even be counterproductive when there is a high degree of uncertainty due to multiple conflicting and confusing signals. This type of situation can be exemplified when clinicians are trying to prognosticate outcomes for their patients with severe traumatic brain injury (TBI).

K. M. Ho (*) Department of Intensive Care Medicine, Medical School, University of Western Australia, Perth, Western Australia, Australia Royal Perth Hospital, Perth, Western Australia, Australia School of Veterinary & Life Sciences, Perth, Western Australia, Australia e-mail: [email protected] © Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_15

15.2 Background Information on Prognostic Factors of TBI TBI is one of the leading causes of mortality and disability in young people. Predicting long-term outcomes for young people following severe TBI can be both difficult and emotionally draining, because such assessment is often linked to either an irreversible decision about performing life-­ sustaining surgery or whether treatment should be withheld or withdrawn [2]. As such, accurate outcome prediction is paramount for all parties involved, not only for the benefits of the patients and their families but also for the psychological well-being of the attending clinicians. Many factors have been identified to be associated with a poor prognosis following severe TBI.  These include advanced age, low initial post-resuscitation Glasgow Coma Score (GCS) or motor response, absence of pupillary reaction to light, extracranial injuries, secondary brain injury from hypoxia and hypotension, computed tomographic (CT) brain scan features such as traumatic subarachnoid haemorrhage, intracerebral contusions, or high Rotterdam or Marshall CT brain grading, evidence of blood–brain-­ barrier disruption, refractory intracranial hypertension, low brain tissue oxygenation, loss of cerebrovascular autoregulation, high serum astrocyte biomarker (S-110B) concentrations, bilateral absence of somatosensory evoked potential, impaired alpha variability on continuous 161

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electroencephalography, and presence of diffuse axonal injury on the magnetic resonance imaging (MRI) especially when brainstem structures— substantia nigra and mesencephalic tegmentum—are involved [3]. Many TBI outcome studies were small and heterogeneous, had often included patients with TBI from different mechanisms of injury, and the prognostic predictors assessed were measured at different time points after the injury. To confound this further, many studies also reported a variable amount of missing data, and there were variations in the intervals between the initial injury and the outcome assessment. Indeed, almost none of the factors described earlier would be reliable enough on their own to avoid making either overpessimistic or overoptimistic predictions. Because there are many factors that may affect neurological recovery following TBI, clinicians may find it extremely difficult—if not almost impossible—to consider all factors simultaneously and to summarise all available information to determine a patient’s prognosis accurately. For example, GCS is often considered as one of the most simple but key elements predictive of outcomes after TBI. Ensuring its clinical validity consistently can be challenging, however. Previous studies have showed that there is a substantial variability in how to assess the initial GCS both within the same hospital and between different hospitals. It is also well-established that inter-observer variability in GCS assessments between experienced and inexperienced practitioners—often due to differences in where and how to apply and how to interpret a painful stimulus—exists, even without considering the effects of sedative and paralytic medications. Using a single source of information to make any outcome prediction is thus potentially erroneous. In an old clinical study by Kaufman et al. [4], they described the accuracy of outcome predictions of an experienced neurosurgeon and neuroradiologist for 100 patients with severe TBI based on the best GCS obtained within 24  h after injury, in addition to age, pupillary reaction to light, blood pressure, heart rate, laboratory blood tests, and initial CT brain scan. Outcome classification was

K. M. Ho

correctly predicted in less than 60% by both neurosurgeon and neuroradiologist; and poor outcomes were overestimated by 32%–52%, while good outcomes were underestimated by 35%. In interpreting clinical studies on predicting outcomes following severe TBI, clinicians should note the difference between statistical significance and clinical significance. Even though many factors have been reported to be associated with a poor outcome following severe TBI— often with an impressively small p-value—this does not mean that these factors are important in explaining the variability in outcomes we may observe. A small p-value merely suggests that the difference in the prevalence of the predictor under investigation between the good and bad outcome groups is unlikely to occur by chance, and this provides no confirmation that misclassification does not occur in a clinically and ethically unacceptable rate. For instance, although the presence of diffuse axonal injury on an MRI scan, especially when substantia nigra and mesencephalic tegmentum areas are involved, is associated with a higher risk of poor neurological outcome [3], this is by no means deterministic; and good functional recovery is still possible in a significant proportion of patients who have severe diffuse axonal injury on the MRI scan [5]. Furthermore, it is increasingly clear that some prognostic factors are correlated. While it is intuitive to think that a patient with more poor prognostic factors will do worse than those with less, this assumption may not be correct if one of the prognostic factors has already captured all the prognostic information contained in the other prognostic factors. For example, recent studies suggested that although the presence of cerebrospinal fluid evidence of blood-brain barrier disruption and diffuse axonal injury on MRI scan are associated with a poor outcome after severe TBI, both of these prognostic factors do not appear to add prognostic information over and above a validated TBI prognostic model [5, 6]. As such, clinicians should be prudent not to rely on their heuristic reasoning—which can be swayed by a small number of prognostic factors—in determining the prognosis of their patients.

15  Predicting Outcome Following Traumatic Brain Injury

15.3 Recent Developments Improvements in statistical analysis combined with access to large clinical databases have enabled researchers to develop objective TBI prognostic calculators. The IMPACT (International Mission for Prognosis and Analysis of Clinical Trials) model incorporates a number of prognostic factors to provide a prediction of unfavourable neurological outcome at 6 months (defined on the Glasgow Outcome Scale as severely disabled, vegetative, or dead) [7]. The full IMPACT model requires information on age, pupil reactivity to light, motor response, presence or absence of hypoxia and hypotension, plasma glucose and haemoglobin concentrations, and CT brain features including the presence of epidural haematoma, subarachnoid haemorrhage, volume of the drainable or non-drainable intracerebral/ extradural/subdural haematoma, and Marshall CT brain grading to calculate the predicted risks of unfavourable outcome at 6  months. The IMPACT TBI prognostic calculator is available for download on the Internet (the IMPACT model: http://journals.plos.org/plosmedicine/ article?id=10.1371/journal.pmed.0050165#s5). The Marshall CT brain grading ranges from I to VI: (a) grade I means no visible pathology; (b) grade II means diffuse injury, basal cisterns are present with midline shift of 0–5  mm, and no high- or mixed-density lesions (or contusions) >25 cm3 which may include bone fragments and foreign bodies; (c) grade III means diffuse injury, basal cisterns compressed or absent with midline shift of 0–5 mm, and no high- or mixed-density lesions (or contusions) are >25 cm3; (d) grade IV means diffuse injury, midline shift >5  mm, and no high- or mixed-density lesions (or contusions) >25 cm3; (e) grade V means the presence of any lesion surgically evacuated; and (f) grade VI is defined by the presence of high- or mixed-density lesions >25  cm3 not surgically evacuated. The volume of contusion or haematoma can be estimated ­ by the following formula: width × depth × height/2. A number of studies have subsequently externally validated this prognostic model and confirmed its strong ability to discriminate between

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favourable and unfavourable outcomes at 6 months or longer after the injury (areas under the receiver operating characteristic curve [AUROC] >0.8) [8]. There are, however, two important caveats about how to use a prognostic model. First, it is important to understand that the predicted risks of unfavourable outcome derived from this prognostic model are only, at best, the average risks of a group of similar patients, and we cannot be sure how similar any individual patient would be to other patients [9]. Furthermore, most people, including the next of kin of any patients with severe TBI, are likely to have difficulty in understanding and interpreting probability [1, 10]. If clinicians are to use these models, it would be prudent to use the predicted risks of unfavourable outcomes merely as a guide for themselves, perhaps to help support clinical decisions but never to replace clinical judgement. If this information is needed for the family of the patient, clinicians should frame the predicted risk in a way that can be easily understood; e.g. perhaps use frequency instead of percentage (e.g. 5% chance is easier to understand if it is framed as 1 in 20). Second, although the IMPACT model has a large AUROC, this statistical parameter only reflects how well a prognostic model can discriminate between unfavourable and favourable outcomes. While this is useful to reflect whether two treatment groups in a clinical trial are comparable, this statistical parameter will not be useful to tell us whether a prognostic model is accurate as a decision-making tool [9]. To achieve this latter objective, we will need a well-­calibrated prognostic model, which means the predicted risks actually track closely with the observed risks (in a calibration plot). Clinicians should assess the calibration of any prognostic models, preferably using their local cohort, before using them as a prognostic tool. It is well-established that heuristic reasoning can lead us to a biased conclusion when there are multiple conflicting signals (e.g. large cerebral contusions with high intracranial pressure but without effacement of basal cisterns and midline shift on the CT brain scan as in our following illustrated case). Unless we realise and accept

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how easily our decision-making process can be tricked erroneously by our heuristics subconsciously, the importance and utility of an objective validated prognostic model will be difficult to be appreciated and accepted. Illustrative Case A 19-year-old previously healthy male developed severe TBI after he was assaulted by a stranger with a hard object. His initial Glasgow Coma Score was 11 (Eye 3, Motor 5, Verbal 3). His initial CT brain scan on admission showed the presence of bilateral frontal contusions (Fig.  15.1). An intraparenchymal intracranial pressure was inserted, which showed intracranial hypertension, and a decision was made to proceed to bilateral decompressive craniectomy immediately. The CT brain scan on the day of admission after surgery is shown in Fig. 15.2. Despite the craniectomy, the patient had refractory intracranial hypertension with an intracranial pressure (ICP) over 40  mmHg recorded most of the time. His pupils remained small and reactive bilaterally despite the high ICP. The CT brain scan on day 3 showed that severe swelling around the right frontal contusions remained, and there was also increasing midline shift (Fig. 15.3).

Fig. 15.2  CT brain scan on day 1 after traumatic brain injury after bilateral decompressive craniectomy

Fig. 15.3  CT brain scan on day 3 with persistent high intracranial pressure >40  mmHg despite bilateral decompression

Fig. 15.1  Initial CT brain scan on admission to the trauma centre

In view of the CT brain scan and the high ICP, a medical decision to withdraw treatment was suggested to the family of the patient. The family did not accept that suggestion; life support was continued followed by a tracheostomy on day 7. The patient was discharged to the ward with the expectation that he would remain comatose and eventually in a vegetative state. Nonetheless, the patient continued to make neurological recovery within

15  Predicting Outcome Following Traumatic Brain Injury

Fig. 15.4  CT brain scan at 6 months after cranioplasty to repair skull defects

the next few months, and cranioplasty was performed 6  months after TBI (Fig.  15.4). By 12 months after TBI, the patient’s CT brain scan was almost back to normal (Fig. 15.5), and eventually, the patient could go back to his university for further studies and graduated within 3  years following TBI.  The family and some healthcare workers involved in his care believed that this patient was remarkably lucky, and his recovery was purely a miracle. However, when his CT brain scans were re-examined carefully, it was obvious that his brainstem was never compromised by the apparent high intracranial pressure (Fig.  15.6), which was consistent with why he never developed fixed and dilated pupils despite the high intracranial pressure. When his admission details were entered into the IMPACT TBI prognostic calculator [7], his risk of poor neurological outcome at 6 months was predicted to be only 20% (95% confidence interval 16–26) (Fig. 15.7).

15.4 Future Directions Prognostic models are not meant to replace judicious judgement in our decision-making. Its main utility is to allow us to cross-check the accuracy

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Fig. 15.5  CT brain scan at 12  months after traumatic brain injury

Fig. 15.6  CT brain scan on day 3 showing preserved basal cistern despite high intracranial pressure

of our clinical judgement and whether such assessment is unduly influenced by different forms of heuristics or biases, including confirmation and implicit bias, availability, and representativeness heuristic [1, 11]. How we can easily make erroneous decisions due to overconfidence and self-fulfilling prophecy under the pressure of

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166 Prediction of 6 month outcome after TBI Nr: Predictor

Coding

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years 1,2,3,4,5,6,9 1=both reacting, 2=one, 3=none 0=no, 1=yes 0=no, 1=yes 1,2,3,4,5,6 0=no, 1=yes 0=no, 1=yes 3 - 20 6 - 17

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0 Value

Predicted probability of 6 month unfavorable outcome: Core 11% Confidence interval

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Fig. 15.7  The display of the predicted risks of the illustrative case based on the IMPACT traumatic brain injury calculator

limited healthcare resources can be illustrated by the map of the Island of Medical Prediction (Fig. 15.8) [11]. Although we already have good prognostic models to predict functional outcomes at 6 months following severe TBI, we should also be mindful that further neurological recovery beyond 6 months to an extent to become independent is not rare and can occur in up to 25% of patients with severe TBI requiring decompression [12]. Clinicians should also be mindful how to project our own values as our

patients’. Quality of life is a subjective assessment which may change substantially. Human beings are remarkably adaptive under even the most difficult circumstances by recalibrating their value system [13], and hence, further refinement of our current prognostic models will need to cater to this unmet need. In addition, healthcare resources are limited; policymakers and society at large have to decide whether financial implications and cost-­ effectiveness should constitute as essential elements of an acceptable outcome [14].

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Fig. 15.8  Map of the Island of Medical Prediction (reproduced with permission from [11])

15.5 Conclusions

References

The ability to accurately predict outcome following severe TBI is an elusive Holy Grail. Clinicians should be mindful of the pitfalls of relying on only a few prognostic factors in predicting their patients’ outcome. Humans can be easily misguided by a number of psychological limitations, including a wide range of different heuristics and biases. Sophisticated and validated, web-based, prognostic models are now widely available and can be used to confirm whether a clinician’s clinical judgement is consistent with what is to be expected objectively (compared to similar patients in the past). As medical treatment is continuously advancing, further refinement of the current prognostic models is needed. Predicting outcome following severe TBI involves a good understanding of both science and humanity.

1. Kishida KT, King-Casas B, Montague PR. Neuroeconomic approaches to mental disorders. Neuron. 2010;67:543–54. 2. Honeybul S, O’Hanlon S, Ho KM.  Decompressive craniectomy for severe head injury: does an outcome prediction model influence clinical decision-making? J Neurotrauma. 2011;28:13–9. 3. Abu Hamdeh S, Marklund N, Lannsjö T, et  al. Extended anatomical grading in diffuse axonal injury using MRI: hemorrhagic lesions in the substantia nigra and mesencephalic tegmentum indicate poor long-term outcome. J Neurotrauma. 2017;34:341–52. 4. Kaufmann MA, Buchmann B, Scheidegger D, et  al. Severe head injury: should expected outcome influence resuscitation and first-day decisions? Resuscitation. 1992;23:199–206. 5. Ho KM, Honeybul S, Ambati R.  Prognostic significance of magnetic resonance imaging in patients with severe nonpenetrating traumatic brain injury requiring decompressive craniectomy. World Neurosurg. 2018;112:277–83. 6. Ho KM, Honeybul S, Yip CB, et  al. Prognostic significance of blood-brain barrier disruption in patients with severe nonpenetrating traumatic brain injury requiring decompressive craniectomy. J Neurosurg. 2014;121:674–9.

Conflict of Interest  None declared.

Funding  None.

168 7. Steyerberg EW, Mushkudiani N, Perel P, et  al. Predicting outcome after traumatic brain injury: development and international validation of prognostic scores based on admission characteristics. PLoS Med. 2008;5(5):e165. 8. Honeybul S, Ho KM.  Predicting long-term neurological outcomes after severe traumatic brain injury requiring decompressive craniectomy: a comparison of the CRASH and IMPACT prognostic models. Injury. 2016;47:1886–92. 9. Ho KM. Use and limitations of prognostic models for the critically ill. J Crit Care. 2016;36:298. 10. Chapman AR, Litton E, Chamberlain J, et  al. The effect of prognostic data presentation format on perceived risk among surrogate decision makers of critically ill patients: a randomized comparative trial. J Crit Care. 2015;30:231–5.

K. M. Ho 11. Ho KM.  Predicting outcomes after severe traumatic brain injury: science, humanity or both? J Neurosurg Sci. 2018;62:593–8. 12. Ho KM, Honeybul S, Litton E. Delayed neurological recovery after decompressive craniectomy for severe nonpenetrating traumatic brain injury. Crit Care Med. 2011;39:2495–500. 13. Honeybul S, Gillett GR, Ho KM, Janzen C, Kruger K.  Long-term survival with unfavourable outcome: a qualitative and ethical analysis. J Med Ethics. 2015;41:963–9. 14. Ho KM, Honeybul S, Lind CR, et  al. Cost-­ effectiveness of decompressive craniectomy as a lifesaving rescue procedure for patients with severe traumatic brain injury. J Trauma. 2011;71:1637–44.

Biomarkers in Traumatic Brain Injury

16

Jussi P. Posti and Olli Tenovuo

16.1 Introduction: The Need for Biomarkers in TBI Medicine Since the discovery of other specific organ-based biomarkers, there has been considerable research effort aimed at finding similar markers for the brain. At the tissue level, it would be logical to think that since there are only two types of basic brain cells (neurons and glial cells), markers describing their damage would be easy to find, and the diagnoses based on the biomarker concentrations would be straightforward. Unfortunately, this has not been the case. Neuronal bodies, dendrites, synapses, axons as well as (micro) vessels vary in their susceptibility to injury. Astroglial and oligodendrocyte cells belonging to the glial cell family are damaged in conjunction with neural damage. There is considerable variability in axons’ type, structure, configuration, length and especially function, and this leads to variation in their susceptibility to traumatic injury. Moreover,

TBI is a complex continuum of progressive, simultaneous, parallel and interacting events at the organ, tissue, cellular and molecular levels (Fig. 16.1). All these factors variably contribute to the initial severity, disease progression and brain tissue fate, which largely determine the patient’s physical and cognitive recovery. There is an unmet clinical need for biomarkers that could help in assessing the true and dynamic severity of injury to characterise injury pathophysiology, predict disease evolution, monitor treatment effects and improve outcome prediction. The current evidence already shows that biomarkers––even a single biomarker––may be used as standalone tools for specific clinical questions, such as identifying patients with intracranial radiological abnormalities after TBI [1]. However, an increasing body of evidence indicates that biomarkers should be used as combinations [2], which may also be combined with clinical and imaging variables [3, 4].

J. P. Posti (*) Neurocenter, Department of Neurosurgery and Turku Brain Injury Center, Turku University Hospital and University of Turku, Turku, Finland e-mail: [email protected]

16.2 Challenges in Developing Biomarkers for Clinical Use in TBI

O. Tenovuo Neurocenter, Turku Brain Injury Center, Turku University Hospital and University of Turku, Turku, Finland e-mail: [email protected]

Biomarkers of TBI are measured in body fluids, and the current clinical literature consists of data based on biomarker measurements in blood, cerebrospinal fluid (CSF) or saliva. Several

© Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_16

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170 UCH-L1

S100B

NF-L

tau

Relative biomarker concentration

GFAP

0

24

48

72

96

120

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Fig. 16.1  Traumatic brain injury biomarker kinetics after TBI (hour 0) over time. Relative biomarker concentrations in blood are on y-axis and time in hours on x-axis. The evolution of the concentrations is presented based on the

current evidence on the peak times and half-lives of the proteins. Note that the kinetic curves are estimates and represent a single TBI without progressive secondary insults that may lead to secondary peaks

promising protein, metabolite and genetic biomarker candidates have been found for different clinical questions, but the translation of TBI biomarkers to clinical medicine has been limited. Small sample sizes, variable sampling times, heterogeneous analytical methods, lack of appropriate control groups and poorly characterised heterogeneous study cohorts have hampered process. Although clinical interpretation of the research results is difficult, the greatest work remains to be done in understanding the underlying biological processes reflected by different biomarkers. Measured levels may be affected by the integrity of the blood-brain barrier (BBB) and proteolytic degradation of some biomarkers. Transport of biomarkers from the brain to the bloodstream is much more complex than from other organs such as the heart, lungs or liver because it is not completely understood how the brain-enriched biomarkers enter the bloodstream. It is generally recognised that some low molecular weight biomarkers may passively diffuse through the BBB, some may pass through with a varying degree depending on the integrity of the BBB, and some can pass through only when the BBB is disrupted. Other possible

routes include efflux via the recently characterised glymphatic system as an extravasation pathway. The glymphatic system acts as an early-phase drainage pathway of the brain and includes a perivascular network for transporting extracellular proteins and other wastes to the general lymphatic network [5]. To what extent different biomarkers enter the blood through the glymphatic system or through the BBB remains poorly understood. Another major obstacle is that most TBI biomarkers are brain-enriched, but they are not necessarily brain-specific, and they may be variably expressed outside the central nervous system (CNS). Thus, patients with injuries in the extracranial tissues, especially in the peripheral nervous system, cartilage, long bones, fat tissue and muscles, appear to exhibit elevated levels of some biomarkers that have been proposed to be useful in TBI.  This is particularly problematic in patients with orthopaedic injuries or polytrauma, because they may often show levels of biomarkers that overlap with those measured from patients with mild TBI (mTBI). Elevated biomarkers in these situations will give the impression that a TBI is more severe than it actually is, and this may predispose patients

16  Biomarkers in Traumatic Brain Injury

without a TBI to unwarranted diagnostics and recurrent head imaging with significant radiation load.

16.3 T  he Role of Biomarkers in Specific Clinical Situations TBI results in a complex series of events, which include structural, functional, metabolic and inflammatory changes. These changes are reflected in the levels of brain-enriched proteins and metabolites that are released into the bloodstream. Because of the aforementioned practical problems discussed earlier, there is insufficient data available to develop clinical guidelines on the use of biomarkers in most clinically relevant situations.

16.3.1 Identifying Patients with Mild Traumatic Brain Injury From a practical clinical viewpoint, assessing whether the patient has mTBI or not is one of the most common problems encountered by emergency physicians. A typical example is an inebriated man found lying on the street with a wound on his head. Is the slight drowsiness because of alcohol or because of a TBI? Or has a patient involved in a traffic accident and with a normal level of consciousness sustained a TBI? As recent research has shown, the whole concept of TBI is not as straightforward as previously appreciated. Any impact to the head causing alterations in brain microstructure or function but without any obvious clinical symptoms fulfils the current definition of a TBI. Should we be able to detect all TBIs, including those without clinical symptoms? Probably not, but what is the ‘lower limit’ of a clinically significant TBI? Does it depend on the patient’s age, gender or the site, severity or frequency of head trauma, which is especially relevant for athletes participating in high-impact sporting events? It is probably not necessary to identify all episodes of mTBIs, especially when there is likely to be no risk of further injury and therefore negli-

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gible long-term consequence. However, in situations where they be a cumulative risk due to repeated mTBI (such as in boxing or American football), it is becoming increasingly clear that there may be practical long-term consequences. Identifying those individuals who are sustaining repeated mTBIs may provide guidance regarding issues such as the following: • Removal from the field of play • Sick leave and safety to return to play • Modification of sporting circumstances (field position and sporting tactics) • Retirement from sporting activities Given that the TBI severity is a continuum, it should be expected that the levels of TBI-related biomarkers increase along that continuum, from normal levels within healthy controls to what would be considered pathological levels depending on the injury severity. Currently, the use of biomarkers is relatively imprecise, and there remain unanswered questions regarding the degree to which biomarker levels: • Are able to detect a significant mTBI • Vary according to the nature of the injury (e.g. impact site, severity and acceleration or deceleration) • Are dependent on issues such as age, gender, presence and nature of other injuries

16.3.2 Assessing the Need for Imaging After Mild Traumatic Brain Injury A CT of the brain is frequently used to identify patients who have intracranial lesions requiring in-hospital, intensive or neurosurgical care, and there are several international guidelines regarding the clinical indications for imaging based on a patient’s medical history, presenting symptoms and clinical examination. However, in the acute setting, the diagnosis of mTBI can be challenging because symptoms are often nonspecific and may be also either transient or delayed. In these cir-

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cumstances, the criteria for obtaining an acute head CT may either not be fulfilled where it may actually be required (symptom delay) or patients may undergo a head CT upon admission, which is not really required (symptoms transient). In these circumstances, biomarkers have been shown to be useful as a screening tool to determine those patients who do not need a CT scan (i.e. where the biomarker levels make visible CT abnormalities highly unlikely). Currently, this is the only indication for clinical TBI biomarker use with an official approval (see Sect. 16.4. Current Evidence) or inclusion in guidelines for selected patients with mTBI [Scandinavian Guidelines for Initial Management of Minimal, Mild and Moderate Head Injuries in Adults] [6]. Adhering to these guidelines has been shown to reduce the number of CT scans by about 30%, which not only is costeffective but also reduces the exposure of individuals to unnecessary ionising radiation. Outside the Nordic countries, the clinical use of biomarkers in these circumstances has been low, mainly because in the emergency department, it is often impractical to wait for the results of the analysis, which may take some hours. In addition, measuring the levels of the biomarker S100B must occur within 6 h of the injury because of its short half-life, and this time window is often exceeded in milder cases of TBI, or when the exact time of the injury is unknown. When rapid, point-of-care assays for these promising markers become more widely available, their use will probably increase.

16.3.3 Outcome Prediction Predicting outcome is important for many reasons. In the context of mild and moderate head injury, patients and their families will want to know when it will be possible to either return to work or perhaps return to the sporting activity that caused the TBI in the first place. In the context of severe TBI, questions will focus on issues such as regaining consciousness and reintegration into the social environment. However, notwithstanding the importance of predicting long-term outcomes, there is also the need to predict short-term outcomes when considering

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issues of either treatment withdrawal or the benefit or otherwise of surgical intervention. It is in this regard that biomarkers may be clinically useful in determining injury severity. A good example of this can be seen in situations where a patient has an initial GCS of 3 and fixed pupils. Traditionally this type of case would have been deemed unsalvageable, and treatment would either have been withheld or withdrawn. However, there are many such cases where patients survive and go on to make a favourable long-­term recovery. This kind of situation offers an excellent place for biomarkers, since they might inform about the possibility for meaningful recovery. The biomarker or panel of biomarkers will of course have to have a high degree of sensitivity and specificity; any may be used in conjunction with clinical findings rather than in isolation; however, the decision to either proceed or withdraw potentially aggressive therapy will always be problematic.

16.3.4 Monitoring the Injured Brain One of the greatest needs for TBI biomarkers is to help in monitoring the acute course of disease and efficacy of treatment interventions. Currently, most patients are monitored by clinical and radiological examination, and physiological monitoring is usually reserved for patients in the intensive care environment. There is no doubt that monitoring physiological parameters, such as the intracranial pressure (ICP), can be prognostically useful; however, in many ways, the ICP represents a marker of endorgan injury, and one of the fundamental problems in the management of neurotrauma has been demonstrating that therapy aimed at reducing the ICP is converted into an improvement in clinical outcome. Likewise, monitoring brain tissue oxygenation can be potentially useful; however, this only provides information from a very small focal area, and the same can be said of microdialysis. Therapeutic intervention based on information gained from any of these monitors is reactive, and what is really required is some marker of the developing pathophysiology

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such that a more targeted proactive intervention can be initiated. It is in this regard that biomarkers may be potentially useful; however, currently there have been relatively few clinical studies. S100 calcium-­binding protein B (S100B) is probably the most extensively studied biomarker; however, the evidence for clinical efficacy remains to be established. Ideally, biomarkers would provide point-of-care monitoring that reflects the cellular fate of different cells or cell compartments, such as glial cells, axons or synapses, and the current evidence of the various markers will now be outlined.

16.4 Current Evidence This section will not cover all TBI biomarkers but will focus on the most studied diagnostic and prognostic blood-based biomarkers. Currently, cerebrospinal fluid sampling cannot be considered clinically appropriate in patients with mTBI.

16.5 Protein Biomarkers Traditionally, proteins have been the most studied biomarker group because of their widespread use in a variety of disease processes, and the laboratory analytics has evolved accordingly.

16.6 N  euronal Cell Body Biomarkers 16.6.1 Neuron-Specific Enolase (NSE) This is also known as gamma-enolase or enolase 2, and it is the most studied biomarker of neuronal cell body injury. NSE has mass of 78 kDa and is coded by the ENO2 gene. Despite its name, NSE is also expressed in erythrocytes and neuroendocrine cells and is present as homodimer in neuronal cytoplasm. The main limitation in using NSE as a biomarker of neuronal injury is its high sensitivity to haemolysis, which is particularly problematic when assessing NSE in the CSF (in

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the context of a traumatic lumbar puncture) or in case of polytrauma. Because of these issues, there is limited interest in using NSE as a diagnostic and prognostic TBI biomarker. There is insufficient evidence to support the use of NSE in either identifying patients with mTBI or assessing the need for imaging after a mTBI, but it has some value in predicting mortality after a severe TBI [7].

16.6.2 Ubiquitin C-Terminal Hydrolase-L1 (UCH-L1) This protein is extremely abundant in the brain, where it is estimated to make up 1–5% of total neuronal protein. It is involved in both adding and removing ubiquitin from proteins, which are targeted for internal metabolism within cells. UCH-L1 has a mass of 25 kDa and is coded by the UCH-L1 gene. Expression of UCH-L1 outside the CNS has been reported in cells of the testis, ovaries and kidney, as well as in certain lung tumour cell lines. UCH-L1 has gained interest as a counterpart of glial fibrillary acidic protein (GFAP), because they are thought to be surrogate markers for neuronal and astroglial injury burden, respectively. UCH-L1 is detectable within 1 h from TBI, peaks at 8 h [8]) and exhibits a short half-life compared to other TBI biomarkers (reports of half-life vary between 7 and 12 h). There are studies showing that UCH-L1 is able to identify patients with concussion, but there are also reports that UCH-L1 is unable to differentiate between patients with CT-negative mTBI and patients with orthopaedic injuries. The strongest evidence for using UCH-L1  in TBI diagnostics is its utility in identifying patients who require an acute CT following mTBI.  A recent study reported high sensitivity of GFAP and UCH-L1 for the prediction of traumatic intracranial lesions on head CT.  However, the added value of UCH-L1 on the performance of GFAP was modest [1]. Nevertheless, several studies have shown moderate diagnostic value of UCH-L1  in these circumstances, although its ­performance has generally been lower than that

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of GFAP [9]. UCH-L1 has also been reported to be predictive of unfavourable outcome after severe TBI, but studies in patients with mTBI are scarce [3]. Overall, there is insufficient evidence to support the use of UCH-L1  in identifying patients with mTBI, but it has some value in identifying patients who are likely to have positive findings on an acute head CT scan or who are likely to have an unfavourable outcome after severe TBI.

16.7 Axonal and Axon Terminal Biomarkers 16.7.1 Neurofilament Light Polypeptide (NF-L) Also known as neurofilament light chain, NF-L is the smallest of the three neurofilament subtypes (68  kDa) and abundantly expressed in the long myelinated axons. In humans, NF-L is encoded by the NEFL gene and is expressed in the neuronal cytoskeleton. The half-life of NF-L is unknown, but it is obvious that it is the longest of the currently known protein TBI biomarkers. Levels of NF-L seem to increase over the first 2 weeks after injury but appear to decrease thereafter [10, 11]. Based on the current body of literature, it is impossible to draw conclusions whether this is related to extended release from the brain or slow breakdown. Though the expression of NF-L has not been reported outside the CNS, there is evidence that extracranial injuries may affect its levels [2]. NF-L has been mostly studied in the subacute phase following mTBI. Admission levels of NF-L have been reported to be significantly correlated with late outcome after mTBI [4, 12] and severe TBI [4, 10]. In predicting incomplete recovery following mild TBI, NF-L somewhat outperforms GFAP [12]. Though the most robust diagnostic evidence of NF-L is related to outcome prediction, levels of NF-L also perform well in discriminating patients with normal and abnormal intracranial findings on head CT in patients with TBI upon admission [2]. This suggests that although NF-L levels con-

tinue to rise for several days after TBI, NF-L has diagnostic potential from day 1 following the injury.

16.7.2 Tau Tau is a microtubule-associated protein expressed in the axonal cytoskeleton. Tau stabilises and stiffens microtubules but has also functional roles. Human tau is encoded by the MAPT gene, resulting in a series of six tau protein isoforms. Most of the tau biomarker research in the neurotrauma field has focused on the total tau (t-tau). TBI results in both hyperphosphorylation and cleavage of tau proteins. Therefore, research interest has arisen for both cleaved tau (c-tau) and phosphorylated tau (p-tau). The current body of literature is inadequate to provide evidence for half-life of tau after TBI. Levels of tau appear to peak before 24  h, but the levels decrease relatively slowly. P-tau and t-tau levels and p-tau/t-tau ratio are reported to discriminate between patients with mTBI and healthy volunteers [13]. Both t-tau [2, 9] and p-tau and p-tau/t-tau ratio [13] have been reported to discriminate between patients with traumatic intracranial findings on head CT scans and patients with normal imaging findings after head injury. Tau appears to have diagnostic value in identifying patients with traumatic intracranial findings in isolation but also as part of a biomarker panel. A combination comprising heart fatty acid-binding protein + S100B + t-tau could identify mTBI patients with traumatic head imaging findings with clinically useful accuracy [2]. Tau levels have been shown to predict outcome following TBI, although studies have been conducted mainly in cohorts with more severely injured patients. The p-tau levels and p-tau/t-tau ratio outperformed the t-tau level in discriminating patients with favourable and unfavourable outcome [13]. Overall, there is insufficient evidence to support the use of tau in identifying patients with mTBI or unfavourable outcome. There is preliminary evidence to support the use of tau in ­identifying patients with traumatic intracra-

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nial findings following TBIs of different severities.

16.8 Astroglial Biomarkers 16.8.1 Glial Fibrillary Acidic Protein (GFAP) GFAP is a cytoskeletal monomeric filament protein present in astrocytes located both in white and grey matter. GFAP is coded by the GFAP gene in humans and is also expressed in non-glial and non-CNS cells, such as Schwann cells, chondrocytes, fibroblasts, myoepithelial cells, lymphocytes and liver stellate cells. GFAP is released into the bloodstream both as an intact protein (50 kDa) and as breakdown products (38–44 kDa) after TBI. It is detectable within 1 h after injury and peaks within 20–24 h with a biological half-­ life of 24–48 h [8]. GFAP is currently the most studied TBI biomarker, and it has gained special interest due to its specificity to TBI and relatively long half-life compared to other biomarkers. The Food and Drug Administration recently approved GFAP and UCH-L1 to be used to screen for patients who require an acute head CT scan following a TBI. The study on which this approval was granted showed that the results were driven largely by GFAP [1]. There is evidence that GFAP can identify patients with concussion and mTBI and can discriminate these patients from healthy individuals and patients with orthopaedic injuries. GFAP has been shown to be able to discriminate between patients with positive and negative CT brain scan findings in almost every study that has investigated this issue, and the scientific evidence in this regard can be considered the strongest of all current biomarkers. In a recent study, GFAP outperformed S100B, NSE, UCH-L1, neurofilament light (NF-L) and t-tau in identifying patients with traumatic intracranial abnormalities, both in patients with mTBI and among the whole cohort [9]. GFAP has also shown promise in predicting unfavourable outcomes in patients with TBIs of all severities [14] and also in predicting an incomplete recovery in patients with mTBI [12].

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Overall, there is some evidence to support the use of GFAP in identifying patients with mTBI. There is a large body of evidence to support the use of GFAP in identifying patients who are more likely to have traumatic intracranial findings on imaging and in predicting unfavourable outcomes after severe TBI.  There is some evidence to support the use of GFAP in predicting the outcome after mTBI.

16.8.2 S100 Calcium-Binding Protein B (S100B) S100B was the first biomarker to gain major attention in TBI diagnostics. It is an astroglial, 11 kDa calcium-binding protein, which is coded by the S100 gene. S100 proteins are involved in the regulation of a vast number of processes, such as cell cycle progression and differentiation. S100B levels are detectable in blood within 1 h of TBI, but the levels decline rapidly with a biological half-life ranging from 30 min to 2 h. S100B is expressed in many extracerebral cells, such adipocytes and chondrocytes. Blood levels of S100B increase in various sporting activities, and they are also increased in patients who sustain extracranial injuries. There are studies reporting that S100B can identify patients with concussion, but the evidence is somewhat conflicting, and some studies have found that S100B is unable to differentiate between patients with mTBI and patients with orthopaedic injuries. Notwithstanding these issues, S100B is the only biomarker that has been incorporated in a clinical guideline [6]. In these guidelines, an S100B level of less than 0.1 ug/L can be used as part of a management algorithm to rule out the need for head CT in patients with isolated mild head injuries with low clinical risk for intracranial bleeding when they are seen within 6 h of the injury. S100B has an excellent negative predictive value for pathological intracranial CT findings in this selected group of patients. However, S100B cannot be used in isolation as a screening tool. S100B also has prognostic value in patients with severe TBI.

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Overall, there is insufficient evidence to support the use of S100B in identifying patients with mTBI.  S100B has an excellent negative predictive value for pathological intracranial CT findings in a selected group of patients with mTBI.  There is insufficient evidence to support S100B in the outcome prediction of TBI.

16.9 Metabolomic and Lipidomic Biomarkers Protein biomarkers have partially failed to fill the expectations in TBI medicine. The main problems can be attributed to specificity for TBI and the brain and the inability to pass an intact BBB.  There is a clear need for comprehensive TBI-specific biochemical profiling and individual fingerprint diagnostics. Metabolomics is a method that studies structures, functions and interactions of metabolites in cells, tissues and body fluids. The research of crosstalk between genetics and metabolomics produces a substantial amount of information. Analysing these vast amounts of information has become possible due to developments in systems medicine. Perhaps the best known metabolomics methodology is cerebral microdialysis, a targeted focal method. It is mostly based on assessing the lactate/ pyruvate ratio, though other metabolites have been measured. An increase in this ratio reflects a decrease in the oxidative mitochondrial metabolism and mitochondrial failure. Transition to anaerobic metabolism is associated with unfavourable outcomes in patients with severe TBI. Microdialysis is currently used as a routine monitoring tool in many large neurointensive care units. Proton nuclear magnetic resonance spectroscopy is widely applied in research. It is an extensively studied, quantifiable and reproducible method. However, the method has a limitation for TBI biomarker assessment due to its poorer micromolar concentration range and regional scope. Usually, methodologies in metabolomics are based on mass spectrometry combined with gas or liquid chromatography.

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Medium-chain fatty acids, decanoic and octanoic, and some sugar derivatives including 2,3-bisphosphoglyceric acid were strongly associated with the severity of TBI in a two-cohort study that was conducted as a discovery-­ validation setting, which is typical for metabolomics studies. In that study, metabolite levels in patients with mTBI followed the same pattern as in severe TBI, but the magnitude of change compared to controls was less than in severe TBI. As the secondary aim in the study, an outcome prediction model was developed with an area under the curve of the receiver operational characteristic (AUC) of 0.84. The added value of the model was studied together with the prognostic CRASH (Corticosteroid randomisation after significant head injury) model, which provides a prediction of mortality at 14  days and unfavourable outcomes (severe disability, vegetative or death) at 6 months based on clinical and radiological findings at presentation. The AUC of the CRASH model in isolation was 0.74. When the top-­ ranking metabolites, decanoic acid and pentitol-­ 3-­desoxy, were included in the CRASH model, the AUC reached 0.80 [15]. Lipidomics is a method that studies structures, functions and interactions of lipids in cells, tissues and body fluids. Lipids consist of a relatively small number of heterogeneous groups of lipid classes. Lipids in these classes tend to correlate with each other and change consistently in different conditions. Brain tissue is enriched with lipids, making up approximately half of the brain dry weight. Brain lipidomics is an interesting and emerging field in TBI research. Glycerophospholipids and sphingolipids are two important lipid groups that are involved in the neurotransmitter regulation and programmed cell death. They have lately gained interest as diagnostic biomarkers of TBI.  It is likely that lipidomics studies and combinations of metabolomics and lipidomics studies will provide new interesting diagnostic windows for TBI research, but currently the number of published studies is small. Currently, in terms of metabolic and lipidomic markers, there is only limited evidence to support the use of lactate/pyruvate ratio in

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microdialysis to predict unfavourable outcomes of patients with severe TBI in the intensive care unit setting.

16.10 Future Directions and Conclusions The recent large prospective international TBI studies CENTER-TBI and TRACK-TBI will produce many more important papers on potential TBI biomarkers. They will also offer good possibilities to look for biomarker correlations with clinical variables, imaging and outcomes. Yet, these studies do not offer a sufficient granularity of samples needed to capture the kinetics of biomarkers in different clinical situations. Considering the vast pathophysiological complexity of TBI, its very dynamic nature and the great variety of other factors, which may affect biomarker levels, true understanding of the role of different biomarkers will require large rich datasets to be analysed using machine learning approaches. The narrower the clinical question, and the more homogeneous the patient material studied, the more can be expected using only few well-validated markers. A major challenge will be to know what biomarkers and biomarker panels should be used in different clinical situations at different points of time. Most previous studies have focused in one time point, usually admission, which is only a snapshot of this highly dynamic and often evolving disease process. Furthermore, time to hospital admission in reality takes place at very variable intervals from the trauma event. The following is a tentative list of the research questions that have to be addressed to enable a better understanding of biomarkers in TBI: • The kinetics of different biomarkers after a TBI • Data on how the biomarkers enters the bloodstream in different clinical conditions • How different biomarkers correlate with each other, with clinical variables and with imaging characteristics

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• How demographic variables (age, gender, race), other injuries and different diseases affect the biomarker levels • How genetic properties affect biomarker levels and responses • What are the useful time windows for different biomarkers after a TBI, and what biomarkers produce significant complementary information when used together Rapid point-of-care panels of TBI biomarkers, where the results are analysed together with other available data using AI developed algorithms, will be the future of TBI medicine within the next decade. In order to reach the best results and a rapid development, all these should be entered into a common international database and server, which thus improves the diagnostic accuracy constantly based on machine learning. Financial Support Jussi P. Posti is funded by the Academy of Finland (grant 17379). Conflict of Interest  None declared.

References 1. Bazarian JJ, Biberthaler P, Welch RD, et  al. Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study. Lancet Neurol. 2018;17:782–9. 2. Posti JP, Takala RSK, Lagerstedt L, et al. Correlation of blood biomarkers and biomarker panels with traumatic findings on computed tomography after traumatic brain injury. J Neurotrauma. 2019;36:2178–89. 3. Thelin E, Al Nimer F, Frostell A, et  al. A Serum protein biomarker panel improves outcome prediction in human traumatic brain injury. J Neurotrauma. 2019;36:2850–62. 4. Lagerstedt L, Azurmendi L, Tenovuo O, Katila AJ, Takala RSK, Blennow K, et  al. Interleukin 10 and heart fatty acid-binding protein as early outcome predictors in patients with traumatic brain injury. ­ Front Neurol. 2020;11:376. 5. Plog B, Dashnaw M, Hitomi E, et al. Biomarkers of traumatic injury are transported from brain to blood via the glymphatic system. J Neurosci. 2015;35:518–26. 6. Undén J, Ingebrigtsen T, Romner B.  Scandinavian guidelines for initial management of minimal, mild and moderate head injuries in adults: an evidence and

178 consensus-based update. Scandinavian Neurotrauma Committee (SNC), editor. BMC Med. 2013;11:50. 7. Olivecrona M, Rodling-Wahlstrom M, Naredi S, et  al. S-100B and NSE are poor outcome predictors in severe traumatic brain injury treated by an ICP targeted therapy. J Neurol Neurosurg Psychiatry. 2009;80:1241–7. 8. Papa L, Brophy G, Welch R, et al. Time course and diagnostic accuracy of glial and neuronal blood biomarkers GFAP and UCH-L1  in a large cohort of trauma patients with and without mild traumatic brain injury. JAMA Neurol. 2016;73:551–60. 9. Czeiter E, Amrein K, Gravesteijn BY, et al. Blood biomarkers on admission in acute traumatic brain injury: Relations to severity, CT findings and care path in the CENTER-TBI study. EBioMedicine. 2020;56:1–11. 10. Shahim P, Gren M, Liman V, et al. Serum neurofilament light protein predicts clinical outcome in traumatic brain injury. Sci Rep. 2016;6:36791. 11. Shahim P, Politis A, van der Merwe A, et  al. Time course and diagnostic utility of NfL, tau, GFAp, and

J. P. Posti and O. Tenovuo UCH-L1  in subacute and chronic TBI.  Neurology. 2020;95:e623–36. 12. Hossain I, Mohammadian M, Takala RSK, et  al. Early levels of glial fibrillary acidic protein and neurofilament light protein in predicting the outcome of mild traumatic brain injury. J Neurotrauma. 2019;36:1551–60. 13. Rubenstein R, Chang B, Yue J, et  al. Comparing plasma phospho tau, total tau, and phospho tau-total tau ratio as acute and chronic traumatic brain injury biomarkers. Investigators and the T-T, editor. JAMA Neurol. 2017;74:1063–72. 14. Takala RSK, Posti JP, Runtti H, et al. Glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 as outcome predictors in traumatic brain injury. World Neurosurg. 2016;87:8–20. 15. Orešič M, Posti JP, Kamstrup-Nielsen MH, Takala RSK, Lingsma HF, Mattila I, et  al. Human serum metabolites associate with severity and patient outcomes in traumatic brain injury. EBioMedicine. 2016;12:118–26.

Erythropoietin, Progesterone, and Amantadine in the Management of Traumatic Brain Injury: Current Evidence

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Davi Jorge Fontoura Solla and Wellingson Silva Paiva

17.1 Introduction Neuroprotection represents the holy grail of traumatic brain injury management (TBI). As detailed elsewhere in this book, TBI is a global healthcare issue that leads to significant socioeconomic problems, which are likely to increase in the years to come. It is also recognized that the central nervous system response to trauma is complex and pathophysiologically heterogeneous. At the macroscopic level, areas of ischemia coexisting with mass lesions, contusions, and disturbances in CSF hydrodynamics, as well as areas where the brain parenchyma is relatively normal, can be observed. At the cellular level, there are innumerable parallel, interacting, and independent biological cascades and cellular reactions that are caused by the primary injury and amplified by secondary insults, such as hypoxia and hypotension. These include but are not limited to early neuronal energy failure, glial dysfunction, the generation of free radicals, prolonged cell depolarization, tissue and cell edema, neuroexcitotoxicity, disruption of the blood-brain barrier, disturbed calcium homeostasis, activation of coagulation and inflammatory pathways, and mitochondrial dysfunction.

D. J. F. Solla (*) · W. S. Paiva Department of Neurology, Division of Neurosurgery, University of Sao Paulo, Sao Paulo, Brazil © Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_17

The subsequent cell death leads to raised intracranial pressure (ICP), which is highly predictive of death and disability. Over the past few decades, management of raised ICP in the context of severe TBI has been at the forefront of medical and surgical therapy, and there is no doubt that measurement of ICP can provide useful information regarding the following: • Outcome prediction • Optimizing cerebral perfusion • The development of pathological lesions such as intracerebral hematomas However, one of the fundamental difficulties encountered in neurotrauma intensive care has been the inability to demonstrate that lowering the ICP by various therapeutic interventions is necessarily converted into an improvement in clinical outcome. For many years, patients were routinely hyperventilated, placed in a barbiturate coma, or more recently rendered hypothermic because these therapies were demonstrated to reduce the ICP.  However, notwithstanding the potential neuroprotective effects of barbiturates and hypothermia, the predominant mechanism by which these three therapies reduce the ICP is by cerebral vasoconstriction. Given the well-­ known deleterious effects that ischemia has on cerebral tissue, it is perhaps not entirely surprising that these therapies are used far more judiciously than in the previous years. 179

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These findings encouraged researchers to investigate potentially neuroprotective therapies that can mitigate some of the aforementioned deleterious cellular responses to trauma, and this is based on the premise that raised ICP is essentially a marker of end-organ injury. Once intracranial hypertension develops, most of the damage has already been done, and what is required are not so much therapies that can lower the ICP but rather therapies that prevent intracranial hypertension developing in the first place. Many researchers have undertaken a huge amount of laboratory and animal studies investigating not only the pathophysiological response to neurotrauma but also the potential neuroprotective agents that may mitigate some of the effects of this pathology. Many therapies that have shown potential in the laboratory have got as far as phase I and phase II clinical studies, but few have got as far as phase III trials, mainly because of failure of efficacy or toxicity. Currently, there are three agents that have been extensively investigated, and these are erythropoietin, progesterone, and amantadine. The aim of this chapter is to discuss the evidence currently available for these potentially neuroprotective agents.

is also known that blood transfusion is an independent risk factor for poor outcome in trauma due to its contribution to the following: • • • • •

Coagulopathy Electrolyte disturbance Immunosuppression and immunomodulation Hyperinflammation Multiple-organ failure, especially lung injury

One of the key problems in the anemia encountered in critically injured patients is that the production of endogenous erythropoietin is not increased sufficiently in response to the reduction in hemoglobin levels. These findings prompted researchers to conduct early randomized controlled trails investigating the efficacy of epoetin alfa (a synthetic erythropoietin) initially in critically ill, anemic patients [2]. The first randomized controlled trial (RCT) was double-blind and had a factorial design to compare the effects of erythropoietin at two transfusion thresholds (7 and 10 g/dL) on neurological recovery after moderate or severe TBI.  EPO dosage was an initial 500 IU/kg followed by two additional doses each day and then weekly for the next 2 weeks. A total of 200 patients were randomized in two centers in the USA within 6  h of injury. There was no difference in the primary outcome of favorable outcome, defined as a Glasgow Outcome Score 17.2 Erythropoietin (GOS) of 4 or 5, 6 months after injury. There was Erythropoietin (EPO) is a member of the type 1 also no difference in the secondary outcomes of cytokine superfamily and a glycoprotein hor- mortality, disability rating scale score, acute mone. A number of preclinical and animal stud- respiratory distress syndrome, infection, or ies had shown it to be potentially neuroprotective thromboembolic events. Finally, there was no due to its anti-inflammatory, anti-apoptotic, anti-­ interaction detected between EPO and the hemooxidative, angiogenic, and cytoprotective effects globin transfusion thresholds. The following year the EPO-TBI trial was on endothelial cells, neurons, and glial cells, which were independent of the effects on eryth- published, and this was a large double-blind, multicenter, high-quality RCT [3]. Within 24 h ropoiesis [1]. Interest increased in the use of erythropoietin of injury, 606 patients with moderate or severe as a neuroprotective agent following the observa- TBI were randomized to receive 40,000  IU of tion that there was a survival benefit for patients EPO once per week (for a maximum of three receiving erythropoietin as a means of avoiding doses) or placebo. The primary outcome based blood transfusion. For many years, it has been on the extended GOS (GOS-E) at 6 months and well known that anemia secondary to blood loss the findings of the trial was that there was no is common in critically injured trauma patients. It difference between the two arms. There was

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also no difference in the secondary outcomes (mortality included) and the occurrence of adverse events, such as thromboembolic events and acute kidney injury. There has subsequently been a number of other smaller, low-quality RCTs published that have provided mixed results [4, 5]. One of the major limitations has been the limited consensus regarding optimal dosaging regimes and timing and methodology of outcome assessments. Notwithstanding these limitations, these trials have contributed to a number of meta-analyses, all of which have consistently demonstrated lack of clinical efficacy [6, 7]. There has been a suggestion of a small reduction in mortality, but there is no encouraging evidence supportive of further trials. Considering the current evidence provided by high-quality clinical trials combined with the unclear mechanism of action and the absence of functional outcome benefit, there would appear to be insufficient evidence to recommend routine EPO in the management of TBI.

17.3 Progesterone The potential neuroprotective effect of progesterone originated from the observation that there seems to exist a gender difference in vulnerability to either stroke or TBI in humans in terms of both risk and outcome. This prompted researchers to propose that this could be due to the effect of sex steroid hormones. This belief was supported by early animal studies, suggesting that female rats recover better from TBI than male rats, including those with high endogenous progesterone (i.e., pseudopregnant) at the time of injury compared to untreated males. A systematic review of 18 animal studies and 480 experimental subjects suggested that progesterone was capable of reducing lesion volume in a dose-dependent manner if administered early (within hours) after injury [8]. A number of mechanisms have been demonstrated, in which the progesterone receptor has been shown to play a key role. These include the following:

• Inhibition of inflammatory cytokines • Prevention of blood-brain barrier disruption • Prevention of excitotoxicity and reduction of apoptosis • Control of vasogenic edema These findings prompted researchers to conduct clinical studies, and the first two phase II trials demonstrated promising findings that supported subsequent phase III trials. The ProTECT trial was the first human clinical trial and was published in 2007 as a phase II, double-blind RCT designed to evaluate the safety and potential efficacy of progesterone in patients with moderate to severe TBI within 11 h of injury [9]. One hundred patients admitted at a single center received intravenous progesterone (77 patients) or placebo (23 patients) for up to 3 days. There were no major safety concerns, and those receiving progesterone had a lower 30-day mortality rate. Seven of the 23 patients (30.4%) randomized to placebo died within 30 days of injury compared with 10 of 77 patients (13%) randomized to progesterone (relative risk [RR] 0.43; 95% confidence interval 0.18–0.99). It was also noted that a small subgroup of patients with a moderate TBI, who were randomized to the progesterone arm of the trial, were more likely to have better neurologic outcomes than those patients receiving placebo. In the following year, a small, placebo-­ controlled, double-blind RCT evaluating intramuscular progesterone for up to 5  days was published [10]. A total of 159 patients with a severe TBI, who arrived at a single center within 8 h of injury, were enrolled. The mortality rate in the progesterone treatment group was significantly lower at 6-month follow-up compared with the placebo group (18% versus 32%, P = 0.039). Functional outcomes were also more favorable in those patients randomized to the progesterone arm of the trial, and there was no significant increase in adverse events. Two other small, single-blind RCT were initiated between 2010 and 2013 [11, 12]. Both were conducted in single centers of Iran and evaluated progesterone for up to 5  days. Each included a total of 48 and 76 patients at the early phase after

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TBI and supposedly had diffuse axonal injury (as evaluated by a head CT only). The progesterone groups had better functional outcomes at 3–6 months after injury. The findings from these relatively small, phase II trials prompted researchers to continue with larger phase III trials, and two of these high-­ quality trials were published simultaneously in The New England Journal of Medicine in 2014. Both were double-blinded and multicentered. The SYNAPSE trial was multinational and included 1195 severe TBI patients, who were randomized within 8 h of injury to receive either intravenous progesterone for up to 5  days or a placebo [13]. The primary outcome based on the GOS at 6  months was similar between the two arms of the trial as was mortality and the incidence of adverse events. The ProTECT III trial, conducted in the USA, recruited moderate or severe TBI patients within 4 h of injury [14]. It was stopped for futility after 882 of the planned sample of 1140 patients underwent randomization. There was no difference between each arm of the trial group in the primary outcome of GOS-E at 6 months; however, phlebitis or thrombophlebitis was more frequent in the progesterone group. A preplanned secondary analysis of the ProTECT III also concluded that progesterone does not improve neuropsychological outcomes [15]. Following these large RCTs, a number of meta-analyses have been published, all of which consistently indicated that there was no evidence that progesterone treatment decreased the risk of mortality or unfavorable outcomes in TBI patients. Finally, the last version of a Cochrane review regarding progesterone in TBI concluded that there was no evidence for benefit in mortality or disability, but there was a possible harm (evidence of increase phlebitis in a single study, the ProTECT III) [16]. In conclusion, despite promising results from animal studies and early clinical trials, these findings have not been replicated in subsequent high-­ quality RCTs, and there is currently no rationale or evidence base for the routine administration of progesterone in the management of TBI.

17.4 Amantadine Amantadine is a dopamine agonist and N-methyl-­ D-aspartate (NMDA) receptor antagonist. Although initially used as an antiviral agent for influenza-A and thereafter as an anti-Parkinson agent, its off-label use as a neuroprotective medication is predicated on the assumption that TBI leads to neurotransmitter derangements in the dopaminergic and noradrenergic systems, which could be ameliorated through amantadine. Amantadine is one of the most commonly prescribed medications for TBI patients to enhance arousal and behavioral responsiveness [17]. The first human double-blind, placebo-­ controlled trial to assess the effect of amantadine was N of one study published in 1995 by Van Reekum et al. in a patient with amotivational syndrome after TBI [18]. There were a total of four 2-week treatment periods (two with active medication, amantadine 100 mg three times daily, and two with placebo). Across four therapy cycles, and for both treatment pairs, a behavioral inventory score significantly favored the amantadine group, and there were no side effects. The first double-blind, placebo-controlled RCT was published in 1999 [19]. Using a crossover design at a single center, ten patients who had sustained a severe TBI were randomized in the acute phase to receive amantadine 100– 300  mg per day or a placebo. The study had a duration of 6 weeks (2 weeks for each arm interposed by a 2-week washout period). Neuropsychological outcomes representing orientation, attention, executive function, memory, and behavior were evaluated. No specific primary outcome was defined a priori. It was observed that some recovery could be attributed to the normal, expected recovery that occurs over time, but there was no significant effect of amantadine on clinical recovery. Another pilot double-blind, placebo-­ controlled, crossover design RCT by Meythaler et  al. suggested a benefit for amantadine [20]. Moderate and severe TBI patients were recruited at a single center within 24 h of injury to receive either 200 mg of amantadine per day or a placebo

17  Erythropoietin, Progesterone, and Amantadine in the Management of Traumatic Brain Injury: Current… 183

for a period of 6 weeks. After 6 weeks, there was outcome) NPI-I was similar between the groups. a blinded crossover and a total of 35 subjects Participant-rated NPI-I and physician-rated cliniwere enrolled. From a total of five primary out- cal global impression (CGI) were marginally sigcomes, four favored amantadine (Mini-Mental nificant (but not after multiple comparison Status Examination [MMSE], Disability Rating adjustment). The third paper reported a preScale [DRS], GOS, and FIM cognitive score). No planned sub-study of the Amantadine Irritability between-group differences were observed for the Multisite Study, in which 119 individuals with 2 Galveston orientation and amnesia tests, and no or more neuropsychological measures greater serious adverse side effects were reported. than 1 standard deviation below normative means A larger and higher-quality amantadine trial were evaluated regarding cognitive functioning at was published in 2012 [21]. In a multicenter, 28 and 60 days after randomization. A battery of double-blind, placebo-controlled RCT, inpatient neuropsychological tests (composite indices of vegetative or minimally conscious patients, who general cognitive index, learning memory index, had sustained a serious TBI, were recruited attention/processing speed index) revealed no 4–16 weeks after their injury. One hundred and amantadine effect. In fact, in the first 28  days, eighty four patients were randomized to receive amantadine appeared to have impeded cognitive either amantadine 200–400  mg per day or pla- processing. Other adverse events didn’t differ cebo over the course of 4  weeks. Functional between groups in the latter three studies. recovery, measured through the primary outcome The most recent RCT on amantadine for TBI DRS score, was significantly faster in the aman- was conducted at a single center by Ghalaenovi tadine group during the treatment period. et  al. in 2018 [25]. It was a double-blind, conHowever, the overall improvement in DRS scores trolled RCT with 40 severe TBI patients. They from baseline to week 6 (2 weeks after treatment were randomized as soon as oral feeding was was discontinued) was similar in the two groups. started (1–10  days) to receive amantadine An improvement in the Key Behavioral 200  mg/day or placebo for a total of 6  weeks. Benchmarks on the Coma Recovery Scale-­ After 6  months, MMSE, GOS, DRS, and KPS Revised was observed at 4 weeks. No safety con- were not improved by amantadine. cerns were detected. Overall, recently published systematic reviews Three sequential double-blind, placebo-­ and meta-analyses have concluded that no reccontrolled RCTs by Hammond et  al. were pub- ommendation could be made regarding the use of lished in the following years, investigating the amantadine due to important sources of bias in efficacy of amantadine in patients with chronic the studies and a lack of standardization regardTBI (defined as more than 6  months following ing clinical outcome and safety assessment the initial injury) [22–24]. The first study was [26–28]. conducted at a single center, and the findings sugCurrently, the evidence would suggest that gested a benefit for irritability and aggression more research is needed before amantadine can management with amantadine; however, the fol- be recommended in the acute phase of TBI lowing multicenter studies didn’t replicate these patients. For those at the subacute phase, a few findings. In the first, single-center study, 76 TBI months after TBI, amantadine could potentially patients referred for irritability management were accelerate the rate of recovery, but there is no evirandomized to receive amantadine or placebo for dence that the final functional outcome will be 28 days. Both primary outcomes, neuropsychiat- improved at the midterm or long term. For ric inventory irritability (NPI-I) and aggression chronic TBI patients, amantadine should not be (NPI-A), were significantly improved with aman- routinely recommended. Although there is a tadine. The second trial, the Amantadine doubtful physician-observed improvement in Irritability Multisite Study, randomized 168 irritability and aggression, the patient caregivers patients to receive amantadine 200  mg/day or didn’t observe the same advance, and there is placebo for 60 days. The observer-rated (primary also a potential for cognition prejudice.

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17.5 Future Directions

References

Overall, despite promising laboratory and animal studies conducted that have investigated a multitude of potential neuroprotective agents over the past 30 years, it has currently not been possible to convert these preclinical findings into a clinically effective neuroprotective agent. The reasons for this may be multifactorial; however, there can be little doubt that neurotrauma researchers remain constrained by the “heterogeneity paradox” as outlined in Chap. 19 on hypothermia. This paradox reflects the observation that:

1. Lykissas MG, Korompilias AV, Vekris MD, et al. The role of erythropoietin in central and peripheral nerve injury. Clin Neurol Neurosurg. 2007;109:639–44. 2. Robertson CS, Hannay HJ, Yamal JM, et al. Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial. JAMA. 2014;312:36–47. 3. Nichol A, French C, Little L, et  al. Erythropoietin in traumatic brain injury (EPO-TBI): a doubleblind randomised controlled trial. Lancet. 2015;386: 2499–506. 4. Min LZ, Lei XY, Xin ZJ, et al. Recombinant human erythropoietin improves functional recovery in patients with severe traumatic brain injury: a randomized, double blind and controlled clinical trial. Clin Neurol Neurosurg. 2016;150:80–3. 5. Bai XF, Gao YK. Recombinant human erythropoietin for treating severe traumatic brain injury. Medicine (Baltimore). 2018;97:e9532. 6. Motao Liu WAJ, Yu C, et  al. Efficacy and safety of erythropoietin for traumatic brain injury. BMC Neurol. 2020;20:399. 7. French CJ, Glassford NJ, Gantner D, et  al. Erythropoiesis-stimulating agents in critically Ill trauma patients: a systematic review and meta-­ analysis. Ann Surg. 2017;265:54–62. 8. Gibson CL, Gray LJ, Bath PMW, et al. Progesterone for the treatment of experimental brain injury; a systematic review. Brain. 2008;131:318–28. 9. Wright DW, Kellermann AL, Hertzberg VS, et  al. ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med. 2007;49:391–402. 10. Xiao G, Wei J, Yan W, et al. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Crit Care. 2008;12:1–10. 11. Shakeri M, Boustani MR, Pak N, et al. Effect of progesterone administration on prognosis of patients with diffuse axonal injury due to severe head trauma. Clin Neurol Neurosurg. 2013;115:2019–22. 12. Soltani Z, Shahrokhi N, Karamouzian S, et al. Does progesterone improve outcome in diffuse axonal injury? Brain Inj. 2017;31:16–23. 13. Skolnick BE, Maas AI, Narayan RK, et al. A clinical trial of progesterone for severe traumatic brain injury. N Engl J Med. 2014;371:2467–76. 14. Wright DW, Yeatts SD, Silbergleit R, et al. Very early administration of progesterone for acute traumatic brain injury. N Engl J Med. 2014;371:2457–66. 15. Goldstein FC, Caveney AF, Hertzberg VS, et al. Very early administration of progesterone does not improve neuropsychological outcomes in subjects with moderate to severe traumatic brain injury. J Neurotrauma. 2017;34:115–20.

• Acute traumatic brain injury is a very heterogeneous disease with multiple evolving pathologies (as detailed previously). • Most potential neuroprotective agents are evaluated in a homogeneous fashion, i.e., as a single agent compared with a placebo. • Long-term clinical recovery and the effect that this has on a patient’s quality of life are extremely varied and heterogeneous. • The assessment of clinical efficacy of many neuroprotective agents is not standardized, and therefore outcome is often limited to fixed, homogeneous factors such as mortality. In order to address some of these issues, an alternative to the evaluation of potentially neuroprotective drugs may be required. Finally, if the pharmacological response to neurotrauma is to become more sophisticated, so must the assessment of efficacy. Mortality reduction is obviously important, but mitigating some of the neurocognitive, behavioral, and psychological effects of neurotrauma, even if this is relatively modest, will go some way to reducing the global burden of TBI.  In order to achieve this, assessments must be standardized in both quality and timing, and this must be the focus of subsequent research. Financial Support No financial support has been required for this work. Conflict of Interest  None declared.

17  Erythropoietin, Progesterone, and Amantadine in the Management of Traumatic Brain Injury: Current… 185 16. Ma J, Huang S, Qin S, et al. Progesterone for acute traumatic brain injury. Cochrane Database Syst Rev. 2016;12:CD008409. 17. Hammond FM, Barrett RS, Shea T, et al. Psychotropic medication use during inpatient rehabilitation for traumatic brain injury. Arch Phys Med Rehabil. 2015;96:S256–S273.e14. 18. Van Reekum R, Bayley M, Garner S, et  al. N of 1 study: amantadine for the amotivational syndrome in a patient with traumatic brain injury. Brain Inj. 1995;9:49–54. 19. Schneider WN, Drew-Cates J, Wong TM, et  al. Cognitive and behavioural efficacy of amantadine in acute traumatic brain injury: an initial double-blind placebo-controlled study. Brain Inj. 1999;13:863–72. 20. Meythaler JM, Brunner RC, Johnson A, et  al. Amantadine to improve neurorecovery in traumatic brain injury-associated diffuse axonal injury: a pilot double-blind randomized trial. J Head Trauma Rehabil. 2002;17:300–13. 21. Giacino JT, Whyte J, Bagiella E, et  al. Placebo-­ controlled trial of amantadine for severe traumatic brain injury. N Engl J Med. 2012;366:819–26. 22. Hammond FM, Bickett AK, Norton JH, et  al. Effectiveness of amantadine hydrochloride in the reduction of chronic traumatic brain injury irri-

tability and aggression. J Head Trauma Rehabil. 2014;29:391–9. 23. Hammond FM, Sherer M, Malec JF, et al. Amantadine effect on perceptions of irritability after traumatic brain injury: results of the amantadine irritability multisite study. J Neurotrauma. 2015;32:1230–8. 24. Hammond FM, Sherer M, Malec JF, et al. Amantadine did not positively impact cognition in chronic traumatic brain injury: a multi-site, randomized, controlled trial. J Neurotrauma. 2018;35:2298–305. 25. Ghalaenovi H, Fattahi A, Koohpayehzadeh J, et  al. The effects of amantadine on traumatic brain injury outcome: a double-blind, randomized, controlled, clinical trial. Brain Inj. 2018;32:1050–5. 26. Hicks AJ, Clay FJ, Hopwood M, et  al. Efficacy and harms of pharmacological interventions for neurobehavioral symptoms in post-traumatic amnesia after traumatic brain injury: a systematic review. J Neurotrauma. 2018;35:2755–75. 27. Ter Mors BJ, Backx APM, Spauwen P, et al. Efficacy of amantadine on behavioural problems due to acquired brain injury: a systematic review. Brain Inj. 2019;33:1137–50. 28. Hicks AJ, Clay FJ, Hopwood M, et  al. The efficacy and harms of pharmacological interventions for aggression after traumatic brain injury-systematic review. Front Neurol. 2019;10:1169.

Tranexamic Acid in the Management of Traumatic Brain Injury

18

Omar K. Bangash, Kwok M. Ho, and Stephen Honeybul

18.1 Introduction Tranexamic acid (TXA) is an antifibrinolytic. Structurally, it is a lysine analogue that inhibits the conversion of plasminogen to plasmin, thereby reducing its proteolytic action on fibrin clots. Its effect can be thought of as inhibiting fibrinolysis. In doing so, it stabilises established clots. There has been great interest in the use of TXA in the control of haemorrhage. A wide-­ ranging set of clinical indications have been considered, including postpartum haemorrhage, dental procedures, elective surgery such as orthopaedic and spinal surgery, trauma and more recently traumatic brain injury (TBI). However, there remains controversy regarding its clinical indications, efficacy and safety [1]. In this chapter, we will provide an overview of the coagulation cascade, current understanding of TBI pathophysiology and associated coagulopathy as well as the mechanism of TXA’s

O. K. Bangash (*) · S. Honeybul Department of Neurosurgery, Sir Charles Gairdner and Royal Perth Hospitals, Perth, WA, Australia e-mail: [email protected] K. M. Ho Department of Intensive Care Medicine, University of Western Australia, Perth, Western Australia, Australia e-mail: [email protected] © Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_18

action. We will then review the current evidence surrounding the use of TXA and in particular its use in TBI.

18.2 Coagulation and Coagulopathy in Traumatic Brain Injury In the 1960s, the “cascade” theory of blood coagulation was first described by Macfarlane, which was shortly followed by the description of the “waterfall” hypothesis by Davie and Ratnoff. These two concepts taken together outlined the formation of fibrinogen during haemostasis through a series of stepwise reactions, in which clotting factors act in pairs, one as an enzyme and the other as a substrate. Haemostasis begins when platelets aggregate in the subendothelial membrane in response to injury. In normal conditions, the coagulation system is kept under inhibitory control to avoid excessive intravascular thrombus formation. The balance between thrombosis and haemorrhage is maintained by a carefully controlled interaction between platelets, the vessel wall and the coagulation, anticoagulation and fibrinolytic systems. The tendency to thrombosis may occur if there is an increase in thrombogenic factors or a decrease in antithrombogenic factors. Likewise, certain pathological conditions may affect the haemostatic system, and 187

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these include, but are not ­limited to, trauma, surgery, sepsis or autoimmune conditions. Further disruption may occur following metabolic abnormalities such as hypoxia, hypothermia or extracorporeal circulation. In the context of trauma, uncontrolled haemorrhage is the leading cause of potentially preventable death. The tendency to excessive haemorrhage is often compounded when trauma patients develop a coagulopathy, the cause of which is often multifactorial and includes consumption of coagulation factors, platelet dysfunction and excessive fibrinolysis. The viscous cycle of coagulopathy, hypothermia and acidosis in a severely injured patient is often referred to as the lethal triad, and it is associated with a high mortality. A number of studies have shown that a coagulopathy is more common in trauma patients who have an associated TBI, and this is probably because the overall injury is likely to be more severe [2]. In these circumstances, progressive enlargement of intracranial haemorrhagic contusions may be a significant contributor to long-­term neurological morbidity and overall mortality. Whilst understanding of TBI-associated coagulopathy remains relatively limited, a number of factors are known to contribute. These include the following:

the reported prevalence varies from 10% to 97% [3, 4]. When a patient develops a coagulopathy, a tailored approach to address the problem is undertaken, including a variety of options such as the following: • • • • •

Recombinant factor VIIa Vitamin K Cryoprecipitate Fresh frozen plasma Platelets and more recently TXA

18.3 Tranexamic Acid

Tranexamic acid is an antifibrinolytic medication that is a trans-stereoisomer of 4-(aminomethyl) cyclohexanecarboxylic acid. It competitively blocks the lysine-binding sites on plasminogen, of which there are five. Of these five binding sites, only one has a high affinity for TXA. Binding of TXA inhibits plasmin formation and displaces plasminogen from the fibrin surface, preventing clot lysis. It is important to understand that its mechanism of action is to stabilise established clots as opposed to promoting clot formation (as is the common perception) [1]. Other potentially beneficial effects of TXA may occur because of the anti-inflammatory effects achieved by the reduc• Release of tissue factors from the injured brain tion of plasmin-mediated release of vasoactive • Protein C activation in response to shock peptides, including histamine and bradykinin [5]. • Cerebral hypoperfusion following raised Following intravenous administration of TXA, intracranial pressure peak plasma concentrations are observed rapidly • Hyperfibrinolysis [2] and subsequently decline in an exponential manner. It is distributed to all tissues and has been In patients who require neurosurgical inter- reported to have about 10% of the plasma convention, this coagulopathy may lead to greater centration in cerebrospinal fluid. The antifibrinoblood loss during surgery, which may increase lytic effect is thought to persist for up to 8 h after operating time and increase the risk of postopera- administration, and thereafter 90% is renally tive intracranial haematoma formation. excreted, unchanged within 24 h [5]. Notwithstanding these difficulties, there is no Contraindications to its use include severe clear consensus as to what constitutes TBI-­ renal impairment, hypersensitivity reaction, disassociated coagulopathy, and this is reflected in seminated intravascular clotting and previous the wide variance in which it is reported. A recent history of seizures. Seizures are a relatively rare prospective study of TBI-associated coagulopa- complication of TXA administration; however, thy found an incidence of about 35%; however, they have been reported in the context of cardiac

18  Tranexamic Acid in the Management of Traumatic Brain Injury

surgery, orthopaedic surgery, neurosurgery and obstetrics [5, 6]. A recent meta-analysis on the use of TXA during cardiac surgery found an incidence of 2.7% with an odds ratio of 5.39 (95% CI 3.29–8.85; P 13) without intracranial blood will receive the drug, exposing them to potential side effects without gaining benefit. Overall, this is an excellent trial conducted in a large challenging cohort of patients. A tremendous amount of data has been generated to guide further research. The implications for clinical practice though are unclear. The subgroup analysis of this important study revealed it is the mild-­ to-­moderate injury group that appear to benefit from TXA administration within 3  h of injury. However, the data does not appear conclusive and

18  Tranexamic Acid in the Management of Traumatic Brain Injury

definitive to establish the use of TXA in TBI guidelines, as there is a very real chance some patients may not benefit from the intervention and may be exposed to harm. Further work is required to help clarify the appropriate subset of patients for whom TXA may be indicated. The recently published out-of-hospital RCT comparing TXA vs placebo by Rowell and colleagues for moderate to severe TBI (GCS ≤ 12) is an important study that has shed further light on early administration, as well as providing further evidence to assess TXA efficacy in TBI [20]. A cohort of 966 patients had TXA or placebo administered within 2 h of injury. Patients were randomised to three groups, 1g bolus TXA out-of-hospital followed by 1g infusion over 8 h in hospital, out-of-­ hospital administration 2g TXA bolus only and thirdly placebo bolus with placebo infusion. Overall, preplanned primary analysis compared the combined TXA group (n  =  657) vs the placebo group (n  =  309) and found no significant improvement in the primary end point of 4 or more on the extended Glasgow Outcome Scale (65% of patients with TXA and 62% with placebo; P = 0.16). Furthermore, there was no reduction in secondary outcomes of mortality with TXA (14% vs 17%; 95% CI −7.9 to 2.1%) or progression of intracranial haemorrhage (16% vs 20%; 95% CI −12.8% to 2.1%).

a

b

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Seizure rate was higher in the bolus-only group (5% in the bolus only group, 2% in the bolus maintenance group and 2% in the placebo group). The illustrative case below serves to provide an example of a typical scenario often encountered in neurosurgical practice that may benefit from TXA administration. Illustrative Case A 36-year-old male was brought in by ambulance to the emergency department having had a fall whilst intoxicated about an hour prior. He was drowsy and inappropriate with a blood alcohol level of 0.18, though he was able to obey commands (E3, V4, M6). His initial computed tomography (CT) of the brain at 05.00 am demonstrated bifrontal contusions, though the basal cisterns remained patent (Fig. 18.1a). He was admitted to the neurosurgery ward for close observations, and he was loaded with anti-epileptic medication. He was subsequently noted to have a fall in conscious level, and was unable to follow commands. He required endotracheal intubation for airway management. Repeat neuroimaging reveals evolutions of the frontal contusions; however, the basal cisterns remained patent (Fig. 18.1b). He was transferred to the intensive care unit and an intracranial pressure (ICP)

c

Fig. 18.1  CT scan of the illustrative case showing progressive evolution of contusions at (a) 05.00 am, (b) 06.00 am and (c) 16.30 pm, respectively

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monitor was inserted. His initial ICP measurement was 25 mmHg, though with medical therapy including elevation of head, titrated sedation, hypertonic saline and paralysis, this was reduced to 17  mmHg. Initially, the ICP remained stable; however, from 15.00  pm onwards, there was a progressive rise despite maximal medical therapy. A repeat CT of brain revealed massive evolution of the bifrontal contusions with basal cistern effacement (Fig. 18.1c). He was urgently taken to the operating theatre for a bifrontal decompressive craniectomy. Despite an uneventful operation, he failed to make a recovery and died 12 days following his injury. The obvious clinical question is whether the administration of tranexamic acid on admission would have stabilised the contusions and prevented their maturation.

18.8 Future Directions To become part of the contemporary TBI treatment guidelines, further work is required to establish the risk-benefit profile of TXA.  The CRASH-3 trial has helped identify a subgroup of patients with mild-to-moderate (GCS 9–15) injury that may have a small mortality benefit. However, there are concerns regarding the possibility of harm with increased mortality observed with delayed administration of TXA as well as the potential for adverse effects, including the potential increase in thromboembolic complications and seizures. It could certainly be argued that given the time-sensitive nature of TBI and the relatively favourable side effect profile of TXA, there is now sufficient evidence to administer the drug for all mild-to-moderate TBI patients based on an experienced clinician’s judgement, either prior to neuroimaging or in cases where significant parenchymal contusions are identified. However, if the use of TXA is to continue for this subgroup, it is important to set up appropriate studies to monitor for clinical indications, efficacy and adverse events.

18.9 Conclusions Current evidence does not constitute grounds for the administration of tranexamic acid for all patients with traumatic brain injury. Tranexamic acid may provide a moderate benefit for a subset of patients with traumatic brain injury, particularly those with mild-to-moderate injury; however, they may also be exposed to the risk of adverse events, specifically an increased risk of seizures. Further work is required to better define the subset of patients who may benefit as well as to evaluate the long-term functional benefit in order to determine if there are patients who may be harmed. Conflict of Interest  None declared. Funding None. Financial Support  No financial support has been required for this research.

References 1. Lier H, Maegele M, Shander A. Tranexamic acid for acute hemorrhage: a narrative review of landmark studies and a critical reappraisal of its use over the last decade. Anesth Analg. 2019;129:1574–84. 2. Stein SC, Smith DH. Coagulopathy in traumatic brain injury. Neurocrit Care. 2004;1:479–88. 3. Laroche M, Kutcher ME, Huang MC, et  al. Coagulopathy after traumatic brain injury. Neurosurgery. 2012;70:1334–45. 4. Harhangi BS, Kompanje EJ, Leebeek FW, et  al. Coagulation disorders after traumatic brain injury. Acta Neurochir. 2008;150:165–75. 5. Yates J, Perelman I, Khair S, et  al. Exclusion criteria and adverse events in perioperative trials of tranexamic acid: a systematic review and meta-­ analysis. Transfusion. 2019;59:806–24. 6. Lin Z, Xiaoyi Z. Tranexamic acid-associated seizures: a meta-analysis. Seizure. 2016;36:70–3. 7. Lecker I, Wang DS, Whissell PD, et  al. Tranexamic acid-associated seizures: causes and treatment. Ann Neurol. 2016;79:18–26. 8. CRASH-2 Trial Contributors, Shakur H, Roberts I, et  al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-­ 2): a randomised, placebo-controlled trial. Lancet. 2010;376:23–32.

18  Tranexamic Acid in the Management of Traumatic Brain Injury 9. Morrison JJ, Dubose JJ, Rasmussen TE, et al. Military application of tranexamic acid in trauma ­emergency resuscitation (MATTERs) study. Arch Surg. 2012;147:113–9. 10. WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-­ partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017;389:2105–16. 11. Ioannidis JP.  Why most published research findings are false. PLoS Med. 2005;2:e124. 12. Michaeleen Doucleff. Overlooked drug could save thousands of moms after childbirth. Available at: https://www.npr.org/sections/goatsandsoda/2017/04/26/525639110/overlooked-drug-could-­ save-thousands-of-moms-after-childbirth 13. Gallagher J.  Postpartum haemorrhage: Cheap life saver ‘cuts deaths by a third’. Available at: https:// www.bbc.com/news/health-­39717694 14. Spahn DR, Bouillon B, Cerny V, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition. Crit Care. 2019;23:98. 15. Kozek-Langenecker SA, Ahmed AB, Afshari A, et al. Management of severe perioperative bleeding: guide-

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lines from the European Society of Anaesthesiology: First update 2016. Eur J Anaesthesiol. 2017;34: 332–95. 16. CRASH-3 Trial Collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-­ controlled trial. Lancet. 2019;394:1713–23. 17. Servadei F, Nanni A, Nasi MT, et  al. Evolving brain lesions in the first 12 hours after head injury: analysis of 37 comatose patients. Neurosurgery. 1995;37:899–906. 18. Cepeda S, Gómez PA, Castaño-leon AM, et  al. Traumatic intracerebral hemorrhage: risk factors associated with progression. J Neurotrauma. 2015;32:1246–53. 19. Can tranexamic acid (TXA) reduce death from traumatic brain injury? Available at: https://rebelem.com/ wp-­content/uploads/2019/10/CRASH-­3-­Infographic. png 20. Rowell SE, Meier EN, McKnight B, et  al. Effect of out-of-hospital tranexamic acid vs placebo on 6-month functional neurologic outcomes in patients with moderate or severe traumatic brain injury. JAMA. 2020;324(10):961–74.

Hypothermia in the Management of Traumatic Brain Injury

19

Stephen Honeybul

19.1 Introduction The role of therapeutic hypothermia remains a controversial subject; however, it is by no means a new concept. One of the most cited observations of its possible therapeutic value came from Napoleon’s chief surgeon, Baron Dominique Jean Larrey, during the French invasion of Russia in 1812. de Larrey observed that soldiers who were hypothermic and placed closer to a fire died faster than those who remained hypothermic. This may be one of the first instances in which hypothermia has shown to be protective in a significant group of trauma patients. Or it may that the more severely injured and therefore less mobile soldiers were placed nearer the fire and this represents one of the earliest demonstrations of selection bias. The aim of this chapter is to explore the history of therapeutic hypothermia and consider why some of the promising experimental and basic science evidence for efficacy has not necessarily been translated into clinical benefit.

S. Honeybul (*) Department of Neurosurgery, Sir Charles Gairdner and Royal Perth Hospitals, Perth, WA, Australia e-mail: [email protected] © Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_19

19.2 History of Therapeutic Hypothermia References to the clinical benefit of hypothermia can be found as far back as the ancient Egyptians. It was Hippocrates (circa 450 BC), who advised packing wounded soldiers in the snow to slow down the biological processes in order to avoid death. Total body cooling was used for tetanus treatment in the fourth and fifth century BC, and centuries later in 1650, a 22-year-old female by the name of Anne Greene survived hanging, proposedly because the sentence was carried out on a very cold day. She was brought down half an hour after her initial hanging and then began to show signs of life. She went on to make a full recovery, was pardoned, and subsequently went on to be married, have three children, and live a normal life. Notwithstanding these historical examples, contemporary interest in the clinical application of therapeutic hypothermia began in the 1930s when there were several case reports of drowning victims in freezing waters, who were successfully resuscitated despite prolonged asphyxia. In the late 1930s, it was Temple Fay who is credited with introducing therapeutic hypothermia to modern-day medicine when he published one of the first scientific papers relating to its clinical use. In 1938, he cooled (the term he used was refrigeration) a female with intractable pain from metastatic breast cancer, and he went on to repeat 197

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this method for other patients with malignancy-­ related pain. He reported good levels of pain control, and he subsequently developed the first cooling blankets, which could be adapted to include a hood for cooling the head. Unfortunately, this early pioneering work was interrupted by the Second World War, and this was especially regrettable, because the Nazi’s intercepted some of his work and incorporated his findings into some of the unethical experimentation that occurred in the concentration camps. The association with Nazi atrocities set back the field of therapeutic hypothermia many years, and it was not until the late 1950s that interest returned. A number of researchers investigated it use in a variety of clinical settings initially in animal studies where beneficial effects on the brain were demonstrated during cardiac surgery. There were also the first experimental traumatic brain injury (TBI) studies in dogs that demonstrated that hypothermia could control the intracranial pressure (ICP) by reducing cerebral blood flow and oxygen consumption. The promising results of these studies led to the expansion of hypothermia into clinical medicine, and the following years saw its use applied for aneurysm surgery, TBI, and following cardiac arrest. However, despite early enthusiasm, interest in its use subsequently declined mainly because of difficulty managing what at the time were unexpected side effects such as cardiac arrhythmias, coagulopathies, electrolyte disturbances, and the increased susceptibility to infection. During the 1970s, use of hypothermia fell largely out of favor; however, during the late 1980s and early 1990s, there was a resurgence of interest, predominantly in its neuroprotective properties following cardiac arrest. There followed numerous animal studies that demonstrated the neuroprotective effects of hypothermia, and a number of small clinical studies were published that seemed to show clinical benefit. However, it was really the two, outof-hospital cardiac arrest randomized controlled trials (RCTs) published in The New England Journal of Medicine in 2002 that cemented the use of hypothermia as a neuroprotective agent.

In the landmark trial by Bernard et al., 49% of the patients who had had an out-of-hospital cardiac arrest and were treated with hypothermia survived, compared with 26% of the control patients [1]. Following these trials, there was a real resurgence in interest, and it was almost assumed that hypothermia was clinically beneficial. Its use was expanded to include a number of clinical indications including: • • • • • •

Acute ischemic stroke Aneurysmal subarachnoid hemorrhage Spinal cord injury Intracranial infection Acute encephalography Acute traumatic brain injury

However, notwithstanding this expansion, it was increasingly apparent that hypothermia was associated with several significant complications. Until recently, the effects that these complications were having on long-term outcome were largely unknown especially in the context of traumatic brain injury. However, the results of recent RCTs have not only provided good evidence on which to base current practice but have also prompted a re-examination of the underlying pathophysiology in order to understand why continued use of this therapy must be more judicious.

19.3 The Pathophysiology of Traumatic Brain Injury The rationale for the use of therapeutic hypothermia in the context of traumatic brain injury is based on two pathophysiologically related, but clinically distinct, observations. The first observation is that hypothermia can reduce intracranial pressure which is known to be predictive of mortality and poor neurological outcome. The second observation is that experimental studies of hypothermia have demonstrated that it can mitigate many of the deleterious cellular responses that occur following trauma and can therefore potentially provide a degree of neuroprotection.

19  Hypothermia in the Management of Traumatic Brain Injury

These two observations prompted widespread use of hypothermia over the past three decades; however, evidence for clinical efficacy has not been forthcoming. Indeed, in order to appreciate the possible limitations of hypothermia in the context of neurotrauma, there are two concepts that require consideration. Firstly, there is the Monro-Kellie doctrine and the effects of hypothermia on cerebral blood flow. Secondly, there is the concept of neuroprotection and the limitations of the heterogeneity paradox.

19.3.1 The Monro-Kellie Doctrine Despite considerable advances in the management of traumatic brain injury, we are still bound by the Monro-Kellie doctrine which was first described over 200 years ago, and this is described in detail in Chap. 8. An appreciation of the doctrine provides an explanation as to why certain therapies that were once considered routine in the management of severe TBI are now used far more judiciously. For many years, the observation that hyperventilation, barbiturates, and hypothermia could consistently reduce intracranial pressure (ICP) led to these therapies being incorporated into several TBI management guidelines. This was based on the strong association between intracranial hypertension and poor outcome, and the rationale were that by lowering the intracranial pressure, cerebral perfusion would be improved and this in turn would prevent secondary brain injury and improve clinical outcome. However, notwithstanding the intuitive benefit of ICP control, the negative effects that these interventions have on cerebral blood flow suggest that use of these therapies has limitations. Despite the potential neuroprotective effects of barbiturates and hypothermia, the predominant mechanism by which these three therapeutic modalities can rapidly reduce intracranial pressure is by inducing cerebral vasoconstriction. Hyperventilation reduces the arterial carbon dioxide which in turn alkalinizes the CSF and induces a reflex vasoconstriction. Barbiturates and hypothermia depress neuronal activity and reduce cerebral metabolism, which leads to a

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reduction in cerebral blood flow and blood volume due to autoregulatory flow metabolism coupling, and the subsequent reduction in cerebral blood flow has been clearly demonstrated [2–4]. In view of the well-known deleterious effect that ischemia has on outcome, it is perhaps not entirely surprising that while these measures reduce intracranial pressure, they do not necessarily provide long-term clinical benefit [5, 6].

19.3.2 Neuroprotection and the Heterogeneity Paradox It is well established that TBI is an extremely heterogeneous disease process. At the macroscopic level there are areas of ischemia coexisting with mass lesions, contusions and disturbances in CSF hydrodynamics, as well as areas where the brain parenchyma is relatively normal. At the microscopic level, the cellular response to trauma is similarly diverse with varying degrees of tissue damage induced by: • • • • • • •

The generation of free radicals Prolonged cell depolarization Tissue and cell edema Numerous neuroexcitotoxicity cascades Disruption of the blood-brain barrier Disturbed calcium homeostasis Activation of coagulation and inflammatory pathways • Mitochondrial dysfunction A substantial amount of time and money has been invested into research regarding possible mechanisms whereby some of the damaging consequences of these pathological processes can be attenuated. Many therapies that have shown potential in the laboratory have got as far a phase I and even phase II clinical studies; however, considering the amount of resources invested in basic science research, the number of therapies that have reached phase III trials is extremely small. There may be a number of reasons why a single clinically effective neuroprotective agent has not been developed and the heterogeneity paradox

S. Honeybul

200 Table 19.1  The heterogeneity paradox and the approach to neuroprotection Traumatic brain injury A very heterogeneous problem Macroscopic appearances Normal brain Petechial hemorrhages Intra- and extra-parenchymal hemorrhages (EDH, SDH, ICH) Ischemia CSF hydrodynamic disturbances Altered cerebral autoregulation

Microscopic changes Tissue and cell edema Neuroexcitatory cascades Blood–brain barrier disruption Disturbance of calcium regulation Generation of free radicals Activation of inflammatory pathways Mitochondrial dysfunction

Blanket solution Hypothermia

goes some way to explaining the difficulties encountered (Table  19.1). The paradox reflects the observation that, as previously described, traumatic brain injury is a very heterogeneous process. However, efforts to develop a neuroprotective agent have almost exclusively been approached with single therapies that have initially been tested in isolation in the laboratory setting, often targeting one or two individual aspects of the aforementioned cellular responses. It is perhaps not surprising given the myriad of pathological processes that are often proceeding concurrently, independently, and sometimes interdependently that targeting one particular aspect of the response (e.g., excitotoxicity) is circumvented by another (e.g., inflammatory). It may be that future strategies aimed at neuroprotection may involve combination therapies aimed at influencing multiple aspects of the pathological process, simultaneously. It is in this regard that hypothermia was thought to have a possible role in neuroprotection because it challenges the heterogeneity paradox by acting as a blanket therapy that can attenuate many of the temperature-sensitive pathophysiological cascades and deleterious cellular responses at the same time [7]. These include but are not limited to: • Suppression of free radical production • Reduction in antioxidant production

Possible therapeutic solutions All shown to be potentially neuroprotective Tirilazad (anti-inflammatory) Methylprednisolone Progesterone Erythropoietin Amantadine Amphetamine and other promoters of neuroaminergic neurotransmission Magnesium sulfate Cerebrolysin Cyclosporin A Rivastigmine

• Stabilization of cell membranes • Reduction in the neuroexcitotoxicity response • Attenuation of the inflammatory response It was these promising preclinical findings that prompted researches to conduct several large well-designed randomized controlled trials to provide evidence that this is necessarily converted into clinical benefit.

19.4 Hypothermia: Clinical Evidence Over the past decade, there have been a number of high-quality trials that have investigated the clinical efficacy of hypothermia; however, none have demonstrated convincing benefit (Table 19.2). Some of the earlier trials have been criticized due to methodological flaws, which is in some part justified. In the National Acute Brain Injury Study: Hypothermia (NABISH:H 1), there was some variability in intercenter protocols and expertise, and there was a high incidence of hypotension, hypovolemia, and electrolyte imbalance in the treatment group [8]. The Hutchison pediatric trial showed a higher death rate in the hypothermia group. (23 [21%] of 108 patients in the hypothermia group died vs 14[12%] in the normothermia group.) There were also some randomization discrepancies, a short

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Table 19.2  Some of the important randomized controlled hypothermia trials in the field of traumatic brain injury (TBI) Trial Clifton et al. (2001) NABISH I trial (National Acute Brain Injury Study: Hypothermia I)

Design A multicenter RCT conducted at 11 sites in the USA. Adult patients aged 16–65 years with a severe TBI and a GCS of 3–8 were randomized within 6 h of injury to hypothermia (33 °C) which was maintained for 48 h or to standard care

Hutchison et al. (2008)

A multicenter RCT conducted at 17 centers in 3 countries. Children aged 1–17 years with a GCS of 8 or less were randomized within 8 h to hypothermia (32.5 °C) for 24 h or to standard care

Clifton et al. (2011) NABISH II trial (National Acute Brain Injury Study: Hypothermia II)

A multicenter RCT conducted at six centers in the USA. Adults aged 16–45 years were randomized within 2.5 h of injury if they were initially not responsive to instructions to hypothermia (initially 35 °C and then 33 °C if they met a second set of inclusion criteria) for 48 h or to standard care

Results 199 patients were randomized to hypothermia and 193 patients to standard care The outcome was poor (defined on the GOS as dead, vegetative, or severe disability) in 57% of the patients in both groups There was a higher incidence of complications in the hypothermia group 108 patients were randomized to hypothermia and 117 patients to standard care The outcome was poor (defined on the GOS as dead, vegetative, or severe disability) in 32 patients (31%) in the hypothermia arm and in 23 patients (22%) in the standard care arm There were more episodes of hypotension while rewarming in the hypothermia arm 119 patients were randomized to hypothermia (reduced to 52 who met the second set of inclusion criteria) and 113 patients (reduced to 45) to standard care The outcome was poor (defined on the GOS as dead, vegetative, or severe disability) in 31 patients (60%) in the hypothermia arm and in 25 patients (56%) in the standard care arm There was no difference in adverse events between the two arms The trial was terminated early due to futility

Mortality 53 (28%) hypothermia 48 (27%) standard care

23 (21%) hypothermia 14 (12%) standard care

12 (23%) hypothermia 8 (18%) standard care

(continued)

S. Honeybul

202 Table 19.2 (continued) Trial Adelson et al. (2013) Cool Kids trial

Design A multicenter RCT conducted at 15 sites in the USA, New Zealand, and Australia. Children younger than 18 years with a GCS of 3–8 (motor less than 6 after resuscitation) were randomized with 6 h to hypothermia (32–33 °C) for 48–72 h or to standard care

Andrews et al. (2015) Eurotherm3235

A multicenter RCT conducted at 47 sites in 18 countries. Adults with an ICP of more than 20 mmHg despite stage 1 treatments were randomized to hypothermia (32–35 °C) for at least 48 h or to standard care

Cooper et al. (2018) POLAR study

A multicenter RCT conducted at 14 sites in 6 countries. Adults aged 18–60 years with a GCS less than 9 and intubated (or imminent) were randomized by paramedics or emergency staff up to 3 h of injury to hypothermia (33 °C for 3 days, 35 °C if there are bleeding concerns) or to standard care

Results 39 patients were randomized to hypothermia and 38 patients to standard care The outcome was poor (defined on the GOS as dead, vegetative, or severe disability) in 16 patients (42%) in the hypothermia arm and in 18 patients (47%) in the standard care arm There was no difference in adverse events between the two arms The trial was terminated early due to futility 195 patients were randomized to hypothermia and 192 patients to standard care The outcome was favorable (defined as GOS-E of 5–8) in 49 patients (25.7%) in the hypothermia arm and in 69 patients (36.5%) in the standard care arm Serious adverse events were more common in the hypothermia arm Recruitment was suspended due to safety concerns 266 patients were randomized to hypothermia and 245 patients to standard care The outcome was favorable (defined as GOS-E of 5–8) in 117 patients (48.8%) in the hypothermia arm and in 111 patients (49.1%) in the standard care arm Adverse events were slightly more common in the hypothermia arm

Mortality 6 (15%) hypothermia 2 (5%) standard care

68 (34.9%) hypothermia 51 (26.6%) standard care

54 (21.1%) hypothermia 44 (18.4%) standard care

RCT Randomized controlled trial, GCS Glasgow outcome scale, ICP Intracranial pressure, GOSE Glasgow outcome scale, extended

cooling period of only 24 hours, and a fairly rapid rewarming with few facilities for treating rewarming complications [9]. The subsequent trials were methodologically more robust; however, they have also failed to demonstrate benefit. The NABISH II trial investigated early cooling within 2 h of injury, and the outcomes were worse in the hypothermia group although this was not statistically significant [10]. The “Cool Kids” trial was stopped on the

grounds of futility because hypothermia initiated early, used globally for 48–72 h, and with a slow rewarming did not reduce mortality at 3 months [11]. Indeed, there was again a non-statistical increase in mortality in the hypothermia group (6 [15%] of 39 patients in the hypothermia group vs 2 [5%] in the normothermia group). The Eurotherm study failed to show not only that hypothermia provided clinical benefit but also that there was a tendency to cause harm such that

19  Hypothermia in the Management of Traumatic Brain Injury

the trial also had to be halted early [12]. Sixty-­ nine (36.5%) of the 192 patients in the control group achieved a favorable outcome compared with 49 patients (25.7%) in the hypothermia arm of the trial. In addition, there was, again, an increased mortality in the hypothermia group (68 [34.9%] in the hypothermia group died vs 51 [26.6%] in the normothermia group). This was a well-conducted study, and while there may be some discussion regarding methodology, the pragmatic approach aimed to investigate efficacy in the context of routine clinical practice. As such, the results require careful consideration given that, as noted by the authors in their exclusion criteria, patients were excluded if they were already receiving therapeutic hypothermia. The implication would be that a number of centers have already adopted hypothermia into their routine clinical practice. Finally, the POLAR study conducted out of Australia was clearly designed with neuroprotection as its goal as patients were randomized and therapy was started by paramedics either in the field or in the hospital emergency department. The results of the trial were again no benefit in the hypothermia arm of the trial with a small, statistically non-significant increase in mortality [13]. Overall, given the findings of this study and the previous studies, this practice may need to be reconsidered in much the same way that the routine use of hyperventilation and barbiturate therapy has been re-evaluated over recent years.

19.5 Future Directions It is perhaps premature to abandon the use of hypothermia; however, based on the clinical evidence available, it is perhaps time to reconsider the direction of future research. The difficulties revolve around a number of key issues. In the first instance, the fundamental management strategies regarding timing, target temperature, duration, and rewarming have yet to be determined. Secondly, the question remains as to whether any clinical benefit is likely to be offset by the well-documented detrimental effect of complications.

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19.5.1 Management Strategies Among the various strategies that require consideration, the time between injury and initiating cooling would seem to be one of the most important issues. The animal studies that demonstrated the neuroprotective effect of hypothermia have commenced cooling either directly after trauma or within 2  h. Thereafter, most of the harmful cascades will have been initiated. While there is no doubt that hypothermia can lower the ICP due to its effect on cerebral blood flow, in order to provide neuroprotection, cooling must be initiated as soon as possible in order to prevent rather than treat the subsequent cerebral insults. This may limit the use of cooling in many trauma situations because of delays in resuscitation, transfer, and initial clinical and radiological assessment. This limitation was highlighted by the results of the POLAR study which was designed specifically to address this issue; however, for those patients randomized to the hypothermia arm of the trial, the time from injury to the initial temperature target of 35 °C was a median of 2.5 h (IQR, 0.8–5.5), and for 186 patients (71.5%), the time to reach the final temperature target of 33 °C was a median of 10.1 h (IQR, 6.8–15.9). If further trials are to be considered, some change in management strategies will be required in order to achieve more rapid cooling. A final consideration may be evaluating outcome in patients who present with hypothermia. In the NABISH II study, it was this subgroup that showed a tendency toward better outcomes, and this may be a useful avenue of future investigations.

19.5.2 Complications It is becoming increasingly apparent that the use of hypothermia causes significant complications and these will require better management if evidence from experimental studies is to be t­ranslated into clinical practice. Most notable complications include electrolyte disturbances, cardiac arrhythmias, coagulopathy, and infections most notably pneumonia [14]. It is notable that the number of adverse events reported in the large trials has reduced significantly over recent years, and this

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highlights the need to be vigilant when introducing new, potentially powerful neuroprotective agents. One such complication that has received increasing attention is that of reperfusion injury which is well known to cause considerable tissue damage following myocardial infarction. Indeed, it is the generation of free radicals that occurs following cardiac reperfusion that can sometimes cause more injury than the initial ischemic event. Over the past two decades, much attention has been focused on a slow controlled rewarming phase in order to prevent rebound intracranial hypertension in TBI; however, it may be beneficial to focus future research on potential neuroprotective agents that can attenuate any potential reperfusion injury. Finally, there are the significant implications when considering the altered metabolism of many of the drugs that are routinely used in the intensive care environment such as morphine, midazolam propofol, vecuronium, and phenytoin to name but a few. These drugs all have significant side effects in themselves, and altered metabolism, half-life, and interactions may have subtle deleterious effects on outcome. In summary, while the use of hypothermia as a neuroprotectant has been established in experimental models, clinical benefit in patients with traumatic brain injury has not been demonstrated. Despite these discouraging results, it is perhaps premature to consider abandoning this therapy. There is no doubt that hypothermia has a role in the context of intractable intracranial hypertension; however, its use must be tempered with the realization that this may come at cost in terms of outcome. What remains to be established are the therapeutic time frame and optimal management strategies that are most likely to be beneficial, and this must be the focus of future research. Conflict of Interest  None declared. Funding None.

References 1. Bernard SA, Gray TW, Buist MD, et  al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557–63.

S. Honeybul 2. Kassell NF, Hitchon PW, Gerk MK, Sokoll MD, Hill TR. Alterations in cerebral blood flow, oxygen metabolism, and electrical activity produced by high dose sodium thiopental. Neurosurgery. 1980;7:598–603. 3. Rosomoff HL, Holaday DA. Cerebral blood flow and cerebral oxygen consumption during hypothermia. Am J Physiol. 1954;179:85–8. 4. Sakoh M, Gjedde A.  Neuroprotection in hypothermia linked to redistribution of oxygen in brain. Am J Physiol Heart Circ Physiol. 2003;285:H17–25. 5. Ward JD, Becker DP, Miller JD, et al. Failure of prophylactic barbiturate coma in the treatment of severe head injury. J Neurosurg. 1985;62:383–8. 6. Curley G, Kavanagh BP, Laffey JG. Hypocapnia and the injured brain: more harm than benefit. Crit Care Med. 2010;38:1348–59. 7. Sahuquillo J, Vilalta A.  Cooling the injured brain: how does moderate hypothermia influence the pathophysiology of traumatic brain injury. Curr Pharm Des. 2007;13:2310–22. 8. Clifton GL, Miller ER, Choi SC, et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med. 2001;344:556–63. 9. Hutchison JS, Ward RE, Lacroix J, et al. Hypothermia Pediatric Head Injury Trial Investigators and the Canadian Critical Care Trials Group. Hypothermia therapy after traumatic brain injury in children. N Engl J Med. 2008;5:2447–56. 10. Clifton GL, Valadka A, Zygun D, et  al. Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): a randomised trial. Lancet Neurol. 2011;10:131–9. 11. Adelson PD, Wisniewski SR, Beca J, et al. Paediatric Traumatic Brain Injury Consortium. Comparison of hypothermia and normothermia after severe traumatic brain injury in children (Cool Kids): a phase 3, randomised controlled trial. Lancet Neurol. 2013;12:546–53. 12. Andrews PJ, Sinclair HL, Rodriguez A, Harris BA, Battison CG, Rhodes JK, et al. Eurotherm3235 Trial Collaborators. Hypothermia for intracranial hypertension after traumatic brain injury. N Engl J Med. 2015;373:2403–12. 13. Cooper DJ, Nichol AD, Bailey M, et al. Effect of early sustained prophylactic hypothermia on neurologic outcomes among patients with severe traumatic brain injury: the POLAR randomized clinical trial. JAMA. 2018;320:2211–20. 14. Kabadi SV, Faden AI. Neuroprotective strategies for traumatic brain injury: improving clinical translation. Int J Mol Sci. 2014;15:1216–36.

Decompressive Craniectomy in the Management of Traumatic Brain Injury

20

Sara Venturini, Peter Hutchinson, and Angelos G. Kolias

20.1 Introduction Traumatic brain injury (TBI) is a major health issue and contributor to morbidity and mortality globally, with an estimated 69 million individuals suffering TBI each year worldwide [1]. Despite these figures, the true incidence of TBI is likely to be greater than the reported numbers due to cases unaccounted for, especially in low- and middle-income countries. Patients with TBI suffer a primary injury at the time of trauma, but also secondary injuries that develop as a consequence of injury to the brain. These secondary insults are associated with worse clinical outcomes and increased mortality, requiring prompt recognition and treatment. Modern neurocritical care protocols focus on carefully monitoring the injured brain following TBI through objective parameters, including intracranial pressure (ICP), cerebral perfusion pressure, brain tissue oxygenation and others [2]. Sustained and severe intracranial hypertension, if left untreated, will eventually lead to brain herniation and death. Several studies have found intracranial hypertension to be associated with increased morbidity and mortality, and this is the

S. Venturini (*) · P. Hutchinson · A. G. Kolias Division of Neurosurgery, Department of Clinical Neurosciences, Addenbrooke’s Hospital and University of Cambridge, Cambridge, UK e-mail: [email protected] © Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_20

rationale behind a number of management strategies. Decompressive craniectomy (DC) is a relatively straightforward surgical procedure that involves removing a large section of the calvarium in order to provide extra space into which the injured brain can expand. It can be performed as a primary decompression after evacuation of a mass lesion, such as a subdural haematoma, if the brain is thought to be too swollen to safely replace the bone flap. Alternatively, it can be performed as a secondary procedure when a patient develops intracranial hypertension that does not respond to medical therapy. The aim of the procedure is to reduce intracranial pressure (ICP) by creating a large opening in the otherwise closed and rigid intracranial space, reducing the risk of cerebral herniation and ischaemia. Over the past three decades, it has been recognised as an important step in the management of TBI; however, controversies remain regarding its clinical indications, surgical timing and impact on long-term outcome. For example, DC has been used as a preventative measure to avoid high ICP [3] or as a later intervention for refractory intracranial hypertension [4]. In recent years, the rationale, techniques and effect of DC have been systematically studied; this chapter summarises the current evidence around this topic.

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20.2 Background Information 20.2.1 History Decompressive craniectomy is not a new surgical concept. There is evidence of procedures involving removal of a portion of the skull dating back to Ancient Egypt, Ancient Greece and the Roman times, where skull trephination was described as a treatment for patients who developed symptoms following head trauma [5]. In later years, scientific descriptions of hemicraniectomies intended to decrease ICP were documented in the late 1800s in France, and Kocher in the early 1900s described more systematically the concept of opening the cranium in order to treat raised intracranial pressure, and a number of various techniques were described.

20.2.2 Pathophysiology The role of DC in the management of closed traumatic brain injury is underpinned by the principles outlined by the Monro-Kellie doctrine, first described by Dr Monro and Dr Kellie over 200  years ago. The Monro-Kellie doctrine outlines that the intracranial space is a fixed volume confined by the rigid boundary of the skull where brain tissue, arterial and venous blood and cerebrospinal fluid exist in equilibrium at a normal ICP.  Increase in the volume of one component (e.g. brain haematoma) leads to disruption of the equilibrium. To compensate for an increase in one of the components and to maintain a constant ICP, the volume of another component must decrease (e.g. CSF), but if that is not sufficient, it leads to raised ICP and ultimately in brain herniation. When brain swelling and/or focal brain lesions in TBI result in increased intracranial pressure, ‘opening the box’ by performing a DC creates more space and controls the rising ICP.

20.3 P  ractical Aspects: Surgical Techniques, Indications and Patient Selection In current practice, a variety of surgical techniques exist and are based on local practice, resource availability and expertise. However, the following are common surgical techniques used for DC.

20.3.1 Hemicraniectomy Unilateral decompressive craniectomy or hemicraniectomy is useful where hemispheric brain swelling is present, such as in cases where the traumatic brain injury is more localised to one hemisphere. Radiologically, these patients usually have evidence of midline shift. For this operation, the patient is positioned with the head tilted slightly head up and rotated towards the contralateral side to the hemicraniectomy. It is important to avoid compromise of venous drainage by excessively rotating the head, and consideration should be given to lateral/semi-lateral positioning if there is a concern for cervical spine injury. The most common skin incision is a question mark incision starting at the zygoma, 1cm anterior to the tragus. It ascends superiorly curving around the pinna of the ear, extending backwards and then returning to the frontal area ending just across the midline behind the hairline. The length of the skin flap should not exceed the width of the base of the flap to preserve adequate vascular supply. A T-shaped incision is a reasonable alternative especially if there are lacerations that can be extended. The craniotomy is usually started with a burr hole at the key hole, and further burr holes can be used to facilitate access. The craniotomy is subsequently completed using a craniotome. The bone flap in this procedure, also called trauma flap, should be adequately large, and the recommended size is at least 11–12 cm in the AP diameter. Care should be taken to avoid bringing the medial cut to the midline in order to minimise

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the risk of injuring the sagittal sinus and/or bridging veins. The dura is opened with a curvilinear incision or multiple radial cuts, and evacuation of any haematomas then takes place. There is no need for a watertight sutured duraplasty. A layer of haemostatic material (e.g. sheet of Surgicel) or dural substitute can be left above the dura. A drain can be left deep to the temporalis, although suction should be avoided. The scalp is closed in layers.

feasible, which will allow division of the falx down to the crista galli. This manoeuvre provides an additional axis of brain expansion but may not always be feasible or necessary. It is also important to remove the temporal squama down to the middle cranial fossa floor, as one would do with a hemicraniectomy in order to ensure adequate decompression of the mesial temporal lobe and upper brainstem. The rest of the procedure is the same as described above for a hemicraniectomy.

20.3.2 Bifrontal Decompressive Craniectomy

20.3.3 Indications

A bifrontal decompressive craniectomy is often used in cases where there is diffuse brain swelling following traumatic brain injury. During this surgical procedure, the patient position on the operating table is supine with the head in neutral position and a mild degree of head elevation. Care should be taken to ensure the neck is not flexed too much to avoid venous compression. The head can often be supported with a horseshoe headrest, but fixation with a head clamp (Mayfield) is also a reasonable option, paying attention to any potential skull fractures. The skin incision for bifrontal DC starts 1cm anterior to the tragus, at the level of the zygoma (condylar point), runs superiorly just posterior to the coronal suture and terminates at the contralateral condylar point. A separate pericranial flap should be raised, as it can be used if there is a frontal sinus breach and the sinus needs to be cranialised. Otherwise, the scalp flap is then retracted anteriorly towards the supraorbital ridge. Burr roles are used bilaterally to start the craniotomy, usually three on each side: one above the zygomatic process, one behind the anterior end of the superior temporal line and one at the coronal suture lateral to the superior sagittal sinus. Care should be taken to dissect the dura away from bone flap, especially at the midline. A craniotome is used to complete the craniotomy joining the burr holes. The dura is opened separately on each side: with either a curvilinear incision as a flap (with its base on the superior sagittal sinus) or multiple radial cuts. The sagittal sinus can then be ligated, as anteriorly as technically

Recent large-scale studies have tried to strengthen the evidence base to provide robust evidence on the specific role of decompressive craniectomy. As previously mentioned, decompressive craniectomy can be performed as a primary or secondary procedure. Patient with mass lesions, such as acute subdural haematomas that require evacuation, may undergo a DC at the time of evacuation of the haematoma; this is termed primary DC, and here, the bone flap is left out either because there is significant brain swelling that prevents safe replacement of the bone flap at the end of the above procedure or because it is anticipated that brain swelling will worsen in the ensuing days [6]. Patients who have diffuse brain swelling and/or multifocal contusions occasionally require a DC; this can be either after a period of medical management of raised ICP (this is known as secondary DC) or early after admission when a patient develops clinical or radiological features of raised intracranial pressure. Use of DC in the latter scenario is more commonly prevalent in resource-limited settings, as the ability to monitor and manage raised ICP with medical means is limited. A secondary DC is usually part of a tiered approach to treat post-traumatic intracranial hypertension. In these cases, it is recommended to utilise ICP monitoring where available in conjunction with other clinical parameters such as patient examination, imaging and other monitoring modalities to guide decision-making. It is important to involve family members in discussions regarding surgical decompression because it is now well established that there are

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important issues to consider regarding outcome and these are discussed in the ethical section of this book [7].

20.3.4 Patient Selection Patients suffering severe traumatic brain injury are nowadays often treated in dedicated neurointensive care units, and the availability of such units in resource-limited setting is scarce. Treatment algorithms commonly comprise interventions delivered in a tiered manner, aimed at lowering ICP and maintaining adequate cerebral perfusion pressure. Patients are looked after by a multidisciplinary team involving neurosurgeons, intensive care doctors and allied professionals. Together, this team determines the need to proceed with a secondary decompressive craniectomy, if ICP is becoming refractory to standard measures and assuming that a primary DC has not already been undertaken. If a patient requires a secondary DC, coordination of actions required to transfer the patient safely from the intensive care unit to the operating theatre for surgery is required, bearing in mind that these patients are often unstable. Attention needs to be placed on ensuring the safety of the procedure, which involves evaluation of laboratory parameters including platelet count, coagulation profile, blood typing and other physiological abnormalities which may require correction prior to surgical intervention. Intra-operatively, it is important to maintain the ICP-lowering treatments and avoid an increase in the partial pressure of carbon dioxide and sudden changes in the systemic arterial blood pressure in order to minimise the risk of intra-operative malignant brain swelling.

20.4 After Decompressive Craniectomy 20.4.1 Specific Aspects of Care After Decompressive Craniectomy In the short term, patients who have had a bone flap removed during DC need to be cared for by trained staff aware of the practical steps involved

in the management of this patient group. DC leaves the underlying brain without a rigid protective layer, therefore making it more vulnerable to injury. Patients should not be turned to rest their head on the side of the decompressive craniectomy, and care should be used not to put pressure on the area without bone flap. As patients recover and rehabilitate to regain function and reintegrate into society, they require education to take care of their craniectomy site to avoid further injury, until a cranioplasty is performed. Patients who are prone to falling frequently or those with recurrent generalised tonic-clonic seizures may require helmets or protective equipment to avoid injuries at the site.

20.4.2 Complications Complications following decompressive craniectomy can be classified as intra-operative, early and late [6]. Intra-operative complications include malignant brain swelling and bleeding or air embolism from injury to the superior sagittal sinus during the operation. Early post-operative complications are those occurring in the immediate post-operative period. Ongoing brain swelling leading to ischaemia can occur, especially in situations where the craniectomy window is too small to accommodate ongoing tissue swelling. Furthermore, impairment of cerebral autoregulation has been seen following DC, which can also contribute to ongoing brain swelling. Extra-axial haematomas under the skin flap or in the contralateral hemisphere need to be suspected if the ICP is initially controlled and after a few hours starts rising. Expansion of intra-­axial haematomas or maturation of contusions can also occur and may manifest in a similar way. There are many ways in which cerebrospinal fluid (CSF) hydrodynamics can be disturbed, and these include the development of hygromas, which can form in the subdural space of the ipsilateral or contralateral convexity and occasionally the parafalcine area. These hygromas often resolve spontaneously; however, they may be an early manifestation of post-traumatic ­ hydrocephalus. Infections and

20  Decompressive Craniectomy in the Management of Traumatic Brain Injury

wound healing issues can also occur in these patients especially those with multiple injuries involving craniofacial contamination. Late post-operative complications are those ensuing in the weeks or months following the initial surgery. In the context of DC, these are often associated with changes in pressure and dynamics of CSF flow in a situation where a large bone defect is present, making the intracranial space more susceptible to external pressure variations. Clinically these can manifest as postural symptoms especially in cases of sunken skin flaps and can lead to neurological deterioration. Similarly, the late development of hygromas can also be seen, and whilst they can appear quite impressive, they frequently resolve spontaneously or following the cranioplasty procedure. In a small group of patients, a ventriculo-peritoneal shunt may need to be considered.

20.4.3 Cranial Reconstruction Following the initial recovery period, cranial reconstruction, known as cranioplasty, can be offered to patients. A cranioplasty can improve cosmesis and protect the underlying brain, and there is a suggestion that it can promote neurological recovery [8]. Different techniques exist for cranioplasty, based on local resource availability, expertise and practice protocols. The optimal timing of cranioplasty is also a topic of debate with a few authors advocating early reconstruction in recent years in order to avoid issues, such as sinking skin flap, and promote neurological recovery. An autologous cranioplasty can be completed where the bone flap removed intra-operatively has been preserved in the patient’s subcutaneous tissue, often in the abdomen, or has been stored frozen. This is an option often used in resource-limited settings where manufactured plates are not available due to the high costs. An advantage of autologous cranioplasty is that there is no foreign material implanted but it is subject to resorption and thus the risk of revision is higher than manufactured plates [9].

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Cranioplasty implants, manufactured using titanium, hydroxyapatite and other synthetic materials, are widely used in well-resourced environments. These plates can be custom-made to precisely fit the bone defect, using high-­ definition volumetric imaging.

20.5 Current Evidence Base One of the concerns regarding use of decompressive craniotomy has been that many survivors will be left with severe disability and dependency. In order to address these issues, a number of large-scale research studies have been conducted that aimed to define the specific role of DC in the management of TBI patients. Two international randomised controlled trials are of particular relevance, the DECompressive CRAniectomy (DECRA) and the Randomised Evaluation of Surgery with Elevation of Intracranial Pressure (RESCUEicp) trials [4, 10], as well as a few other trials. Their findings are described below, and key study components are summarised in Table 20.1.

20.5.1 DECRA Trial The DECRA trial investigated the role of early, neuroprotective bifrontal decompressive craniectomy in TBI patients with intracranial hypertension that could not be managed with first-tier medical treatment strategies [10]. It tested the hypothesis that early bifrontal DC improves long-term neurological outcomes in patients with severe TBI.  DECRA was an international randomised trial that enrolled 155 patients in 3 countries—Australia, New Zealand and Saudi Arabia. The patients were randomised to either (1) bifrontal DC or (2) ongoing medical treatment for raised ICP within 72 h of TBI, if their intracranial pressure was above 20  mmHg for more than 15 min within a period of 1 hour that did not respond to first-tier medical therapies. The trial’s primary outcome measure was the GOSE (extended Glasgow Outcome Scale) at 6 months following initial injury.

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Table 20.1  Adapted from: The value of decompressive craniectomy in traumatic brain injury [11]. Summary of published RCTs on decompressive craniectomy Authors Taylor et al. [3]

Study design Randomised trial (pilot, single-­ centre)

Jiang et al. [12]

Randomised trial (multi-­ centre)

Qiu et al. [13]

Randomised trial (single-­ centre)

Cooper et al. [10]

Randomised trial (multi-­ centre)

Hutchinson et al. [4]

Randomised trial (multi-­ centre)

Population 27 children with a TBI and intracranial hypertension (median age 10.1 years) 486 patients with severe TBI and large hemispheric contusions (mean age 44.5 years)

Intervention Bitemporal DC (without opening dura) plus conventional medical management Standard-sized trauma DC (12 × 15 cm flap)

74 patients with severe TBI and a swollen hemisphere with midline shift >5 mm, contusions 30  days to 18 years).

25.8 T  he Role of Communication and of Education and Training Communication and the ability to communicate are critical in any phase of ICU admission. Maintaining an open dialogue with family is critical during all the phases of ICU stay. Family needs support when coping with death. Communication with families on the subject of brain death and its implications is a skill and needs to be learned and continually refined. ICU doctors are closest to family before the death of the patient, and it is important to show respect and empathy in these circumstances. Breakdowns in communication are usually the cause of most conflict, and clinicians may have to go to great lengths to avoid litigation. There will never be “one-size-fits-all” approach to mitigate conflict; however, early recognition and transpar-

ent explanation of a number of issues may be beneficial: These include but are not limited to: • Early acknowledgement that a patient is deteriorating and unresponsive to all clinical efforts. • Early explanation that although patients are on “life support,” they are likely to progress to brain death. • Clear explanation as to the implications of brain death both from a clinical, legal, and where appropriate cultural viewpoint. • The legal obligations of clinicians to certify death based on brain death. • The need to provide appropriate support over a reasonable timeframe, in which to inform families that once death has occurred, continuation of medical or ventilator therapy is no longer an option. • Each step in the clinical examination for brain death diagnosis needs to be clearly documented in order to maintain transparency and to ensure public confidence if ever the process were to be challenged.

25.9 Conclusions These circumstances and the issues that come with a diagnosis of BD can be challenging for all involved. Education and training [14, 15] in brain death determination is of paramount importance, and there is a need to ensure robust educational projects are designed and appropriately implemented. Brain death determination should be part of core curricula for medical as well as nursing staff, and the recent recommendations would provide a useful framework on which to base these curricula. Cultural, religious, and personal views must always be respected and where possible acted upon; however, it is becoming increasingly apparent that clinicians have an ethical duty to the wider community to provide a uniform and transparent response to a patient’s death. The recent recommendations provide clear guidance on these issues and represent a valuable contribution to the literature on this difficult subject.

25  Brain Death: Current Evidence and Guidelines

References

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8. Wijdicks EFM.  Brain death worldwide: accepted fact but no global consensus in diagnostic criteria. Neurology. 2002;58:20–5. 1. Ad Hoc Committee. A definition of irreversible 9. Shappell CN, Frank JI, Husari K, et al. Practice varicoma. Report of the ad hoc Committee of the Harvard ability in brain death determination: a call to action. Medical School to examine the definition of brain Neurology. 2013;81:2009–14. death. JAMA. 1968;5:337–40. 10. Citerio G, Cripp IA, Bronco A, et  al. Variability in 2. Diagnosis of brain death. Statement issued by the honbrain death determination in Europe: looking for a orary secretary of the Conference of Medical Royal solution. Neurocrit Care. 2014;21:376–82. Colleges and their Faculties in the United Kingdom 11. Greer DM, Shemie SD, Lewis A, et al. Determination on 11 October 1976. BMJ. 1976;2:1187–8. of brain death/death by neurologic criteria. The world 3. National Conference of Commissioners on Uniform brain death project. JAMA. 2020;324:1078–97. State Laws: Uniform Determination of death Act 12. Busl KM, Lewis A, Varelas PN.  Apnea testing for (UDDA). Annual Conference Meeting on its eighty-­ the determination of brain death: a systematic scopninth year on Kauai, Hawaii July 26–August 1, 1980. ing review. Neurocrit Care. 2020; Available at: https:// Available at: http://www.lchc.ucsd.edu/cogn_150/ www.ncbi.nlm.nih.gov/pmc/articles/PMC7286635/ Readings/death_act.pdf pdf/12028_2020_Article_1015.pdf 4. The Quality Standards Subcommittee of the American 13. Nakagawa TA, Ashwal S, Mathur M, et al. Guidelines Academy of Neurology. Practice parameters for deterfor the determination of brain death in infants and mining brain death in adults (summary statement). children: an update of the 1987 task force recommenNeurology. 1995;45:1012–4. dations. Crit Care Med. 2011;39:2139–55. 5. Wijdicks EFM, Varelas PN, Gronseth GS, et  al. 14. Manyalich M, Paredes D, Ballesté C, et  al. The Evidence-based guideline update: determining brain PIERDUB Project: international project on education death in adults Report of the Quality Standards and research in donation at University of Barcelona: Subcommittee of the American Academy of training university students about donation and transNeurology. Neurology. 2010;74:1911–8. plantation. Transplant Proc. 2010;42:117–20. 6. Wahlster S, Wijdicks EFM, Patel PV, et  al. Brain 15. Douglas P, Goldschmidt C, McCoyd M, et  al. death declaration. Practices and perceptions worldSimulation-based training in brain death determinawide. Neurology. 2015;84:1870–9. tion incorporating family discussion. J Grad Med 7. Lewis A, Bakkar A, Kreiger-Benson E, et  al. Educ. 2018;10:553–8. Determination of death by neurological criteria around the world. Neurology. 2020;95:1–11.

Part IV Ethical Considerations

Introduction to Bioethics

26

Ahmed Ammar and Stephen Honeybul

26.1 Introduction Over the past 50 years, advances in clinical medicine have seen the introduction and acceptance into everyday practice of a wide range of diagnostic and therapeutic technologies. Many of these advances have significantly increased the capability of doctors to solve complex medical and surgical problems and in many circumstances considerably extend a patient’s lifespan. However, paradoxically, as each clinical problem has been solved, the therapeutic paradigm, rather than becoming easier, often becomes more difficult as increasingly complex clinical situations are encountered. The evolving management options for patients with severe traumatic brain injury provide a good example of some of these issues. Prior to the development of the intensive care unit and modern-day radiological techniques such as computed tomography, neurosurgeons had relatively limited options when dealing with

A. Ammar (*) Department of Neurosurgery, King Fahd University Hospital, Imam Abdulrahman Bin Faisal University, Al Khobar, Saudi Arabia e-mail: [email protected] S. Honeybul Department of Neurosurgery, Sir Charles Gairdner and Royal Perth Hospitals, Perth, WA, Australia e-mail: [email protected] © Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_26

neurotrauma patients. It was possible to evacuate intracranial hematoma’s using either trephination, exploratory burr holes, or a craniotomy. Lesions were localized using either clinical signs such as anisocoria or radiological techniques such as plain skull X-rays, cerebral angiography, or air encephalography. However, during the 1960s and early 1970s, there were a number of key advances. Critical care began as a specialty with the development of the iron lung and negative pressure ventilation in response to the polio outbreak in 1952. Thereafter, the introduction and wide acceptance of the cuffed endotracheal tube and positive pressure ventilation led to the expansion of the specialty into increasingly subspecialized intensive care units. For the first time, it was possible to fully support a patient’s cardiac and respiratory function and provide time either during which their condition could be treated or during which it may improve. The second development was that of the intracranial pressure monitoring which was introduced in the late 1960s and subsequently became widely incorporated into clinical practice. The prognostic significance of raised ICP was soon recognized as were a number of medical and surgical interventions that could reduce intractable raised ICP, and this led to further subspecialization and the development of the present-day neurotrauma intensive care units. The final, and arguably the most important, development was that of computed tomography 269

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(CT). In fact, seldom has a single medical advance had such an impact on medical practice worldwide. British engineer Godfrey Newbold Hounsfield of EMI Laboratories and South African-born Allan Cormack of Tufts University, Massachusetts, constructed the original, gamma radiation-based machines in the late 1960s. Initially, it took 9  days to acquire the data and 2 days to reconstruct a single image from the raw data. They were later awarded the Nobel Peace Prize for their contributions to medicine and science. From these early beginnings, the technology advanced rapidly, such that most hospitals in high-income countries have this facility and can obtain the rapid, whole body scanning that is required by modern-day trauma units. Each of these advances had considerable impact on the management of patients with TBI, in what will historically be regarded as a relatively short period of time. In the modern-day neurointensive care, it is now considered a standard of care to intubate and ventilate patients, optimize cerebral perfusion, and continuously monitor intracranial pressure. Easy access to CT scan enables neurosurgeons to accurately localize and where necessary evacuate intracranial mass lesions and, in cases where ICP becomes intractable, consider more aggressive interventions such as a decompressive craniectomy. However, solving the problem of airway protection, mechanical ventilation, and maintenance of cerebral perfusion has replaced one clinical issue with a veritable myriad of far more challenging clinical decisions that previously did not require consideration. Issues that are often encountered include but are not limited to: • Appropriate patient selection for aggressive therapy • Consent for those who have lost competency • Identification of appropriate surrogate decision-makers • Survival with severe neurocognitive disability and quality of life • Withholding and withdrawing care • Brain death and organ donation • Fair and equitable distribution of healthcare resources

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Similar problems have been encountered across all aspects of medicine, and it was within this environment that the field of bioethics developed. Principlism, as described by Beauchamp and Childress, is the most widely recognized bioethical model, and this sets out the four core principles of autonomy, beneficence, non-maleficence, and justice. These principles provide useful building blocks on which to construct meaningful ethical discourse; however, it is important to acknowledge that modern-day bioethics did not develop in a vacuum and an understanding of its origins is important in order to appreciate not only its origins and evolution but also possible future directions into which the field may develop.

26.2 The History of Bioethics 26.2.1 Virtue Ethics: Greek There is no doubt that early civilizations, even prior to the development of the written language, had some form of guidance in place for the provision of healthcare by various workers, be they shamans, sorcerers, herbalists, or priests. However, the origins of modern-day ethics really began to develop from the ancient Greek philosophers. Indeed, the word “ethics” is derived from the Greek word “ethos” which means “disposition” or “trait” and constitutes part of the Greek phrase ethike aretai which refers to “skills of character.” It was initially Socrates and thereafter his student Plato and then his student Aristotle who sought to determine what characteristics denote a good person. In their view, ethike aretai that make a good person were courage, temperance, wisdom, and justice. They determined that these skills were necessary to function well in society, and even today, these character traits are known as the cardinal virtues. Greek ethics were teleological (also called consequentialist ethics or consequentialism) in that the basic standard of morality is precisely the value of what an action brings into being. This determines that an action is morally justified if the end result is good. For example, the act of

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stealing a loaf of bread can be morally justified if it means feeding a starving family. Their approach emphasized the importance of the moral virtue and the need to adjudge the appropriateness of an action or behavior based on the underlying motive of the person performing that action. They advocated for the development of virtues that were required to fulfill a particular role. In the case of medicine, that might be compassion, knowledge of healing, and skill in human relations.

26.2.2 Virtue Ethics: Christian In the fourth century C.E. (common era), the Christian church added the theological virtues of faith, hope, and charity to the cardinal virtues and also added the Seven Deadly Sins (sloth, lust, greed, gluttony, envy, greed, and pride). Christian ethics place great emphasis on compassion, especially where the physician has reached the limits of what is technically possible. Given that all patients will eventually die, compassion will always be considered a virtue in physicians. This position is slightly at odds with Greek ethics, which were seen as somewhat elitist (the Greeks believed themselves superior to the people the conquered and had no tolerance for other cultures). Christian ethics placed much stock in caring for the poor and disadvantaged. At the time, there is no doubt that virtue ethics both religious and non-religious had much to offer for physicians and their patients; however, they provide limited benefit when considering clinical decisions. In addition, virtue theories generally serve to maintain the status quo over change and tend to be somewhat paternalistic.

26.2.3 Natural Law The concept of natural law has its origins initially in Greek culture and subsequently in Roman culture. Roman stoic philosophers argued that there were certain rules in the texture of the world that were so intimately embedded that they constituted a law in themselves.

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Natural law maintains that human beings possess intrinsic values that govern our reasoning and behavior and that these rules of right and wrong are inherent in people and are not created by society or court judges. Natural law theory recognizes that law and morality are deeply connected, if not one and the same. Morality relates to what is right and wrong and what is good and bad. Natural law theorists believe that human laws are defined by morality, and not by an authority figure, such as a king or a government. Therefore, humans are guided by our human nature to figure out what the laws are and to act in conformity with those laws. The term “natural law” is derived from the belief that human morality comes from nature and everything in nature has a purpose, including humans. Our purpose, according to natural law theorists, is to live a good, happy life. Therefore, actions that work against that purpose, that is, actions that would prevent a fellow human from living a good, happy life, are considered “unnatural” or “immoral.” If it is considered that the purpose of laws is to provide justice, from a natural law perspective, a law that doesn’t provide justice (an unjust law) is considered “not a law at all.” Therefore, a law that is flawed is one that no one should follow. In short, any law that is good is moral, and any moral law is good. Legal positivism is a legal theory that is the opposite of the natural law theory, and this defines laws as those norms which have been created by a person or body who has been given the authority to make law. This approach defines a norm as a law (rather than as some other kind of norm, like a moral principle or religious rule) purely because the norm was created or posited by someone with law-making power. According to positivism, there is no necessary connection between law and morality. Natural lawyers assume that humans have natural rights and that governments have to respect those rights in the form that their laws take. If they fail to do so, then their commands do not have the force of law. Sometimes these arguments are based on theories of social contract, such as those put forth by John Locke. Others, like John Finnis, argue that governments only act

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legitimately when they act to promote intrinsic goods that improve the life of the people. In practice, most laws emerge from modern nation states, and each may have multiple sources. Some will have systems of law created by code or legislation which is made by parliamentary bodies or assemblies. Other laws might originate from custom. Judges may also have the power to make law (as in some common law systems). From a purely practical perspective, natural law has conferred on medical ethics the famous doctrine of double effect, which holds that if an action has two effects, one good and one evil, the evil effect is morally permissible. A good example is providing increasing doses of morphine to a terminally ill patient who is in agony, even if the eventual outcome is respiratory arrest and death. The following premises must be fulfilled: • If the action was good in itself (Yes—providing pain relief) • If the good follows immediately from the cause as did the evil effect (Yes—immediate pain relief) • If only the good effect was intended (The intention is to relieve pain which is good; the bad is foreseen but not intended) • If there was as important a reason for performing the action as for allowing the evil effect (Yes—It would be unkind to ignore intractable pain in someone who is dying)

26.2.4 Deontology and Kantian Ethics Immanuel Kant lived in the so-called period of Enlightenment which was a late seventeenth- and early eighteenth-century intellectual movement that emphasized the importance of reason, individualism, skepticism, and science. While raised as a Christian with religious values, he sought to justify those values based on pure reason as opposed to beliefs about God. He placed great emphasis on the need to act out of a sense of duty rather than considering the consequences of that act. Deontological ethics is the normative ethical

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theory that the morality of an action should be based on whether that action itself is right or wrong under a series of rules, rather than based on the consequences of the action. In terms of medical practice, acts are performed out of a sense of duty, not for treasons of compassion or praise. Doctors should not treat their patients based on their feeling but rather because it is the right thing to do. Fundamental to the Kantian ethics are two moral principles: • A right act is universal. Kantian ethics would always promote truth telling. Lying is inherently wrong even if the consequences of telling a lie may seem better. For example, failure to notice a small lesion on an MRI brain scan 1  year ago may result in a delayed diagnosis of metastatic disease. A consequentialist may argue that the surgeon should not tell the patient and proceed as if this is a new finding as this would lead to potential conflict and loss of trust. However, Kantian ethics would reject this position because the only universalizable rule is “Always tell patients the truth.” • A right act treats people as “end in themselves” never as “mere means.” Patients must be afforded absolute moral worth and cannot be used, for example, in experimentation to advance medical knowledge. This does not mean that they cannot participate in medical research, but rather all steps must be taken to protect their rights and prevent exposure to unnecessary harm. Fundamental to Kantian thinking is the idea of autonomy. This determines that it is only possible to act morally when a person understands that certain rules are inherently right and that a person’s actions reflect those rules. Kant believed that understanding the idea of autonomy was key to understanding and justifying the authority that moral requirements have over us. He also believed that freedom does not consist in being bound by no law, but by laws that are in some sense of one’s own making.

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Overall, there is much to be learned from a Kantian approach to morality and the power of reason to solve human problems. However, critics such as David Hume and later Sigmund Freud have often pointed out that reason is only the tip of the moral iceberg and so much of ethical life is emotional. Kantian ethics also presents practical problems in medicine, especially when faced with competing maxims or when treating each person and as if they have infinite value because triage is part of everyday practice. Notwithstanding these issues, there is no doubt that an important legacy of Kantian ethics is the emphasis on the autonomous will of the free, rational individual as the seat of moral value, and this in many ways sets the stage for modern-day medical ethics.

26.2.5 Utilitarianism and Consequentialism Utilitarianism was developed by Jeremy Bentham and Stuart Mill in the late eighteenth and early nineteenth century as a secular replacement for Christian ethics that aimed to humanize outmoded and exploitative institutions that existed at the time. The movement is based on the premise that right acts produce the greatest amount of good, or utility, for the greatest number of people. At the time, utilitarians provided considerable societal benefit and campaigned against inhumane practices such as slavery, harsh factory conditions, child labor, and capital punishment for petty thefts. They sought to reform the penal system, passed the Corn Laws, ended the debtor’s prison, and advocated to give women the right to vote. In general, there are four basic utilitarian principles: • Consequentialism: Consequence or outcomes matter, not intentions or motives. • Maximization: The more people affected, the more important the result.

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• A theory of value: Good consequences are defined by either pleasure (hedonic utilitarianism) or what people prefer (preference utilitarianism) or some measure of good. • A morality premise: Each being’s good or happiness is to count as one and no more. These contrast significantly with virtue and Kantian ethics who judge a person character based on their motives. Utilitarians, on the other hand, do not disregard motives but think they only count insofar as good motives generally produce good outcomes. It was John Stuart Mill who pointed out that a drowning man does not care about the motives of a lifeguard, but only that they are swimming out to rescue him. However, an alternative interpretation is that the lifeguard is swimming out to rescue the man, which is a good motive, and if the drowning man survives, the good motive has produced a good outcome. In medicine, utilitarianism has most influence in the fields of public health and triage, and it is easy to see why. Improvements in public health have had a much greater population impact than any number of medical and surgical advances. The provision of clean drinking water is one such development, as are improvements in sanitation and coordination of waste disposal. In modern-­ day medicine, public health initiatives, such as coordinated vaccination programs, provide evidence as to the widespread population utility that can be achieved at relatively little cost. Utilitarian’s recognize the need to triage because healthcare resources can be scarce, especially during emergencies. In these circumstances, physicians should not treat each patient equally, but rather focus on those who are likely to benefit. In the context of a mass casualty, rigorous application of this principle can appear fairly ruthless, because patients who are likely to die are abandoned, as are those who are likely to live. The focus of treatment should be on those patients who are on the edge of death because the aim is to save the maximal number of lives. This viewpoint would be a rejection of the Kantian ethics that emphasizes the absolute value of each individual and implies that physicians should at least

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comfort those who are beyond help. However, closer examination of the Kantian approach reveals that it is not necessarily at odds with utilitarianism because the considerable social value in caring for those most in need must be acknowledged, especially if this is undiluted by considerations of cost. While attempts to preserve life at any cost may be incompatible with utilitarian resource allocation, conveying the message that life is precious and worth a great deal of effort to preserve, can be a source of social utility. People obtain benefit from the belief that they are living in a caring and humane society and this can provide people with a feeling of security knowing that they live in a compassionate society which cares for the needs of each constituent member and where those in most desperate need will not be ignored merely on the basis of utilitarian resource allocation.

26.2.6 Feminist Ethics Contemporary feminist philosophers have challenged the inherent masculine approach of “traditional” Western moral philosophy and the historical tendency to devalue women’s experiences and lives. It was Rosemarie Tong who noted that “all feminist approaches to ethics are filtered through the lens of gender” [1]. This can describe a variety of conceptualizations of gender in ethics, including an “ethics of care” which can be considered a “feminine” trait, as well as the role of gender within interpersonal relationships and healthcare institutions as part of an ethical dilemma. There is enormous variability in the methodology taken by feminist ethicists; however, the approach can be conceptualized as a “series of corrective lenses that are meant to improve moral vision” rather than an independent theory of ethics [2]. Features common to the approach include, but are not limited to: • An emphasis on feminine values, such as empathy, interdependence, and caring, and the importance of community and solidarity.

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• Less emphasis on autonomy and individual rights. • Recognize the historical subordination of women, e.g., mind-body, reason-emotion, objective-subjective, public-private, etc. • Reject the idea that ethics should be value-neutral. • An emphasis on the importance of context and the relevance of politics and power to understanding ethics and healthcare.

26.2.7 Contemporary Ethical Frameworks Modern-day bioethics is informed by the field of moral philosophy, which is vast and certainly not limited to the aforementioned theories. As previously mentioned, in contemporary medicine, Principlism, as described by Beauchamp and Childress, is the most widely recognized bioethical model, and this has its origins in two influential publications from the late 1970s in the United States. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research produced a landmark document called the “Belmont Report.” The Commission, which was set up in 1974, met in February 1976 for 4 days at the Smithsonian Institution’s Belmont Conference Center, and this resulted in a statement of three basic ethical principles, namely, autonomy, beneficence, and justice, which should be used as an ethical framework for biomedical and behavioral research [3]. The second landmark publication was the book entitled Principles of Biomedical Ethics by Tom Beauchamp and James Childress in 1979 [4]. In this book, they introduce the fourth bioethical principle of non-maleficence. More recently, the principles of veracity (truthfulness and honesty) and dignity have been added to the initial fourth principles although there is some variation in the way they are interpreted [5]. Each of these principles has equal worth, and each needs to be taken into account, balanced, and specified in any clinical setting [5].

26  Introduction to Bioethics

There is little doubt that the Principlism model has become the most widely recognized and most predominantly taught model of medical bioethics. The authors concede that the principles in themselves do not contain sufficient content to address all the nuances of moral problems encountered in clinical practice. However, the principles are felt to be universal and objective, and their applications through various rules, norms, and virtues continue to evolve in line with case studies in clinical practice. This process of reflective thinking about principles (rather than simply “applying” them to a clinical situation in an unsophisticated or unreflective way) is critically important because even if we agree on our moral commitment to these principles, this does not necessarily mean we will agree on their relative importance. Further problems can occur when principles come into conflict, and this is particularly pertinent in the case of traumatic brain injury where surgical intervention, such as a lifesaving decompressive craniectomy, may expose patients to an outcome (severe neurocognitive disability) that they may feel to be unacceptable. In these circumstances, the principle of beneficence (survival) may be at odds with non-­ maleficence (dependency) which may be further at odds with justice (equitable resource allocation in intensive care). Further problems may occur when considering truthfulness and honesty when considering surgical intervention when the injury is particularly severe. Notwithstanding the prognostic uncertainty and the ability of survivors to adapt to severe disability, circumstances may dictate that there may be occasions where the most honest course of clinical action may be to carefully consider not intervening. Viewed from this perspective, it must be acknowledged that there are limitations when

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attempting strict adherence to a principle-based approach, and in response to these limitations, a variety of alternative methods have been proposed. The Four Topics method proposed by Jonson focuses on medical indications, patient preferences, quality of life, and contextual issues (Table  26.1) [6]. This method aims to clearly identify relevant information that should be taken into account in a pragmatic and practical fashion. There are similarities with the Principlism approach; however, one of the key differences is the emphasis on the medical indications and the need to consider the clinical efficacy of the proposed intervention. This approach has a particular appeal in the context of severe traumatic brain injury where it is necessary to examine evidence obtained from randomized controlled trial in order to justify use of therapies such as hypothermia and decompressive craniectomy [7, 8]. The model also focuses on quality-of-life issues which are again important in the context of TBI, where issues of poor outcome and futility need to be considered [9]. The CASES method is based on the Four Topics method but aims to formulate a full ethics consultation process that starts with an emphasis on clarifying the ethical issue in question. Thereafter, the consultation process aims to systematically work through the issues such that conflicts can be resolved [10] (Table 26.2). Finally, there is the concept of values-based medicine that acknowledges that the personal values vary based on issues such as culture, religion, family, and a whole host of personal values. This approach emphasizes the need to place the patient at the center of care and use information gained from evidence-based medicine, combined with medical professionalism, to produce an outcome that reflects those values [11].

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Table 26.1  The Four Topics for clinical ethics (adapted from Clinical Ethics [6], with permission) Medical indications Patient medical history

Prognosis with or without treatment Clinical efficacy of the proposed treatment Success or otherwise of previous treatment Most likely outcome following surgical or medical intervention

Patient preferences Patient known wishes, current preferences, and consent Advance directive Assessment of a patient’s decision-making capacity

Quality of life Possibility of returning to previous functional status Patient’s acceptance or otherwise of their quality of life Consideration of withdrawal of care or involvement of palliative care measures

Family or surrogate involvement

Contextual features Family and social issues Cultural and religious issues Economic factors

Medicolegal issues Possible conflicts of interest Equitable resource allocation

Table 26.2  The CASES approach for an ethical consultation (adapted from Clinical Ethics [6], with permission) C A S E S

Clarify the ethical issues that require consideration Assemble the appropriate information regarding issues under consideration Synthesize the information through ethical analysis Explain the results of the analysis and synthesis Support the consultation process with subsequent follow-up and evaluation

26.3 Conclusion There will never be a one-size-fits-all approach to modern-day bioethics. There is no doubt that the Principlism approach is a robust model that has withstood the test of time. However, the approach can sometimes fail to resolve some of the more complex issues, and in these circumstances, it may be necessary to turn to alternative approaches. Certainly, the contemporary bioethical landscape would be unrecognizable if viewed from 50  years ago, and there is no reason to believe that the next 50 years will be any different in terms of medical advances. The field of bioethics cannot be stationary and will need to continually evolve if it is to provide answers to questions, the nature of which we are currently unaware. Conflict of Interest  None declared.

Funding: None.

References 1. Tong R.  Feminist approaches to bioethics: theoretical reflections and practical applications. Boulder: Westview Press; 1997. 2. Tong R.  Feminist approaches to bioethics. Medical Ethics Newsletter 1999;1–8. 3. https://www.hhs.gov/ohrp/regulations-­a nd-­p olicy/ belmont-­r eport/read-­t he-­b elmont-­r eport/index. html 4. Beauchamp TL, Childress JF. Principles of biomedical ethics. New York: Oxford University Press; 1979. 5. Beauchamp TL, Childress JF. Principles of biomedical ethics. 7th ed. Oxford: Oxford University Press; 2012. 6. Jonsen AR, Siegler M, Winslade WJ. Clinical ethics: a practical approach to ethical decisions in clinical medicine. New York: MacMillan Publishing; 1982. 7. Honeybul. Reconsidering the role of hypothermia in management of severe traumatic brain injury. J Clin Neurosci. 2016;28:12–5. 8. Honeybul S, Ho KM, Gillett GR. Long-term outcome following decompressive craniectomy: an inconvenient truth? Curr Opin Crit Care. 2018;24:97–104. 9. Honeybul S, Gillett GR, Ho K. Futility in neurosurgery: a patient-centered approach. Neurosurgery. 2013;73:917–22. 10. Toh HJ, Low JA, Lim ZU, et al. Jonsen’s four topics approach as a framework for clinical ethics consultation. Asian Bioethics Rev. 2018;10:37–51. 11. Ammar A, Bernstein M, editors. Neurosurgical Ethics in Practice: Value-Based Medicine. Berlin, Germany/ New York: Springer; 2014.

Consent for Neurosurgery in Cases of Traumatic Brain Injury

27

Camilla Louise Scanlan, Cameron Stewart, and Ian Kerridge

27.1 Introduction Surgical intervention for patients with traumatic brain injury (TBI) can range from insertion of an intracranial pressure monitor or an external ventricular drain through to evacuation of an acute subdural hematoma or a decompressive craniectomy for intractable intracranial hypertension. In most cases, the surgical procedures are relatively straightforward; however, decision-making around the questions of consent may be complex. In the first instance, surgical intervention may not reverse the effects of the initial trauma, and there is potential for patients to be left with significant neurocognitive disabilities. Secondly, while a number of studies have shown that surgical intervention can reduce mortality, the consequence of this is an increase in the number of dependent survivors. Finally, oftenC. L. Scanlan (*) Sydney Health Ethics, Faculty of Medicine and Health, University of Sydney, Sydney, Australia e-mail: [email protected] C. Stewart Sydney Health Ethics, Faculty of Medicine and Health, University of Sydney, Sydney, Australia Sydney Law School, University of Sydney, Sydney, Australia I. Kerridge Sydney Health Ethics, Faculty of Medicine and Health, University of Sydney, Sydney, Australia Royal North Shore Hospital, St Leonards, Sydney, Australia © Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_27

times, these issues cannot be discussed with the patients themselves because they may lack capacity as a consequence of their injury and will rarely, if ever, have indicated in advance their preferences for treatment in such situations. The responsibility for decision-­making, therefore, inevitably falls on families, loved ones, and significant others. Consent for surgical treatment of TBI is, therefore, of central importance as it provides a process by which permission is obtained to undertake surgery, a mechanism for the provision of information about risk and an environment in which the relationship between the treatment team, patients, and their families may be fostered and developed. In this chapter, we outline the elements of consent and the limits of consent, and we then discuss a case example.

27.2 Consent All human societies have developed rules concerning how humans are permitted to touch one another. In countries that are part of the Western legal tradition, those rules are referred to collectively under the umbrella heading of consent. Consent is a central ethical and legal doctrine in healthcare as it governs how, why, and for what reason permission should be sought for medical interventions. The requirement for consent is particularly relevant in the case of surgery when consent can be viewed as permitting highly invasive 277

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acts that would otherwise be illegal (in both a civil and criminal sense) even when the surgery may be intended to benefit the person. The common law tradition of consent is best represented by the oft-quoted words of Cardozo J in Schloendorff v Society of New  York Hospital 195 NE 92 (1914): Every human being of adult years and sound mind has a right to determine what shall be done with his own body; and a surgeon who performs an operation without his patient’s consent commits an assault.

The primary function of consent is therefore to provide the means by which permission is given by patients to be treated. It represents, in part, the respect that the medical profession should display for the autonomy of the patient. The second function of consent is to require health professionals to provide information to patients about material risks (often referred to as “informed consent”). While most accounts of consent focus on these two functions, we argue that there is a third function—a relational function—where the requirement for consent creates an opportunity to develop relationships between patients, their families, and health professionals [1]. Ideally, those relationships will be ones in which the parties get to listen to each other and understand each other’s values, concerns, and fears and use that understanding to negotiate a path forward. That process of negotiation is not just about seeking permission and communicating risk, but it is about building relationships of trust and reassurance. To establish consent in common law jurisdictions, three elements must be satisfied: 1. The patient must have the mental capacity to consent. 2. The consent must be voluntary and given freely without undue influence having been exerted upon the person to consent. 3. The patient must have been provided with material information concerning the intervention proposed, so that she/he can make a reasoned decision. Each of these elements takes on special meaning in the context of cognitively impaired indi-

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viduals as may be the case in people who have sustained a TBI.

27.2.1 Capacity to Consent to Treatment “Capacity” refers to a person’s functional ability to make a decision regarding consent. In common law, all adults are presumed to have mental capacity, whereas children are presumed not to have mental capacity (Re T (adult: refusal of medical treatment) [1992] 4 All ER 649). These presumptions are rebuttable and may be overridden by evidence that an adult lacks capacity or that a child has capacity (Gillick v West Norfolk and Wisbech Area Health Authority [1986] AC 112). While there may be jurisdictional variations, the basic common law test of capacity (see Re C (Adult: Refusal of Treatment) [1994] 1 WLR 290) requires that that patient be able to: 1 . Understand treatment information 2. Retain the information 3. Weigh the information as part of a process of decision-making 4. Communicate the decision to others The onus of assessing capacity lies with the treatment team [2]. A number of useful standardized tools may be employed in this assessment including the MacArthur Competence Assessment Tool-Treatment (MacCAT-T) [3]. However, none of the commonly used tests are universally accepted as the gold standard, and all are subjective measures and carry assumptions about an individual’s values, ethnicity, rationality, logic, and agency. Once a patient’s incapacity has been confirmed, consent may still be possible via an advance directive or some form of substitute decision-making. Jurisdictional differences vary greatly in both these legal areas, but broadly speaking, an advance directive is a decision made by a person usually to refuse treatment in advance of a treatment decision. Common law supports the use of such directives to refuse treatment in cases where the directive was made competently and was intended

27  Consent for Neurosurgery in Cases of Traumatic Brain Injury

to apply to the circumstances which have arisen. Advance consents are also possible but only when the treatment team is ­prepared to offer the treatment option. An advance directive cannot be used to force the treatment team to provide a treatment which the treatment team believes is inappropriate or futile (R (Burke) v General Medical Council [2005] EWCA Civ 1003). Substitute decision-makers may have to be employed in the absence of an advance directive. There are two broad kinds of substitute decision-­ maker—a person who may have been appointed by the patient prior to their incapacity (e.g., a medical power of attorney) and a person appointed by a legal authority such as a court or tribunal to make decisions for the patient (e.g., a guardian). In cases of incapacitated children, parents will usually retain legal authority to consent on their behalf, until the child reaches maturity. Substitute decision-makers in common law countries tend to either use a best interests standard for decision-making (where the substitute must employ their own reasoning regarding the decision to consent, based on an objective and subjective assessment of what is in the patient’s best interests) or a substituted judgment (where the substitute must decide in a way which bests accords with the evidence of what the patient would have decided). Many jurisdictions combine both these notions in substituted decision-­making so it is important to be familiar with the tests in the jurisdiction in which you are working [4]. In 2008, the United Nations created the Convention on the Rights of Persons with Disabilities. That Convention has been ratified by many common law jurisdictions (including Australia, Canada, New Zealand, Ireland, Singapore, and the United Kingdom). That Convention challenges some of the traditional notions of substitute decision-making. For example, Article 12(2) states that all people should be treated as enjoying “equal legal capacity.” Some commentators, including the Committee in charge of implementing the Convention, took this to mean that capacity testing should be abolished and that all patients should be given the right to make decisions for themselves. How that princi-

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ple could apply to unconscious patients or patients with catastrophic brain injury remains to be seen. Perhaps consequently, none of the common law jurisdictions that adopted the Convention have abolished the capacity threshold [5]. In some circumstances, where the patient is incapacitated and no substitute decision-maker is available, medical teams can treat under the doctrine of necessity. Necessity is a common law defense (sometimes described as emergency) which excuses a person from doing something which is illegal (e.g., treating without consent) to avoid a greater harm (death or serious injury). In these circumstances, the treatment must be a proportionate response to the harm that the treatment team are seeking to avoid.

27.2.2 Consent Must Be Voluntary and Free from Undue Influence This element of consent reflects the significance of self-determination and respect for autonomy. Voluntariness is less concerned with the outcome of the decision and more concerned with decision being authentically the patient’s decision. An example of problematic undue influence is the British case of Re T (adult: refusal of medical treatment) [1992] 4 All ER 649, where a woman (who was not a Jehovah’s Witness) refused blood products after having pressure place on her by her mother (who was a Jehovah’s Witness). The Court of Appeal found that pressure from the mother and the patient’s deteriorating condition combined to override the patient’s will, invalidating her refusal.

27.2.3 Consent Should Be Accompanied by the Provision of Information Regarding Material Risks The treatment team has a legal duty to provide the patient with information regarding the material risks of having and not having the treatment (Reibl v Hughes [1980] 2 SCR 880; Rogers v Whitaker (1992) 175 CLR 479; Montgomery v

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Lanarkshire Health Board [2015] UKSC 11; Shand v Accident Compensation Corporation (Treatment Injury) [2018] NZACC 152). Ethically, it could be argued that the duty to provide information maximizes the potential for the patient to exercise their autonomy. A risk is material if in the circumstances of the particular case: (a) A reasonable person in the patient’s position, if warned of the risk, would be likely to attach significance to it (the objective limb) (b) The medical practitioner is, or should reasonably be, aware that the patient, if warned of the risk, would likely attach significance to it (the subjective limb) This legal formulation of the duty to provide information recognizes that some patients may not wish to be informed about particular risks and may wish to leave the choice of risk to the treatment team. Ethically, it might be argued that the choice to remain uninformed is itself an exercise of autonomy, but it might also be argued that health professionals have their own ethical duty to probe the patient’s understanding of the risks, so as to share responsibility for the choices that have to be made.

27.2.4 The Ethical and Legal Limits of Consent Consent (and the underlying value of autonomy upon which it is built) is not the answer to every legal and ethical problem of traumatic brain injury. Firstly, the permissive and risk functions of consent both assume that a decision has already been made by the treatment team about the appropriateness of offering treatment. Prior to any conversations regarding consent, the treatment team needs to have discussed and weighed the treatment options and made a decision about what they feel are the most appropriate and ethical treatment options to put before the patient and their family. In the common law, there is a line of authority which originates in

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the decisions of Lord Mustill from the House of Lords, which states that surgery is not legally justified by consent, but rather justified by being “proper medical treatment”: R v Brown [1994] 1 AC 212 at 266F.  While Lord Mustill did not provide a detailed explanation for this concept, it seems to reflect a concern that treatment teams need to carefully consider the costs and benefits of treatment alternatives and apply their professional judgment regarding the best options before any question of consent arises. In other words, patient care must reflect the considered judgment of the surgeon, and patients cannot “simply” be abandoned to their own autonomy. Secondly, discussion of consent in this chapter has assumed that patients make decisions as rational individuals. In cases where the patient cannot make a decision, the argument has assumed that the patient may have an advance directive, logically and clearly drafted, to apply to the circumstances that have arisen. In the absence of such a directive, the discussion has then assumed that there will be a substitute decision-­maker, who will take over the rational deliberation process. It doesn’t take much imagination to see that these assumptions about rational deliberation rarely match the reality of managing patients with a TBI. Conscious patients may be confused, angry, or scared, in pain, and facing the realistic prospect of death or permanent disability. Their decisions may be confused and contradictory. Unconscious patients may be near death, and the treatment team will be faced with the inevitable task of guessing what is preferable: death for the patient or a life with severe disability? The patient’s family members will be stressed, emotional, and facing probably the worst decision in their lives. No doubt there are some individuals, whether they be patients or substitute decision-­ maker, who may shine in these cases, being able to function clearly and decisively. But for many others, their reliance on the guidance of the treatment team, and their friends and family, means that their decision is one based on the interrelationships of dependence and trust, rather than the rational weighing of risk.

27  Consent for Neurosurgery in Cases of Traumatic Brain Injury

These realities require a more nuanced account of autonomy, which assumes that decisions are made within a web of social relationships, including the relationship of patients with their families, their friends, and the treatment team. Relational autonomy allows for a more complex understanding of decision-making that goes beyond the permissive and risk provision functions of consent [6]. Consent not only serves these functions, but it also provides an environment for the development of trust between the patient, their family, and the treatment team allowing them to confront their fears and have some hope of an acceptable outcome. This is what we described above as the relational function of consent [1].

27.2.5 Disputes over Treatment Disputes may arise between the treatment team and the patient and/or their representatives. In cases of dispute, most health services have procedures for mediating and resolving conflict. When possible, it may assuage the fears of patients and family members to receive a second opinion on the options available for treatment. Ultimately, legal action may need to be resorted to, and in such cases, it is important that the treatment team have followed the relevant policies and procedures and applied the relevant legal tests, such as capacity testing and analysis of the patient’s best interests. Disputes often arise over whether treatment is futile. There are different approaches to defining futility including: • The physiological approach, which judges a treatment futile when it fails (or is known to fail) to achieve certain physiological goals • The quantitative approach, where treatments have a very poor probability of success • The imminent demise or lethal condition approach, whereby a treatment is considered futile because it may fail to postpone an imminent death • The qualitative approach, which looks not only at physiological success but quality-of-­

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life factors, such as comfort, wellbeing, and cognition • The procedural approach, where a determination of futility is made via process, often involving conflict resolution [7] Wilkinson and Savelscu (2011) suggest that the term “futile” be replaced with “medically inappropriate” as it makes it clear that the value judgment is made by medical professionals and it serves to highlight the importance of the need to have a clear understanding of what are the goals of the intervention [8]. Importantly, none of these tests of futility (or medical appropriateness) are based on any particular legal rule. Instead, the legal process is based on the determination of the patient’s best interests or substituted judgment. But in the discussion of those issues, the medical opinion regarding whether the treatment is futile holds great weight, and it would be highly unusual for a common law court to override a medical assessment of futility. Some jurisdictions, like Texas and California, have specific pieces of legislation which lay down a process for dispute resolution, with very strict timelines for decision-making and appeals.

27.2.6 A Clinical Example We will now discuss a case example that demonstrates the relationship between these elements and the complexities of negotiating consent to surgery for TBI. In Box 27.1, we set out a basic algorithm to help with approaching the problems with consent. We will use the case example to draw out different steps in the consent process.

Illustrative Clinical Case Adam is a 40-year-old man married to Bethany; they have a 2-month-old baby and a 2-year-old toddler. Despite Bethany’s repeated protestations, Adam continues to enjoy riding his motorcycle from time to time, describing himself as a “dyed-in-the-wool,” avid biker who loves the exhilaration and the physical and emotional

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Box 27.1: A Simple Algorithm for Consent to Surgery for Traumatic Brain Injury

Step 1: Discuss the diagnosis, prognosis, and treatment options with the treatment team, and decide on a course of action. Treatment options include active forms of treatment and palliative care options. Step 2: Does the patient lack capacity? If NO, then go to 3. If YES, then go to 4. Step 3: Discuss the diagnosis, prognosis, and treatment options with the patient. Explain the material risks of treatment and not having the treatment, and listen to the patient’s own wishes regarding treatment, which may require a reconsideration of the treatment options as originally decided upon by the treatment team. If the patient and treatment team agree about the appropriate treatment options, then treat in that way. If the patient and the treatment team cannot agree about which treatment options are appropriate, then go to 6. Step 4: Does the patient have an advance directive that can be applied to the current situation (recalling that patients can consent to and refuse treatment but cannot demand treatment using an advance directive)? If YES, then treat in accordance with the advance directive. If NO, then go to 5. Step 5: Discuss the diagnosis, prognosis, and treatment options with the appropriate substitute decision-maker. Explain the material risks of treatment and not having the treatment, and listen to the decision-­ maker’s own wishes regarding treatment, which may require a reconsideration of the treatment options as originally decided upon by the treatment team. If the decision-­ maker and treatment team agree about the appropriate treatment options, then treat in that way. If the patient and the treatment team cannot agree about which treatment options are appropriate, then go to 6. Step 6: Adopt a form of mediation of the dispute. This may require consideration of an independent assessment of the diagno-

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sis, prognosis, and treatment options. IF mediation is successful, then treat in accordance with the mediated outcome. If mediation is unsuccessful, then seek legal advice.

pleasure he feels when riding. One evening, Bethany’s “greatest fear” is realized when police visit her at home to inform her that Adam has had a serious accident on his bike and has been taken to the Accident and Emergency Department at a large teaching hospital. Evidence gathered by police suggests that Adam was travelling at about 70  km/h on an empty street when the bike hit a light reflector in the road, which was wet from an earlier storm. He lost control of the bike, it began to hydroplane, Adam became airborne, and he smashed into a tree. It appeared, according to the first responders, that Adam’s head took the full impact of the collision with the tree. Adam was unconscious when the paramedics arrived at the scene; he has yet to regain consciousness. Emergency CT scan of the brain reveals a large right-sided acute subdural hematoma with a significant midline shift (Fig. 27.1). There were also areas suggestive of significant ischemic injury. The neurosurgical team assess that Adam’s immediate survival is dependent on surgical evacuation of the hematoma. It is also the considered opinion of the neurosurgical team that if Adam does survive, his life will be beset by severe disability. Adam has previously let his wishes be known to family and friends that a life involving any major disability would not be acceptable to him. While Bethany wants Adam to receive whatever appropriate treatment is deemed necessary, she has confirmed in the strongest possible way to the social worker that she believes she would not be able to cope if Adam was significantly disabled. Neither she nor Adam has any extended family who would be able to offer support in terms of helping with the children or in offering support to Adam in terms of his disability.

27  Consent for Neurosurgery in Cases of Traumatic Brain Injury

Fig. 27.1  CT scan of the brain showing an extensive right-sided subdural hematoma with midline shift. There are also numerous areas of low density suggestive of significant ischemic injury

27.3 Discussion It is clear from our scenario that the treatment team has decided that evacuation of the clot is an option, but they are also open to choosing a palliative pathway, based on an assessment of the likely level of disability should Adam even survive surgery. We know from the case that Adam is unconscious and unable to communicate so would not have capacity. We are also told that his immediate survival is dependent on him undergoing neurosurgery as a matter of urgency; therefore, there is only a narrow window of opportunity in which a decision must be made, and it is medically not advisable to wait for him to regain consciousness. Ethically, a central concern is respect for Adam’s autonomy. He has previously stated that a life beset by disability would be intolerable to him, but he has also spoken of his desire to see his children grow to adulthood. While the principle of self-determination requires that respect

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must be given to the wishes of the patient, even when those wishes may result in death, care needs to be taken when assessing prior expressions of a patient’s wishes which will have been made in other contexts and without the benefit of advice. Adam has not made an advance care directive to refuse treatment in these circumstances, so there is no clear way to respect his autonomy as his stated values are inconsistent. As discussed above, the law makes provision for the appointment of a substitute decision-­ maker to consent on behalf of the incapacitated person. Adam has not appointed a medical power of attorney, so the treatment team need to check which person should be approached for consent in their jurisdiction. Most jurisdictions give preference to spouses, so we will assume that Bethany may be approached to act as a substitute decision-maker. We are told that Bethany feels that she would not be able to cope with Adam living with a severe disability, especially given her two young children and no close family to provide support. It can be assumed that the shock of Adam’s motorbike accident and the sight of him in hospital, probably intubated, catheterized, and with monitors and other machines attached to him, would be frightening for any spouse and Bethany may understandably be in a highly emotional state. Regardless, when making her decision, it is important for her to make it based on Adam’s best interests, or on the basis of a substituted judgment, or on some form of combined test (depending on the relevant jurisdiction). She can be helped to do that by family members, members of the treatment team, social workers, and hospital religious advisors. Some hospitals also have clinical bioethicists who specialize in helping others to make difficult decisions. If the facts were changed and the treatment team chose not to perform evacuation of the hematoma on the grounds of futility, Bethany may well wish to dispute that decision. If the treatment team’s decision is based solely on the grounds of physiological or quantitative futility, then it will be hard for her to challenge the decision, but, if instead the treatment team has made its decision based on qualitative futility, she may have stronger

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grounds [9]. It would be best if the treatment team follow a procedural approach to futility making the decision in concert with other healthcare professionals, in accordance with established guidelines and with appropriate documentation. This will both protect the hospital legally against claims of poor decision-making and increase the chances of gaining Bethany’s agreement. If mediation fails and Bethany opposes the decision, then, ultimately, the dispute about consent may have to be resolved legally. It is therefore vitally important to make sure the treatment team followed appropriate clinical and governance guidelines and the relevant laws of the jurisdiction where the hospital is situated.

27.4 Conclusion Consent is a multidimensional concept. It represents a form of permission, a duty to provide information about material risks, and an environment in which the relationships between the patient, their family, and the treatment team may develop. In this chapter, we have discussed the three functions of consent (permissive, risk, and relational) and tried to provide an easy-to-apply algorithm to help guide decision-making in cases of surgical treatment for TBI. Conflict of Interest  None declared. Financial support: No financial support has been required for this research.

References 1. Dunn M, Clare I, Holland A, et  al. Constructing and reconstructing ‘best interests’: an interpretative examination of substitute decision-making under the Mental Capacity Act 2005. J Social Welfare Family Law. 2007;29:117–33. 2. Grisso T, Appelbaum PS.  Assessing competence to consent to treatment: a guide for physicians and other health professionals. New  York: Oxford University Press; 2008. 3. Mackenzie C, Stoljar N.  Relational autonomy: feminist perspectives on autonomy, agency, and the social self. New  York: Oxford University Press; 2000. p. 213–35. 4. Shulman K, Cohen C, Kirsh F, et  al. Assessment of testamentary capacity and vulnerability to undue influence. Am J Psychiatry. 2007;164:722–7. 5. Stewart C.  Cracks in the lintel of consent. In: Freckelton I, Petersen K, editors. Tensions and traumas in health law. Leichhardt: Federation Press; 2017. p. 214–33. 6. Stewart C, Kerridge I. The three functions of consent in neurosurgery. In: Honeybul S, editor. Ethics in neurosurgical practice. Cambridge, UK: Cambridge University Press; 2020. p. 29–38. 7. Stewart C. Futility determination as a process: problems with medical sovereignty, legal issues and the strengths and weakness of the procedural approach. J Bioethical Inquiry. 2011;8:155–63. 8. Wilkinson DJC, Savulescu J.  Knowing when to stop: futility in the ICU.  Curr Opin Anaesthesiol. 2011;24(2):160–5. https://doi.org/10.1097/ ACO.0b013e328343c5af. 9. Willmott L, White B, Smith, et  al. Withholding and withdrawing life-sustaining treatment in a patient’s best interests: Australian judicial deliberations. Med J Aust. 2014;201:545–7.

Team-Based Decision-Making in Traumatic Brain Injury

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Timothy R. Smith, Brittany M. Stopa, Caroline M. W. Goedmakers, and Aakanksha Rana

28.1 Introduction Illustrative Case: Part 1 A 34-year-old male was admitted to the intensive care unit following a high-speed motor vehicle accident. He had sustained multiple long bone injuries and a severe traumatic brain injury. His initial Glasgow Coma Score has been recorded as 5 (E1M3V1), and his pupils were sluggishly reactive. His CT scan reveals severe cerebral edema with obliteration of the basal cisterns and bifrontal contusions. An intracranial pressure monitor reveals an intracranial pressure of 30  mmHg which is unresponsive to maximal medical management. The intensivists meet with

T. R. Smith (*) Department of Neurological Surgery, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, USA Computational Neuroscience Outcomes Center (CNOC), Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, USA Dana Farber Cancer Institute, Boston, MA, USA e-mail: [email protected] B. M. Stopa Computational Neuroscience Outcomes Center (CNOC), Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, USA

the attending neurosurgeon to discuss surgical options. The neurosurgeon has strong feelings that decompressive surgery may improve the patient’s chances of survival but will leave the patient with an unacceptable (in the neurosurgeon’s opinion) level of disability. The neurosurgeon meets with the patient’s wife and explains the seriousness of the situation. He outlines the need for aggressive medical management but does not mention the option of surgical decompression. Maximal medical management is instigated, but the ICP remains unstable. Thirty-six hours following admission, the ICP climbs rapidly, and the patient expires as a result of brainstem herniation.

C. M. W. Goedmakers Computational Neurosciences Outcomes Center, Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA Department of Neurosurgery, Leiden University Medical Center, Leiden, The Netherlands A. Rana Computational Neurosciences Outcomes Center, Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

Virginia Tech Carilion School of Medicine and Research Institute, Roanoke, VA, USA © Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_28

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28.2 History of Shared Decision-Making Before shared decision-making (SDM) was introduced as a framework, the prevailing model for the doctor-patient relationship was paternalism, in which the doctor determines the best course of treatment without regard for the patient’s wishes or choices. In this model, which prevailed until the 1960s, the physician is seen as the authority, and the patient is passive, does not ask questions, and accepts the decisions of the doctor [1]. Patients were often not even counseled about their prognosis for concerns that it would interfere with their healing process. During this time, patients accepted without question their doctors’ decisions or else were considered noncompliant. With the rise of the civil rights movement in the late 1960s came a movement of unrest though, and patients began to advocate for a shift in the doctorpatient relationship. Then in the 1970s, there was the introduction of the first physician communication courses, although they were still medico-centric, and patient rights and advocacy groups were established, such as the Boston Women’s Health Book Collective [1]. A scientific journal titled Patient Counseling and Health Education (now: Patient Education and Counseling) was established, at the First International Conference on Patient Counseling [1]. These progressive gains in the medical perspective were reinforced by two landmark publications: on the four principles of biomedical ethics and on the introduction of the notion of shared decision-making. Beauchamp and Childress introduced the four principles of biomedical ethics, that of autonomy, beneficence, non-maleficence, and justice, which are the prevailing tenets of bioethics today [2]. Veatch proposed a contractual model for doctor-patient relations that incorporate sharing the patient’s values in order to share the decision-making, which will preserve the moral integrity of both patient and physician. The 1980s was a time of expanding societal emphasis on patient autonomy and the development of patient education. In 1982, the term

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“shared decision-making” was first coined, in a President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research report [3]. This period was marked by the patient rights movement, the promotion of healthy lifestyles, the consolidation of healthcare organizations, and a change in informed consent requirements from physician-­ based to patient-based [1]. In the 1990s, patients became more engaged in healthy lifestyle choices and were taught to care for their health and diagnoses at home [1]. This marked a shift in accountability toward patients as they were seen to be agents of their own health. As the Internet developed, patients could more easily search for health information independently, and they began bringing that information into their conversations with their doctors, which fundamentally shifted the doctor-­patient relationship. This led to more interest and further development of the SDM framework, including several proposed models of the spectrum of the physician-patient relationship, each of which incorporates respect for patient autonomy but varies in its conception of such autonomy. SDM also gained prominence as it was promoted by policy makers, who saw it as a mechanism for reducing healthcare costs. At the start of the twenty-first century, the Institute of Medicine (IOM) published a landmark report, “Crossing the Quality Chasm,” that called for a more patient-centered healthcare system that could close the quality gap [3]. Following this landmark report, progress continued with an emphasis on flattening the vertical authority gradient and improving doctor-patient communication. The foundational biomedical ethics principles from Beauchamp and Childress continue to evolve and garner attention, as they are integrated into specific illustrative case studies. Medical education now includes diversity, awareness, and sensitivity training to better understand and serve patients [1]. With the evolution of technology, patient decision tools, and evidence-­based medicine, the opportunities for consensus between doctor and patient become more attainable.

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Illustrative Case: Part 2 It turns out that the patient’s sister-in-law is an emergency physician in Australia. When she learns of the details of the case, she launches a formal complaint with the hospital because there had been no discussion about surgical decompression, regardless of the possibility of a poor neurological outcome. This case presents several failures of the team to deliver optimal care. These failures include paternalism, shared decision-making, consensus, shared risk, patient-centered care, and the ethics of healthcare. At the center of these failures was a lack of consideration for SDM. The neurosurgeon actions were based purely on his opinion regarding the acceptability or otherwise of survival with severe disability. The patient may well have previously voiced his views regarding the possibility of this outcome; however, this was not explored, and no options were given. In the SDM model, both the physician and patient, or surrogate, should be actively involved in the process of goal-of-care discussions and treatment decision discussions, both should share information with each other, both should take steps to participate in the decision-making process by expressing preferences, and the decision should be made by both parties. Using SDM allows clinicians to understand the experience as the patient does and is therefore the pinnacle of patient-centered care.

28.3 Agency for Healthcare Research and Quality (AHRQ) SHARE Approach to SDM The AHRQ has developed a framework for healthcare professionals to effectively implement SDM into their practice, termed the AHRQ SHARE Approach. In this approach, the healthcare professional should: • Seek the patient’s participation • Help the patient explore and compare treatment options • Assess the patient’s values and preferences • Reach a decision with the patient • Evaluate the patient’s decision

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This five-step process encourages clinicians to explore the treatment options with the patient and consider the patient’s values, which facilitates meaningful dialogue about what matters most to the patient so that the treatment decision made will be that which is most appropriate to the patient as an individual [4]. Patient preferences and values vary widely and often differ from those of their doctor, so this model allows for the patient’s perspective to be central to the decision process. This process is particularly valued in those clinical scenarios where more than one reasonable treatment option exists, such as the case of TBI management. Using the AHRQ SHARE Approach, doctors can integrate patient preferences and values into the weighing of each treatment choice. Importantly, the final step is to evaluate the patient’s decision, which implies a cyclical and iterative process in which the patient’s preferences may change over the course of the disease and allows for the treatment strategy to adjust in accordance. Formalizing this SDM approach, it has been integrated into the framework for quality metrics and insurance reimbursements. The Affordable Care Act (ACA) established the reporting of patient experience and physician performance metrics, through the AHRQ Consumer Assessment of Healthcare Providers and Systems (CAHPS) surveys. These patient satisfaction surveys, which are used partially to determine reimbursement, ask patients whether or not their care providers honored the principles of SDM.  This policy decision ensures that patients are heard and their viewpoints are valued, which puts the impetus on clinicians to incorporate SDM into their practice, knowing that it will be a point of evaluation.

28.4 SDM Foundation The foundation of SDM is built upon four basic principles of bioethics: autonomy, beneficence, non-maleficence, and justice [2]. These principles were originally constructed to bridge the gap between ethical theory and practical problems in medicine, and they have been adapted to the shifting medical landscape with each subsequent

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edition published. Broadly speaking, these philosophical principles provide a moral framework for clinicians to employ as they tackle clinical management, moral dilemmas, and everyday patient encounters. Taken together, these principles can provide guidance on nearly every issue encountered in medicine and healthcare. The first principle, autonomy, involves a respect for patient self-determination and acknowledges that patients have the right to accept or reject recommendations for medical care, so long as they possess appropriate decision-­ making capacity. It has been argued that this principle is the most import of the four, especially as it is a basis for the other three. This is the basis for seeing patients as independent entities capable of engaging in SDM, rather than passive vehicles for accepting doctors’ decisions as in the former paternalism model. Beneficence is the act of doing what is best for the patient, which is a determination derived from the physician’s judgment or the patient’s wishes. In SDM, this principle is expanded to say that what is best for the patient will only become clear after the doctor and patient have had the opportunity to discuss and share their perspectives. Neither the physician’s judgment nor the patient’s wishes alone will result in what is best for the patient. Rather, these perspectives combined will facilitate the attainment of such a decision. Non-maleficence, central to the practice of medicine, is to first do no harm. This principle accepts that physicians are fallible and are equally capable of harming as helping patients. Indeed, it is important to consider the principles of beneficence and non-maleficence together. The role of non-maleficence in SDM is more nuanced because it relies upon the understanding that each patient will have their own conception of harm. Inasmuch, it is only through shared discussion between doctor and patient that appropriate treatment decisions can be made that provide a balance of acceptable benefit and harm. Justice can be considered in three ways: • Rights-based justice • Legal justice • Distributive justice

Rights-based justice refers to a respect for peoples’ rights, which follows from the previous principles and acknowledges the patient as a person in our consideration of the SDM framework. Legal justice refers to the respect for morally acceptable laws, an ethical expectation of all practicing physicians. The third, distributive justice, refers to the fair distribution of scarce resources, which is more challenging. This is a community-level principle, and its application at the individual patient level presents a challenge to physicians because the American Medical Association (AMA) Code of Medical Ethics instructs clinicians not to ration at the bedside and states that decisions about limited resources should only be made using ethically appropriate criteria of medical need [5]. Clinicians should bear in mind their obligation to their patients for upholding the principles of autonomy, beneficence, and non-maleficence at the bedside, while distributive justice may be better addressed in institutional and policy contexts.

28.5 SDM Challenges The SDM model has been well established in the literature, but this model for doctor-patient relations faces some challenges. One such challenge is that as the Internet and social media have rapidly and broadly expanded public access to information, so too has it expanded patient access to medical information and marketing. As patients gain direct access to medical information, products, and services, they have become increasingly autonomous and no longer reliant upon physician expertise or gate-keeping. Considering the ­spectrum of patient versus professional autonomy in healthcare, this has caused a substantial shift, from the outdated provider-dominated model of paternalism to a now patient-dominated pattern of consumerism. In this contemporary context, it could be argued that patients may have too much autonomy, which presents a challenge to the SDM model which inherently aims to share the decision-making process. Furthermore, there are some experts who contend that such a challenge to physician autonomy is detrimental to

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patients and society, on the basis that interference with physician expertise lessens trust and therefore results in fewer pathologies treated. For SDM to be successful, there must remain a role for physician autonomy because a model that is over-­reliant on patient autonomy risks marginalizing the important expertise of physicians. A challenge to SDM that is unique to TBI is that this diagnosis is not a single entity but rather a diagnostic term that encompasses multiple presentations, severities, and complexities. Therefore, the treatment regimen will be highly patient-specific, as there are many options to consider. The challenge of equipoise is great in TBI management, and indeed SDM is a communication model aptly suited to make decisions within the context of multiple treatment options. However, clinicians must still bear in mind the following challenges specific to this setting, such as disease complexity, patient capacity and value assessment, and the role of multidisciplinary teams. SDM can also be challenging in the setting of intense complexity, and specific considerations are needed for the implementation of SDM in an ICU.  The American College of Critical Care Medicine has released a policy statement which outlines when and how SDM should be employed in the ICU, to define overall goals of care and to make major treatment decisions [6]. The importance of SDM in the neurocritical care setting is especially important, as the patient’s values are a major driver of treatment decisions, more so than other areas of less acute medicine. For diagnoses that require complex management plans, such as TBI, it can be difficult to effectively communicate benefit and risk in lay terms that are meaningful to the patient and family while maintaining accuracy and completeness. In the neurocritical care setting, it is often the patient surrogate that must make decisions about the goals of care, and it has been shown that there can be communication discord between the information the surrogate wants and the information that the physician thinks the surrogate could adequately understand and interpret [7]. Furthermore, studies have shown that TBI research often includes

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waivers of consent because it is believed that the surrogate or family cannot make a balanced decision or may be too psychologically distressed to appropriately engage in the consent process [8]. While decision aids have been increasingly developed and implemented in other areas of medicine, their use in neurocritical care is still lacking. Without decision aids to guide surrogates and families as they navigate the complex decision-making required for TBI patients, they are left with a challenging task. Beyond assessing the patient, surrogate, or family for decision-making capacity, it is critical to understand the patient’s values, which may need to be reconstructed in the critical care setting. This is challenging though, as the ability of families to accurately represent patients’ wishes is limited [9]. One of the most frequently underaddressed elements of SDM in the ICU is the family’s role in this process [3, 9]. In a majority of ICU patients, conflict arises between the surrogate and the clinician about representing the patient’s preferences, as clinicians tend to underestimate the ability of families to understand the patient’s values [9]. It is therefore challenging in the setting of TBI management to effectively implement SDM, given the additional obstacle of negotiating treatment decisions with someone other than the patient. The involvement of large multidisciplinary teams managing patient care also presents a challenge to the effective adoption of SDM for doctor-­ patient communication. In multidisciplinary teams, where many highly specialized clinicians are involved in a patient’s care, there is the risk that no individual clinician assumes ownership. If that occurs, messaging from the various clinicians can be conflicting and asynchronous, which is frustrating for patients and indeed can result in poor health outcomes. The larger the care team, the greater the risk of diffusion of responsibility. Effective clinical teamwork must therefore include designation of patient communication responsibilities, so that these challenges can be overcome, as demonstrated in the TEAM-­ TBI study which found success in assigning a clinical coach that was tasked with coordinating

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communication between patients and physicians [10]. It is evident that leaving the responsibility for communication to chance is ineffective and that assigning a designated correspondent for the patient yields better patient outcomes and satisfaction.

28.6 SDM Conflicts SDM has become the contemporary de facto model for communication in healthcare, but it is not without conflict which can be present not only for physicians but also for the patients and their families.

28.6.1 Conflicts for Physicians In consideration of doctors as caring and competent providers, SDM can be seen as a failure to honor these values in favor of exacerbating consumerism. If doctors are measured on whether they comply with all of a patient’s wishes, instead of the doctor’s professional opinion of the best course of action, there is no reason to involve the physician at all. In this way, SDM can introduce moral distress for physicians, if not appropriately implemented. Furthermore, patients may pressure the physician to administer tests or treatments that are not, in the professional opinion of the physician, justified. This conflict exists at all levels of healthcare and is concerning given the current landscape of heavily prioritizing patient satisfaction. Unnecessary or unindicated tests and treatments are a source of added risk, harm, costs, and healthcare utilization. When treating patients in the neurocritical care unit, this conflict presents during end-of-life decision-making, when families and surrogates may request interventions that are physiologically futile. Given the difficulty of definitively classifying inappropriate end-of-life interventions, this leaves physicians and patients with considerable gray areas in what is the best course of action for treatment decisions in the ICU.  Physicians in the ICU also experience internal conflict, arising from the expectation to implement SDM, while families

are often too overwhelmed to effectively engage in a discussion of that nature. It is not uncommon for families to prefer relying on the doctor’s judgment in the ICU, which runs counter to the pressure on physicians to employ SDM.  Ultimately the impact of SDM on clinicians has not been the focus of research efforts, which have instead focused on the patient impact, so we have an incomplete understanding of the systematic consequences of SDM for clinicians.

28.6.2 Conflicts for Family Members There are variable levels of patient interest in information, which influences the decision-­ making process and the opportunity to employ SDM. Even within families, differences of opinion exist regarding the desired level of involvement in decision-making, which complicates the SDM process when multiple family members are involved. In their requests for physiologically futile interventions, families frequently fail to consider whether the long-term outcome would be acceptable to the patient [8]. In this setting of severe injury, the family is unprepared for the sudden devastation of the patient’s injury, and this impacts their intellectual, emotional, and psychological capacity for engaging in SDM. In this way, the expectation of their involvement in critical treatment decisions can introduce moral distress and psychological trauma to the family.

28.7 SDM Drivers Notwithstanding the challenges and conflicts inherent to successful implementation of SDM, this model has several powerful drivers, including value-based healthcare, legal considerations, cultural fluctuations in autonomy, the Internet of things, consensus, and the affect heuristic. Studies have shown that SDM generates cost savings and as such it has generated interest as a means for supporting value-based healthcare (VBH) [11]. VBH is based on the notion of patient-centered value wherein healthcare costs are reduced by focusing on value to the patient,

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but the unintended consequence of such incentives is that the patient is seen as a consumer, the physician as a supplier, and healthcare as a commodity. This reframes the healthcare landscape significantly and introduces such fundamental considerations as whether patients understand quality of care, given the complexity of the science of medicine, and understand cost, where they are inherently shielded from the costs of healthcare by the insurance structure. The difficulty of this frameshift is that patients object to a cost-based focus in healthcare, instead preferring the best care regardless of costs, and that patient satisfaction is not a valid measure of the quality or effectiveness of care. For a complex, long-­ term condition like TBI, generating standardized outcome measures for evaluating the success of VBH is complicated, especially as the diagnosis of TBI encompasses a spectrum of clinical presentations and severities. Furthermore, some attributes of VBH, like cost-effective care and guideline adherence and standardization of care, do not align with the patient-centered care that is at the core of SDM. VBH remains a strong driver of SDM though, because of the contemporary support for VBH as a means for cost savings. Legal considerations are a driver of SDM because patients are frequently viewed as a potential lawsuit, which raises the question of whether this really represents shared decision-­ making or shared risk, especially in the context of TBI. In the USA, 75% of neurosurgeons view a patient as a potential lawsuit, a viewpoint reinforced by the high rate of litigation in the subspecialty and likelihood of at least one lawsuit over the course of a career in neurosurgery [12]. Considering this reality, clinicians may have incentive to shift responsibility for decision-­ making onto the patient. Whether that can reasonably and conscientiously be accomplished with a TBI patient depends on whether that patient is an adult with capacity, an adult lacking capacity, or a child [13]. In the latter two scenarios, a surrogate will be involved in the decision-­ making, a process which is bound by legal requirements but nonetheless introduces legal burden onto a third party who is not directly impacted by the decision. In that scenario, SDM

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provides a vetted framework for approaching the necessary treatment decisions and may provide insulation from risk for both the surrogate and the clinician. While there is currently insufficient evidence to determine whether SDM reduces medical malpractice lawsuits, the expectation of such means that legal considerations remain a driver of SDM [14]. As cultural fluctuations in autonomy have evolved, we now view the patient as independent. Given the advances in patient education and SDM, patients are now understood to be independent of, rather than dependent on, doctors. Patients want to be informed, but there is a limit to how much they want to know and can understand, especially as the complexity of care increases. Patients want to understand, and they want to be part of the conversation and deliberations, but ultimately, they want their doctor to make the decision. The most common question patients ask in the clinic is “What would you do?”. This reflects the difficulty of decision-­ making in the medical context and ultimately the reliance of the patient on the doctor’s expertise. As the pendulum has swung from physician autonomy toward patient autonomy, it has become a significant driver of SDM. As the Internet has developed and become accessible, the patient shifts toward becoming the expert. Equipped with the Internet, patients have medical information, tests, and treatments at their disposal, independent of their doctor. The Internet is a driver of SDM because the well-informed patient is more likely to seek participation in the decision-making process. However, while patients may be more informed, they may not necessarily be more educated, and they remain bound by the limitations of emotionally driven decision-making during stress [15]. Patient reliance on the Internet for medical knowledge can lead to a false sense of being informed, as there is much false and incomplete information to be found online. Beyond medical fact searching, the Internet has brought into the fold online reviews, which raises the question of the role of patient satisfaction. No correlation has yet been established between online reviews and quality of care, although they undoubtedly influence patient

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choice of physician. Because the use of SDM has been shown to improve patient satisfaction scores, clinicians are more likely to take this proactive step, in order to protect their online reputation on these public rating forums [16]. In this way, the proliferation of doctor rating sites on the Internet is driving physicians to incorporate SDM in order to improve patient satisfaction. Given that patients are autonomous, consensus between physician and patient must be reached in order for a treatment plan to proceed, and SDM is a means to assess the available information and reach a consensus. Tools such as evidence-­based medicine (EBM), artificial intelligence (AI) algorithms, and patient decision aids are available to facilitate effective SDM discussions. EBM is a critical component of SDM because its incorporation into the decision-­ making conversation allows patients to develop educated decisions based on scientifically validated information. AI algorithms can further enhance our ability to present relevant information to the patient during SDM discussions, using risk calculators to provide an individual risk profile or interactive tutorials to improve risk comprehension. With the increased attention paid to SDM in the clinical setting has come the proliferation of patient decision aids [17]. However, given the considerable challenges inherent to surrogate decision-making for TBI patients in the ICU, no such decision aids are currently in use for this patient population. Recently, a goals-of-­ care decision aid that meets international decision aid standards successfully underwent early feasibility testing with TBI patient surrogates in the ICU [18]. As these EBM, AI algorithm, and patient decision aid tools support the SDM discussion, so too does SDM support these tools. For example, an AI algorithm in a vacuum would be of limited utility to a patient, and it is only within the context of an SDM conversation that this tool can be appropriately leveraged to increase patient or surrogate understanding and educated decision-making. Within the affect heuristic framework, we acknowledge the patient as human, with all the psychological implications that follow. This involves such phenomena as the thinking fast and

slow decision process, the influence of emotion on risk perception, and susceptibility to nudging. On a subconscious level, the affect heuristic drives SDM because it drives the human thought process. Clinicians can address these drivers in how they present information in the SDM conversation. In the phenomenon of thinking fast and slow decision process, no single decision or preference exists within the patient, but rather two decision-making processes operate in parallel: one to produce a fast, gut response, emotional decision and the other to produce a slow, thoughtful, analytical decision. The way that clinicians frame and present information will trigger one or the other of these processes, and awareness of this reality will allow for more effective SDM conversations. The role of catastrophizing and negative feelings is shown to have a negative impact on perception, so it would therefore be prudent for clinicians to help patients or surrogates feel calm and comfortable before beginning any important SDM conversations [19]. Furthermore, nudging, or the practice of subtly steering an individual toward a decision without overtly violating their autonomy, may provide an ideal balance between physician expertise and patient autonomy. Nudging as a technique is still being debated, as some would claim that it violates the physician’s ethical responsibility to respect individual patient preferences. It is within our human nature as clinicians to subconsciously implement nudging, and so the impetus is upon us to raise our awareness of our use of nudging so that we may limit it and not allow it to overwhelm the patient’s preference. Recognizing that these affect heuristic phenomena are at play for our patients during decision-making, the need for effective SDM is even greater.

28.8 SDM Types Having established the impetus for, framework for, and substance of SDM, we can now explore the types of SDM. The SDM framework can be manifested and implemented in several different ways. The SDM types include shared rational deliberative (SRD) patient choice, SRD paternal-

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ism, SRD joint decision-making, and professionally driven best interest compromise [20]. In both SRD patient choice and paternalism, the process begins with a rational discussion of the relevant preferences, facts, and reasons. Then the final decision is left to the patient or physician, respectively. In this way, the principles of SDM are upheld, but the balance can be struck either toward patient autonomy or toward physician autonomy. This avoids the unattractive extremes of paternalism or consumerism while maintaining a variant of SDM.  In SRD joint decision-­ making, the emphasis is on rational deliberation in the hope of achieving consensus. This model is the most equitable, wherein both parties may speak freely, both parties are open to the other’s interests, and no interest is given more weight than another. This may be difficult to practically implement though, given the inherent power difference of the involved parties. Finally, in professionally driven best interest compromise, the goal is an effective decision, which, although it isn’t rationally preferable, is the one to which the patient would adhere. Through these various adaptations of the SDM model, it is demonstrated that SDM can be adjusted to meet the needs of various clinical settings and personnel.

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with the patient’s family and hopefully avoided the negative experience and subsequent formal complaint. Conflict of Interest  None declared. Funding: None.

References

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294 autonomy in shared decision-making. Health Care Anal. 2020;28:4–24. 14. Durand MA, Moulton B, Cockle E, et al. Can shared decision-making reduce medical malpractice litigation? A systematic review. BMC Health Serv Res. 2015;15:167. 15. Rosenbaum L.  The paternalism preference: choosing unshared decision making. N Engl J Med. 2015;373:589–92. 16. Bot AGJ, Bossen JKJ, Herndon JH, et  al. Informed shared decision-making and patient satisfaction. Psychosomatics. 2014;55:586–94. 17. Austin CA, Mohottige D, Sudore RL, et  al. Tools to promote shared decision making in serious ill-

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Traumatic Brain Injury and Resource Allocation

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Allan Taylor, Solomon Benatar, and Bettina Taylor

29.1 Introduction We live in a world where there is inequitable access to healthcare both internationally and in many cases within countries. The political and economic conditions that give rise to this are unlikely to be resolved despite efforts to promote universal access to healthcare. The reality is that 70% of the world’s population lives on less than 10USD per day, most at the lower range of close to 5 USD per day [1]. The global political economy, which is based on the political ideology of neoliberalism, has led to most of the world’s wealth and political power being in the hands of a few people. While a minority of wealthy countries and people enjoy unlimited privately purchased healthcare, for most, there are limits to what can be accessed. In the few successful high-­ income, public healthcare systems (Canada, the

A. Taylor (*) Division of Neurosurgery, University of Cape Town, Cape Town, South Africa e-mail: [email protected] S. Benatar University of Cape Town, Cape Town, South Africa Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada B. Taylor Cape Town, South Africa © Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_29

UK, Nordic countries), limited rationing results mostly in treatment delays or restriction of novel expensive treatments.

29.2 Contextual Considerations on Resource Limits For the majority of people globally though, there are severe restrictions on available healthcare, as publicly provided healthcare does not extend to costly acute care for all who require this, and private healthcare is unaffordable. Rationing in middle- and low-income countries is therefore not so much by design but by default. Across low-income countries, the average annual health expenditure was only US$ 41 a person in 2017, compared with US$ 2937 in high-income countries—a difference of more than 70 times [2]. Given these different levels of healthcare funding, it is not possible to think of universal standards of care beyond very basic primary care, and even defining universal approaches to rationing becomes difficult. Of course, efforts should be made to narrow the wealth gap, as healthcare disparities hamper world security. The COVID-19 pandemic has highlighted that all populations are vulnerable and that rapidly overwhelming disease pandemics can threaten even the wealthiest of countries.

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29.3 H  ow Do Limited Resources Apply to Traumatic Brain Injury (TBI)? The incidence and prevalence of TBI make it an important public healthcare issue worldwide. In 2016, there were 27·08 million (95% uncertainty interval [UI] 24·3–30·3 million) new cases of TBI. The number of prevalent cases of TBI was 55·5 million (53·4–57·62 million) [3]. Not only is TBI frequent, but the disability it creates results in high societal and economic costs. TBI is estimated to have caused 8·1 million (95% UI 6·0– 10·4 million) years lived with disability (YLDs) in 2016 [3]. The cost of TBI to the global economy is estimated to be 400 billion USD per annum in direct and indirect costs [4]. Good prevention strategies, effective acute care, and rehabilitation would reduce the burden but come at a cost. Advances in healthcare mean that we can save more TBI patients and outcomes are improved, but this is expensive treatment that is not available in all settings. Cost-effectiveness studies may show that treatment of TBI costs less than the long-term disability it creates when not treated well, but these studies require many assumptions when predicting outcomes and costs [5]. Furthermore, data used tends to come from high-income settings and may not apply to patients treated in less-resourced environments. Assuming that it was ultimately cost saving to treat traumatic brain injury though, it is still difficult to translate this into an increase in funding. In cost-effectiveness studies, direct costs refer to the hospital expenses of the acute treatment which are almost always higher for more aggressive care. Indirect costs are the loss of income that occurs because a disabled survivor can’t return to work, and costs are incurred in caring for survivors with a disability. Direct costs come from healthcare spending, but indirect costs do not, and these are costs that accumulate over the lifetime of the TBI survivor. Indirect costs are not funds that can be moved into health budgets. Even if politicians or administrators were to decide to increase funding for TBI to decrease the indirect costs, there are other obstacles to consider. Appropriate infrastructure may not be

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available to utilise the funding, and other diseases require treatment. Across different healthcare systems, there is considerable variation in political and societal priorities. Not only is there competition between diseases for resources, but even when considering TBI, there are competing medical interests. How much should be allocated to prevention, acute care, rehabilitation, chronic care, education, and research?

29.4 Framework for Priority Setting in Clinical Care The benefits and burdens that accrue to individuals in any society are determined by the particular political, economic, and societal frameworks of each society. These frameworks in turn determine the institutions, laws, and policies that apply to individuals. The ethical principle of distributive justice is concerned with providing moral guidance for the structures that determine the benefits and burdens in society. So when considering the benefits and burdens related to distributing health resources, morally relevant criteria such as need, benefit, cost, cost-effectiveness, equity, equality, and the rule of rescue (obligation to rescue from disaster situations) should be considered. As appropriate as these criteria are, they are often in conflict. Is it acceptable to spend large amounts of money to achieve good outcomes in a few or should we spend less on a large number of patients and accept moderate improvements? How much should be spent on end-of-life care and do the sickest patients deserve more funding? Who in society has the authority to make these choices? Philosophers have constructed theories of justice such as utilitarianism, egalitarianism, communitarianism, and capability theory in the quest to achieve fairness and justice, but these emphasise different values and lead to different outcomes [6]. Utilitarianism seeks to achieve the greatest good for the largest number of people. Outcomes are usually measured in quality-­ adjusted life years (QUALY), and a cost is determined per QUALY in order to allocate resources. Egalitarianism emphasises the equal moral status

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of all and hence the right to equity in the allocation of resources. Allocation of insufficient resources through a lottery would give all an equal chance of access, but this reliance on luck would eliminate the judgement required to achieve the best use of resources, to improve the overall health outcomes. Communitarianism stresses that the needs and rights of the individual are balanced within and against the common good of society. It appears utilitarian in seeking to maximise health and happiness within a group but further takes into account the priorities of a society. This may lead to choosing more extensive immunisation for many rather than extending end-of-life care for a few. Capabilities are the real opportunities that individuals have to improve their lives, and a focus on this framework allows enhancing capabilities of varying importance in different societies. Healthcare is viewed by many as a right and rationing as a politically intrusive issue [7]. Explicit rationing at a macro level approved by politicians is likely to be attacked and is therefore often avoided. This muddling through and the evasion of personal responsibility result from a lack of consensus on the best framework for making decisions. In an era of greater public awareness and a demand for transparency when it comes to healthcare funding, this approach, with implicit rationing, is unsustainable. In response to these shortcomings, in their review of limit-­ setting decisions in the USA managed care arena, Daniels and Sabin proposed a standard for procedural fairness in allocating resources— Accountability for Reasonableness (A4R) [8]. This is a practical tool that sets out four criteria that should be met in order for a rationing decision to be transparent and fair. 1. Publicity condition: decisions regarding limit setting in healthcare must be publicly accessible. 2. Relevance condition: these rationales must rest on evidence, reasons, and principles that all fair-minded parties (managers, clinicians, patients, and consumers in general) can agree are relevant to deciding how to meet the

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diverse needs of a covered population under necessary resource constraints. 3. Appeals condition: there is a mechanism for challenge and dispute resolution regarding limit-setting decisions, including opportunity for revising decisions in the light of further evidence or arguments. 4. Enforcement condition: there is either voluntary or public regulation of the process to ensure that the first three conditions are met. While A4R includes ethical, economic, legal, and policy considerations, refinement is required. For example, how stakeholders are chosen, how the debate is constructed/conducted, and how information is made accessible to the public. In practice, it is very difficult to initiate any health funding reform even with processes seeking accountability. Multiple parties are involved: healthcare funders, providers of care, and patients. When funders initiate any kind of restriction, healthcare providers and patients may believe it is to increase profits or protect reserves at the expense of patients’ health and providers’ income. Patients too may have a conflict of interest when deciding what should be treated. Powerful lobby groups exist and can unfairly attract funding for some diseases at the expense of others. Healthcare providers in a public healthcare system have less conflict, but in a private setting, personal income may influence priority setting.

29.5 H  ow Does Resource Allocation Affect TBI? Education, medical treatment, and research of TBI are unlikely to be funded under a single budget making priority setting and consequently rationing a difficult task. It is important to understand though that the more we know about TBI epidemiology, pathology, treatment, and outcome through research, the better placed we would be to allocate resources to treatment. The better physicians and healthcare institutions are informed through education, the more likely policies and

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practice will conform to available evidence, improve outcomes, and reduce costs. While a physician’s primary responsibility is to treat each individual patient, healthcare providers should also be advocates for education, research, and the common good of their society. The primary effect of rationing for patients with TBI and physicians treating them manifests in a clinical care setting in the form of limited access to investigations, operating time, intensive care beds, and rehabilitation services. There is seldom an explicit policy that defines who can access each level of care. Rationing of resources tends to be ad hoc or implicit. In many instances, rationing (or setting priorities) takes place only when resources are not available. For example, severe TBI are admitted to ICU until there are no more beds and those arriving later are denied access even if they have a better prognosis. Many physicians would argue it is not their role to play God and decide who lives or dies and would be reluctant to withdraw care from one patient in order to treat another. This exemplifies a “first come first served” rationing. Although it removes the stress of decision-making from healthcare providers and funders, it is not the fairest solution for patients. Rationing also takes place when there is a delay in patient transport or no access to a CT scan for a patient with TBI.  These result from infrastructure deficiencies that are often not under the control of medical staff and are accepted as “not my responsibility.” Such implicit rationing is not in the interests of patients, but is largely accepted by patients because understanding healthcare rationing is complex and requires insight into how healthcare is delivered. Healthcare providers and funders tolerate implicit rationing because change would be disruptive. Historical allocations of resources would need to be reviewed in light of disease importance, current outcome evidence, cost benefit, and many other variables. Implicit rationing is also tolerated because responsibilities are blurred. When a treatment is not implemented, the treating person can explain the lack of care as being the consequence of decisions made by another parties.

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Why then should there be an explicit rationing of healthcare resources? It can be argued that this is a better way of ensuring that those in need of care get equal access to evidence-based care. It requires that there is an evidence base to formulate guidelines and that such evidence is transparently applied. When evidence is not available, the process at least illustrates its requirement to avoid paternalistic decision-making, and it assigns responsibility to those funding and allocating resources. It also helps to inform patients that there are limited resources and that not all required care can always be implemented. In the 1990s, due to a combination of funding cuts and an increase in trauma seen at Groote Schuur Hospital in Cape Town, the neurosurgery service faced having insufficient resources to continue treating anything except trauma. With the help of bioethicists, lawyers, and administrators, a policy was formulated that limited care to the most severe TBI patients [9]. This enabled ICU beds to be freed and operating time to be available for patients with aneurysms, gliomas, meningiomas, and all the other neurosurgical pathology deserving care. The policy was crafted over the period of a year in line with the A4R principles. It was opened to public discussion and supported by administrators. The policy required all TBI patients to get full resuscitation including removal of compressive extra-axial haematomas. Once resuscitated and stable, patients with a motor score of 3 or less were not given continued intensive care. Families were sensitively informed that TBI patients in this state have a very low chance of an independent outcome and care would continue but not in an intensive care setting. Families were given time to discuss this and almost always accepted the decision. On the few occasions that it was not accepted, families were given the option of transferring the patient to a private facility for further care or a second opinion regarding the prognosis and mediation by an outside party. This policy is still in place and has allowed neurosurgery at the institution to provide care to many deserving patients who might not have

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been treated if all trauma patients were treated. This was not an easy policy to put in place. Not offering every chance to young patients who were well until their injury was hard for physicians and families to accept and no doubt some patients with intensive treatment may have done reasonably well. This needs to be balanced against the odds of a far better outcome for the patients who were given access to treatment. In conclusion, it can be said that there is no easy solution for rationing or priority setting. There will always be differences of opinion on how it should be done and what is a just distribution of resources. We need to be advocates for the patients we are responsible for but not at the expense of others. Conflict of Interest  None declared. Funding: None.

References 1. Kochhar R.  A global middle class is more promise than reality: from 2001 to 2011, nearly 700 million step out of poverty, but most only barely. Washington,

299 DC: Pew Research Center; 2015. https://www.pewresearch.org/global/2015/07/08/a-­global-­middle-­class-­ is-­more-­promise-­than-­reality/ 2. Global spending on health: a world in transition. Geneva: World Health Organization; 2019. https:// www.who.int/health_financing/documents/health-­ expenditure-­report-­2019.pdf?ua=1 3. James SL, Theadom A, the GBD Traumatic Brain Injury and Spinal Cord Injury Collaborators. Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18:56–87. 4. Mass AIR, Menon DK, Adelson PD, et al. Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol. 2017;16:987–1048. 5. Whitmore RG, Thawni JP, Grady MS.  Is aggressive treatment of traumatic brain injury cost-effective? J Neurosurg. 2012;116:1106–13. 6. Benatar S.  Daily Maverick 2020. https://www. dailymaverick.co.za/article/2020-­0 6-­0 9-­t he-­ complex-­j uggling-­a ct-­o f-­h ealthcare-­r esource-­ allocation-­during-­the-­covid-­19-­pandemic/ 7. Constitution of the World Health Organisation. Bull World Health Organ. 2002;80:983–4. 8. Daniels N, Sabin J.  The ethics of accountability in managed care reform. Health Aff. 1998;17:500–64. 9. Benatar SR, Fleischer TE, Peter JC, et al. Treatment of head injuries in the public sector in South Africa. S Afr Med J. 2000;90:790–3.

Research Ethics in Clinical Trials

30

Stephen Honeybul and Kwok M. Ho

30.1 Introduction

negative trials either go unpublished or be presented in a favourable manner that is not fully Medical research is important for many reasons supported by closer examination of the basic not least of which is to determine clinical effi- data. Indeed, it has been demonstrated that some cacy, safety and cost-effectiveness of any thera- highly cited clinical trials that report positive peutic interventions to ensure equitable results can have methodological flaws such that distribution of scarce healthcare resources for the their conclusions are either exaggerated or not maximal benefit of society. It was the recognition strictly correct [1]. These issues have provoked of this need that led to the concept of the evidence-­ considerable debate regarding the validity of the based medicine (EBM) which was introduced EBM movement and the direction in which it is and developed over 30 years ago. For many years, currently advancing. On the one hand, many gova well-designed randomised controlled trial ernment agencies have fully embraced the con(RCT), published in a high-impact journal, was cept and developed national and international seen to be the best way to advance clinical prac- infrastructures that have used evidence from clintice, and there is little doubt that this approach ical trials to develop an extensive array of guidehas significantly advanced clinical practice. lines to which clinicians are encouraged (often However, it has become increasingly apparent financially) to adhere. On the other hand, distinthat researchers are under considerable pressure guished clinicians such as John Ioannidis from to produce positive results in order to either Stanford University have called the movement no secure funding for ongoing research, enhance a more than advertising for the pharmaceutical reputation or elevate institutional status. This has industry. led to a clear publication bias that has seen many As with all such highly polarised debates, there are advantages and disadvantages on both sides of the argument; however, it is increasingly apparent that the approach to the EBM S. Honeybul (*) framework needs to change. Traditionally, eviDepartment of Neurosurgery, Sir Charles Gairdner dence was stratified according to its strength, and Royal Perth Hospitals, Perth, WA, Australia e-mail: [email protected] and a pyramid was constructed with meta-analysis of adequately powered (and well-designed) K. M. Ho Department of Intensive Care Medicine and School randomised controlled trials at the apex and of Global Health, University of Western Australia, clinical experience and background information Crawley, WA, Australia at the base. An alternative approach is to remove e-mail: [email protected] © Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_30

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the hierarchy of evidence completely and instead consider evidence as a whole, based on four independent domains, namely, background scientific information such as pathophysiology, clinical trials, clinical experience and patient preferences (Table  30.1). Each domain should have equal primary importance; however, this may vary depending on the quality and consistency of the clinical material, the trial design and the implications for clinical practice. The aim of this chapter is to explore some of the ethical issues that arise when this approach is applied to recent RCTs in traumatic brain injury (TBI).

30.2 Clinical Trials in Neurotrauma Over the past two decades, there have been a number of clinical trials investigating management strategies aimed at reducing mortality and improving outcome following TBI.  The most significant of these in terms of influencing clinical practice have investigated efficacy of corticosteroids, hypothermia, decompressive ­ craniectomy, intracranial pressure (ICP) monitoring and more recently tranexamic acid (Table 30.2).

Table 30.1  Domains of research

Domain Background scientific information

Clinical trials

Clinical experience

Patient preferences

Benefits A clear understanding of the underlying basic science and pathophysiology of the disease being studied is required to evaluate treatment efficacy and to design clinical trials appropriately A well-designed clinical trial is the most scientific way to evaluate a treatment and guide therapy, and large multicentre trials can be powered to assess small treatment effects that are statistically and clinically significant Clinical trials can be subjected to rigorous scrutiny either in peer review or following publication. They can minimise personal bias, and the results can be easily disseminated to a wide audience Trials with negative results can be just as important clinically as positive trials Allows an appreciation of individual clinical variability and that one size does not fit all Experience of previous clinical cases can guide patient selection for the right therapy at the right time Clinical experience is needed to critically appraise the evidence in a clinically balanced way Consideration of outcome is important because in certain circumstances neurosurgical intervention may expose a patient to an outcome that they and their families may feel to be unacceptable even though that could be considered acceptable to the researchers

Limitations Pathophysiology is not always converted into clinical outcome, and animal models may not be similar to clinical context

Relative importance in TBI trials Corticosteroids Hypothermia ICP monitoring

Researchers are under considerable pressure to produce positive results Half of all trials are never published, and positive trials are twice as likely to be published as negative trials. In addition, results may be presented in such a way that the implications for clinical practice may be overly exaggerated In addition, involvement of industry funding can distort trial design and how the results are presented or emphasised

Corticosteroids Hypothermia Decompressive craniectomy ICP monitoring Tranexamic acid

Clinical experience alone will expose a clinician to a relatively small number of patients (when compared to large clinical trials) Clinicians are subject to a number of conscious and subconscious cognitive biases Experience alone will lead to static patterns of practice Quality of life is subjective and difficult to assess. In addition, patients may adapt to circumstances that they might previously have felt to be unacceptable

Decompressive craniectomy ICP monitoring Tranexamic acid

Decompressive craniectomy

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Table 30.2  Some of the important randomised controlled trials in the field of traumatic brain injury (TBI) Corticosteroids

Hypothermia

Decompressive craniectomy

Trial MRC CRASH (Corticosteroid Randomization After Significant Head Injury) trial

NABISH I (National Acute Brain Injury Study: Hypothermia I) trial NABISH II (National Acute Brain Injury Study: Hypothermia II) trial

Design Randomised 10,008 patients in 239 hospitals from 49 countries with head injury and a Glasgow Coma Score of 14 or less, within 8 h of injury, to a 48 h infusion of methylprednisolone or placebo Randomised 387 patients with TBI to normothermia versus hypothermia (33 °C) within 6 h and maintained for 48 h Very early hypothermia in patients with severe TBI. Enrolled and randomised within 2.5 h of injury to normothermia versus hypothermia (33 °C) for 48 h

Results The risk of death was higher in the corticosteroid group (21%) than in the placebo (18%)

Outcomes in terms of disability, vegetative state or death were the same in both groups No utility of hypothermia as a neuroprotective agent

The DECRA (DECompressive CRAniectomy) trial

Randomised 155 patients with severe diffuse TBI (ICP greater than 20 mmHg for 15 min in the hour refractory to first-tier therapy) to bifrontotemporoparietal craniectomy or standard care

Patients in surgical group had lower ICP and fewer days in intensive care. No difference in mortality but worse functional outcome in the surgical group

The RESCUEicp (Randomised Evaluation of Surgery with Elevation of Intracranial Pressure) trial

Randomised 409 patients with severe TBI (ICP greater than 25 mmHg for 1–12 h despite maximal medical treatment, except barbiturate therapy). Surgical technique at clinician’s discretion

Clear survival benefit in surgical group but at the expense of an increase in the number of survivors either in a vegetative state or with severe disability

Comments Prior to the results of this trial, steroids were used extensively in patients with TBI. The trial significantly changed clinical practice. An important negative trial These are two trials amongst a number of very important trials investigating efficacy of hypothermia in the management of TBI. No protective benefit has been shown, and in all trials, there is a slightly higher mortality in the hypothermia arms of the trials. The results of these studies have had a significant effect on clinical practice The results of this study demonstrated that surgical decompression is not without risk and highlight the morbidity associated with the procedure. An important negative trial that curbed enthusiasm for early prophylactic decompression A positive trial in which the favourable outcome category was changed (similar to the stroke trials) to include upper severe disability. Very high crossover from medical to surgical arm may have confounded results (continued)

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304 Table 30.2 (continued) ICP monitoring

Tranexamic acid

Trial The BEST: TRIP (Benchmark Evidence from South America Trial: Treatment of Intracranial Pressure) trial

Design Randomised 324 patients with severe TBI to either parenchymal ICP monitoring or standard care of serial clinical and radiological assessments

CRASH III (Corticosteroid Randomization After Significant Head Injury) trial

Randomised 12,737 (9202 within 3 h) to receive tranexamic acid (1 g IV over 10 min and 1 g infused over 8 h) versus placebo

30.2.1 The Role of Corticosteroids in the Management of TBI Key domain points: • Background scientific information—Based on sound pathophysiological rationale given the potent anti-inflammatory effects of corticosteroids which may reduce cerebral oedema • Clinical trials—Highlight the harmful effect of corticosteroids in TBI and the importance of publishing negative trials and demonstrate how large well-powered randomised controlled trials can be used to determine small treatment effects (or a lack of it in this case) The Medical Research Council Corticosteroid Randomization After Significant Head Injury (MRC CRASH) trial investigated the role of steroids in traumatic brain injury [2]. Prior to the study, the use of high-dose corticosteroids was commonplace for patients with traumatic brain injury with some studies indicating that they were routinely used in up to 60% of neurotrauma

Results No difference in outcome between the two groups. The results did not support the hypothesised superiority of management guided by ICP monitoring No statistical difference in the primary outcome of head injury-­ related death. Mortality was reduced in patients with mild and moderate TBI who received tranexamic acid (12.5% vs. 14%)

Comments Raised issues of external validity and use of a placebo. Also, important to note that a monitor in itself will not improve outcome. It is the use of therapy guided by the result of the monitor that may be beneficial Essentially a negative trial that has been presented with a positive spin. Subgroup analyses are generally not a very reliable source of data with which to guide therapy but rather as source of hypothesis generation to guide future research. The results should probably guide further research rather than change practice

centres in the USA. Their use was based on sound pathophysiological rationale given the potent anti-inflammatory effects of corticosteroids and the inflammatory nature of some of the molecular responses to neurotrauma. In addition, efficacy of steroids in the context of the vasogenic oedema from cerebral and spinal tumours had been clearly established. However, the role of steroids in the cytotoxic oedema, which is the prominent cause of cerebral swelling, was largely unknown. In addition, there were many well-known side effects of corticosteroids, some of which are especially relevant in the context of acute neurotrauma, e.g. glucose intolerance and hyperglycaemia, hypercoagulopathy, immunosuppression, fluid retention and impaired wound healing. The trial was a well-organised prospective RCT conducted across 239 hospitals from 49 hospitals. There was blinding of both clinicians, patients and data analysts. Adults over 16 years of age with a Glasgow Coma Score (GCS) of less than 15 were randomised within 8 h of injury to receive either a loading dose of 2  g of methylprednisolone, followed by a 0.4 g/h maintenance

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for 48  h, or a placebo. The trial was unmasked after 10,008 patients because of a clear difference in mortality favouring placebo (corticosteroid group 21% mortality vs. placebo group 18% mortality). Notwithstanding some minor discussion regarding hyperglycaemia and possible unbalanced management of the two groups, what the trial clearly established was that steroids provided no benefit and, in some cases, probably caused some harm. Indeed, when considering mortality at 6  months, the number needed to harm was only 29, which is alarming when compared to the number needed to treat (NNT) to benefit (life saved) from aspirin following an acute myocardial infarction is 42 (NNT-42). Overall, this was a landmark trial which had a significant effect on clinical practice. It clearly demonstrated how large well-run studies can be used to detect small treatment effects which are not only statistically but also more importantly clinically relevant. It also demonstrates the importance of publishing a negative trial.

30.2.2 The Role of Therapeutic Hypothermia in the Management of Traumatic Brain Injury Key domain points: • Background scientific information—Highlights the importance of understanding the basic pathophysiology given that hypothermia is neuroprotective after hypoxic brain injury • Clinical trials—Demonstrate that hypothermia is not beneficial after TBI (which has a different pathophysiology from cardiac arrest) and also demonstrate the importance of publishing negative trials that may be statistically insignificant but clinically relevant, especially if the intervention could be harmful For many years, hypothermia was used to manage raised intracranial pressure (ICP) in the context of intractable intracranial hypertension. The rationale was that by lowering the ICP, cerebral perfusion would be improved, and this would

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reduce secondary brain injury and improve clinical outcome. In addition to these clinical studies, there was a significant amount of laboratory work that demonstrated the neuroprotective effects of hypothermia especially in the setting of hypoxic brain injury. However, notwithstanding these findings, it had become increasingly apparent that the use of hypothermia was associated with a number of complications, e.g. pneumonia, electrolyte disturbance, coagulopathy, cardiovascular suppression, impaired gastrointestinal motility and immunosuppression. The concern amongst clinicians was that any benefit gained by ICP control or neuroprotection would be offset by these complications, and this prompted researchers to conduct several large RCTs.

30.3 Hypothermia: Clinical Studies The National Acute Brain Injury Study: Hypothermia (NABISH:H 1) was one of the first large multicentre trials [3]. Three hundred and ninety-two patients with TBI were randomised to normothermia versus hypothermia (33 °C) within 6 h of injury and maintained for 48 h. The trial showed no clinical benefit and a high incidence of hypotension, hypovolaemia and electrolyte imbalance in the treatment group. The Hutchison paediatric trial showed a higher death rate and incidence of poor neurological outcome in the hypothermia group. (23 [21%] of 108 patients in the hypothermia group died vs. 14 [12%] in the normothermia group.) However, there were some randomisation discrepancies, a short cooling period of only 24 h and a fairly rapid rewarming with few facilities for treating rewarming complications [4]. The NABISH II trial investigated early cooling within 2 h of injury, and the outcomes were worse in the hypothermia group although this was not statistically significant [5]. The “Cool Kids” trial was stopped on the grounds of futility because hypothermia initiated early, used globally for 48–72 h and with a slow rewarming did not improve mortality at 3 months. Again, there

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was a non-statistical increase in mortality in the hypothermia group, (6 [15%] of 39 patients in the hypothermia group vs. 2 [5%] in the normothermia group) [6]. The Eurotherm study again showed a tendency to cause harm such that the trial also had to be halted early [7]. Sixty-nine (36.5%) of the 192 patients in the control group achieved a favourable outcome compared with 49 patients (25.7%) in the hypothermia arm of the trial. In addition, there was again an increased mortality in the hypothermia group (68 [34.9%] in the hypothermia group died vs. 51 [26.6%] in the normothermia group). An interesting finding from this study was that patients were excluded if they were already receiving therapeutic hypothermia. The implication would be that several centres had already adopted hypothermia into their routine clinical practice despite the lack of evidence available. Finally, the POLAR study conducted out of Australia was clearly designed with neuroprotection as its goal as patients were randomised and therapy was started by paramedics either in the field or in the hospital emergency department. The results of the trial were again no benefit in the hypothermia arm of the trial with a small, statistically non-significant increase in mortality [8]. Overall, the results of these trials have clearly established that whilst hypothermia can reduce the ICP, it does not provide clinical benefit and may, in certain circumstances, cause harm. These findings may appear to be counterintuitive, and to appreciate why this may be the case, it is necessary to examine the background scientific information carefully. In the first instance, there is the issue of ICP control and the evolution of management strategies for severe TBI over recent years. Throughout the 1980s, patients were routinely hyperventilated, placed in a barbiturate coma and more recently treated with therapeutic hypothermic because it had been repeatedly demonstrated that these measures could reduce the ICP in the context of medically intractable intracranial hypertension. However, aside from the potential neuroprotective effects of barbiturates and hypothermia, the predominant mechanism by which these three therapeutic modalities reduce ICP is

by cerebral vasoconstriction. Hyperventilation reduces the arterial carbon dioxide which in turn alkalinises the CSF and induces a reflex vasoconstriction. Barbiturates and hypothermia depress neuronal activity and reduce cerebral metabolism. This leads to a reduction in cerebral blood flow and blood volume due to autoregulatory flow metabolism coupling, and the subsequent reduction in cerebral blood flow has been clearly shown in several studies. Given the deleterious effect that ischaemia has on outcome, it is perhaps not entirely surprising that the reduction in ICP achieved by hypothermia does not necessarily translate into long-term neurological benefit. In terms of neuroprotection, notwithstanding the aforementioned laboratory studies, all animal models investigating neuroprotection have failed to demonstrate benefit if hypothermia is not instigated either immediately or within 2 h of the initial injury. Overall, the hypothermia studies have demonstrated the need to understand background scientific information of the disease process being investigated. They have also demonstrated the need to publish negative trials. Finally, and perhaps most importantly, the results of these trials have shown a statistically non-significant, but arguably clinically significant, tendency towards harm.

30.3.1 The Role of Decompressive Craniectomy in Severe Traumatic Brain Injury Key domain points: • Clinical trials—Highlight the importance of publishing negative trials and demonstrate how the primary endpoints of a trial can appear favourable depending on how they are defined • Clinical experience—Highlights how clinical experience is required to interpret results • Patient preferences—Demonstrate the need to consider long-term outcome of the intervention

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Decompressive craniectomy challenges the concept of the Monro-Kellie doctrine by providing extra space into which the injured brain can expand. The procedure has been used for many years initially in the context of TBI and ischaemic stroke and more recently in the context of other neurological emergencies. However, surgery will not reverse the effects of the pathology that precipitated the neurological crises, and the concern has always been that any reduction in mortality will come at the expense of an increase in the number of severely dependent survivors. These concerns prompted researchers to conduct several randomised controlled trials initially in the context of ischaemic stroke and more recently following TBI. In the stroke trials for patients under 60 years of age, it was only possible to demonstrate a “favourable” outcome if the favourable outcome category was changed to include a modified Rankin score (mRS) of 4 [9]. For patients over 60  years of age, notwithstanding the investigator’s conclusions that “Hemicraniectomy increased survival without disability”, most surgical survivors were fully dependent with severe neurocognitive disability [10]. In the context of severe TBI, there have now been two large multicentre randomised controlled trials where similar ethical issues require consideration.

30.3.1.1 The DECompressive CRAniectomy (DECRA) Trial This study examined the hypothesis that early bifrontal decompressive craniectomy in the context of diffuse cerebral swelling would optimise cerebral perfusion and improve clinical outcome by reducing secondary brain injury [11]. Patients were randomised at the relatively low ICP threshold of greater than 20  mmHg for more than 15 min in the hour after first-tier medical therapy. The results of the trial were that patients randomised to the surgical arm of the trial had a lower ICP subsequently and spent less time in intensive care. However, even though there was no survival benefit, at 6  months, the outcomes were worse in patients who had been randomised to the surgical arm.

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The lack of survival benefit was probably unsurprising given the enrolment ICP threshold (which is a lower threshold than is usually used in clinical practice); however, what the trial demonstrated was that at that particular ICP threshold, there was insufficient ongoing secondary brain injury and therefore any potential benefit obtained from improved cerebral perfusion was offset by surgical morbidity. Prior to these findings, it had been almost assumed that lowering the ICP would provide clinical benefit and in many ways the results of the trial highlighted that more considered judgement is needed by carefully balancing the risks with the benefits of surgery. The results of this study evoked considerable debate. Some commentators felt that “no conclusions regarding management of the use of decompressive craniectomy in patients with traumatic brain injury should be drawn from this trial and clinical practice should not be changed on the basis of these results”. However, adopting this position fails to recognise the importance of reporting and interpreting negative trials and the potential impact that they can have on clinical practice. Another criticism was that the ICP threshold at which patients were randomised was not representative of current clinical practice (which is to intervene at higher ICP thresholds). This may be a valid observation with the benefit of hindsight; however, if the trial had shown benefit, the patients in the trial would have come to represent the clinical practice of the future, and this would have had a significant impact on neurosurgical practice worldwide.

30.3.1.2 T  he Randomised Evaluation of Surgery with Elevation of Intracranial Pressure (RESCUEicp) Trial In this study, patients were enrolled and randomised at a higher ICP threshold which is more reflective of contemporary clinical practice in most neurotrauma centres [12]. The trial was conducted over a 10-year period between 2004 and 2014, and 409 patients were randomised amongst 2008 eligible patients, at 52 centres in 20 countries. The enrolment threshold was an ICP greater than 25 mmHg for 1–12 h despite maximal medi-

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cal treatment, except barbiturate therapy. Patients were then randomised to ongoing medical therapy with the addition of barbiturates or surgical decompression with the actual technique being at the discretion of the treating surgeon. The results of the study were consistent with the stroke trials in that a clear survival benefit was demonstrated in those patients randomised to surgical decompression. There were further similarities in that this reduction in mortality came as an almost direct result of an increase in the number of survivors either in a vegetative state or with severe disability. At 12-month follow-­up, there was a small statistically insignificant increase in the number of patients with a favourable outcome (34.6% in the medical arm of the trial to 42% in the surgical arm [p = 0.12]). However, this small increase was only seen when patients with upper levels of severe disability were included in the favourable category (in a similar fashion to the stroke trials that deemed a mRS of 4 as favourable). Without this re-­ categorisation of what was deemed to be favourable, the number of patients who survived with lower moderate disability or better (traditionally regarded as a favourable outcome) was very similar (32% favourable in the surgical arm of the trial and 28.5% favourable in the medical arm). There was also an increase in the number of survivors in a vegetative state in the surgical arm of the trial. At 6 months, the number of vegetative survivors increased from 4 out of 188 patients (2.1%) randomised to the medical arm of the trial to 17 out of the 201 patients (8.5%) randomised to the surgical arm. At 12  months, six of these patients had died: five patients in the surgical arm and one patient in the medical arm. A final issue was the high crossover of patients between the medical and surgical arms of the trial. Amongst the 196 patients randomised to receive medical therapy, 73 went on to have a decompressive procedure. This seems to indicate that, for the patients who crossed over, the clinicians were no longer in equipoise regarding the efficacy of the surgical decompression because patients developed what was considered to be genuinely intractable intracranial hypertension. Indeed, it could be argued that for those patients

who were randomised to the medical arm of the trial, either the ICP was insufficiently intractable to justify surgery, or all those patients with genuine medically intractable ICP had decompressive surgery regardless of allocation. How this large crossover of patients from the medical arm of the trial to the surgical arm should affect the interpretation of the results is difficult to determine, but as the authors stated, the observed treatment effect may be somewhat diluted. Indeed, it could be argued that there is a strong ethical imperative to assess the outcome in those patients randomised to the medical arm who subsequently underwent surgical decompression. If many of these patients went on to make a good long-term recovery, there would be strong grounds to argue in favour of the ongoing use of decompressive craniectomy. However, if there were a significant number of survivors either with severe disability or in a vegetative state (and who were analysed in the medical arm of the trial), support for the ongoing use of the procedure would be seriously called into question. Overall, the decompressive craniectomy studies have again demonstrated the need to publish negative trials and the need for clinical experience when interpreting the results and the implications for clinical practice. They have also demonstrated the need to consider patient preferences because surgical decompression represents an aggressive surgical intervention that will not reverse the effects of the primary pathology. There is no doubt that surgical intervention can reduce mortality. However, this increases the risk of survival with severe disability, and the ethical implications of this outcome for the person on whom the procedure is being performed must be carefully considered.

30.3.2 The Role of ICP Monitoring in the Management of TBI Key domain points: • Background scientific information—A high ICP is associated with poor outcome, and intuition suggests that monitoring and reducing the ICP may improve outcomes.

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• Clinical trials—In the population studied, monitoring the ICP did not improve. Highlight the importance of publishing negative trials. • Clinical experience—Highlights how clinical experience is required to interpret results.

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not support the hypothesised superiority of management guided by ICP monitoring over management guided by neurological examination and serial CT brain imaging. The results led to some debate within the literature, and there were several issues raised, two Intracranial pressure monitoring was devel- of which provoked considerable discussion. The oped over 50 years ago and subsequently became first was that of external validity given that the widely adopted as one of the foundations of neu- trial was conducted in a low-income country rotrauma management. The aim of ICP-guided where there was limited access to relatively management is to optimise cerebral perfusion expensive monitoring systems. The second and minimise secondary brain injury. It also iden- revolved around the issue of placebo because the tifies those patients who develop progressive trial involved randomising patients to not receive cerebral swelling which would preclude early a management strategy that would be considered weaning from sedation and on whom medical standard of care in the clinical environment from therapy can be targeted. However, notwithstand- which the primary investigators originated. ing the prognostic significance of raised ICP, one Indeed, such was the concern regarding the trial of the fundamental challenges in neurotrauma design that parallels were drawn with the zidovuhas been the inability to demonstrate that the fall dine trials conducted in Africa in the 1990s, when in ICP achieved by many medical and more HIV-infected pregnant women were randomised recently surgical therapy can be translated into an to receive either zidovudine or placebo. At the improvement in clinical outcome. There is also time, it was known that zidovudine reduced limited evidence that ICP-directed therapy maternal to infant transmission of HIV. The use improves clinical outcome, and this prompted of a placebo would have been denied in any high-­ researchers to conduct the Benchmark Evidence income country; however, because the trial would from South America Trial: Treatment of benefit those patients randomised to receive zidIntracranial Pressure (BEST: TRIP) trial [13]. ovudine (who would not receive therapy without The trial was a multicentre RCT conducted the trial), it was deemed ethically acceptable. across four Bolivian and two Ecuadorian hospi- Further parallels were drawn with the Tuskegee tals amongst a group of intensivists who routinely trial in which African American men with syphimanaged neurotrauma patients without ICP mon- lis were not treated with penicillin (which had itors. The primary hypothesis of the trial was that become available), in order to continue a study a management protocol based on the use of ICP into the natural history of the condition. monitoring would result in reduced mortality and Whilst the trial investigators were robust in improved neuropsychological and functional defence of their study, there remained some recovery at 6  months. Between 2008 and 2011, points of discussion. They had asserted that this 324 patients who were 13 years of age or older, study was not a study of ICP monitoring per se with a GCS of 3–8, were randomised. Patients and there was no placebo because both groups assigned to the pressure monitoring group had a were afforded highly aggressive, protocol-driven, parenchymal monitor placed, and therapy was neurological management and there was no difprotocol driven to maintain an ICP of less than ference in the incidence of prespecified clinical 20  mmHg. Patients randomised to the non-­ neurological deterioration criteria between the monitored group received care based on a pretrial two groups. designated standard of care, using serial clinical However, adopting this position fails to recogand radiological assessments. The results of the nise that monitoring, in itself, cannot improve study were that there was no difference in out- outcome, unless an intervention that can reduce come between the two groups at 6 months, and ICP is proven to confer benefits. What changes the investigators concluded that the results did outcome is the clinician’s interpretation of the

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result from the monitor and the degree to which therapy is guided by the information gained. The therapy of one group was guided by the results obtained from the ICP monitor (which is a management strategy the primary investigators would usually use). The other group’s therapy was not (which is a management strategy the primary investigators would not use). Whilst it is probably unfair and perhaps injudicious to compare the BEST: TRIP trial with the zidovudine trials or the Tuskegee study, it is difficult to see how, from an ethical standpoint at least, they are not receiving care that certain investigators (in high-income countries) would possibly regard as suboptimal. The primary investigator’s position was further weakened by the observation that many of them have been involved in compiling guidelines that support and advocate for the routine use of ICP monitoring [14]. It was precisely because of these guidelines that it was felt that it would be ethically unacceptable to carry out such a study in a high-income country in which ICP monitoring was deemed standard of care. Whether the second group is technically a “placebo” group can be a point of ethical debate; however, a more transparent and ethically acceptable position would be to acknowledge that in this particular trial and in this patient population, ICP-guided therapy has not been proven to provide benefit, similar to the use of a pulmonary artery catheter in circulatory failure. Given that the current brain trauma foundation guidelines also recognise that there is very limited evidence that monitoring the ICP improves outcome and because a significant number of trauma centres do not routinely use ICP monitors, the results of the trial would perhaps lend support to a similar study in a high-income country. Indeed, judging by the tone of some of the debate, it would appear that there are a significant number of commentators with sufficient equipoise to conduct such a study. Overall, the investigators of the BEST: TRIP trial should be congratulated on an excellent collaborative study in a difficult group of patients. There is certainly no need to question their ethical standards and their motives behind conducting such a trial. They have highlighted the need to

publish negative results and perhaps more importantly underscored the issues that need to be considered when investigators from high-income countries conduct research in low-income countries and the ethical imperative to protect what may be perceived to be vulnerable populations in clinical research.

30.3.3 The Role of Tranexamic Acid in TBI Key domain points: • Clinical trials—Highlight the importance of publishing • Clinical experience—Highlights how clinical experience is required to interpret results and their clinical significance Over the past decade, there has been significant interest in use of tranexamic acid (TXA) as a therapeutic agent in the context of severe haemorrhage. There has been a detailed analysis of the data in a previous chapter, so this will not be repeated; however, the presentation of the results of trials investigating clinical efficacy of the drug serves as a good example of the pressure researchers are under to produce positive and impactful results. The World Maternal Antifibrinolytic (WOMAN) trial investigated use of TXA in the context of postpartum haemorrhage [15]. The results of the trial were negative in that the primary outcome (a composite of mortality and hysterectomy) occurred in 5.3% of the TXA group and 5.5% of the placebo group (p  =  0.65). In addition, all-cause mortality was unchanged (2.3% vs. 2.6%, p = 0.16). However, shortly after publication of the trial, headlines appeared in the popular press claiming “Overlooked Drug Could Save Thousands Of Moms After Childbirth” or “Cheap lifesaver cuts deaths by a third”. These would certainly seem at odds with the results of the primary outcome; however, closer examination of the data confirmed that there was a small reduction in one of the secondary outcomes. Death due to bleeding was reduced by 0.4%, and this was statistically significant (1.5% vs. 1.9%;

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p  =  0.045; risk ratio 0·81, 95% CI 0·65–1·00). The difference here is small, and implications for clinical practice are difficult to determine, so it is hard to see how this can justify the aforementioned headlines. More recently, the CRASH 3 trial investigating efficacy of TXA in the context of TBI was published with similar promotion [16]. There were infographics claiming that TXA could save one in five patients with TBI, and this was accompanied by a couple official videos. In one video, the lead investigator claimed that TXA could save tens of thousands of lives worldwide. In another, a patient seems to attribute her fortunate recovery from a TBI to efficacy of the drug (although we do not know which arm of the trial she was enrolled into). However, the results of the trial were negative because there was no statistical difference in head injury-related death (the primary outcome) between those randomised to receive TXA and those randomised to receive placebo (18.5% with TXA and 19.8% with placebo; RR 0·94; 95% CI 0·86–1·02). There was also no difference in disability at 28 days. Despite this negative result, there was a subgroup of patients for whom TXA appeared to provide a small, but significant, benefit, and this was in patients with mild and moderate injury severity. If patients with a severe head injury (GCS 3–8) were excluded from the analysis, amongst the remaining patients, there was a significant reduction in mortality in patients with a mild-to-moderate head injury, i.e. Glasgow Coma Scale (GCS) 9–15 (5.8% TXA vs. 7.5% placebo) (166 vs. 207 events, RR  =  0·78 95%CI 0·64– 0·95). This is potentially important finding that may have huge potential for this subgroup of patients. Or it may not. Subgroup analyses (even in a large subgroup such as this) are generally not an exceptionally reliable source of data with which to guide clinical therapy, but rather to generate hypothesis which can be used to direct future research. There was no doubt that the trial was based on sound pathophysiology because it was aimed at patients who had an isolated TBI and specifically excluded patients with major extracranial bleeding. In these circumstances, patients rarely die

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from loss of blood volume but rather from evolution and expansion of intracranial contusions, which is a well-recognised phenomenon in neurosurgical practice. If a patient survives the “primary” insult with several intracranial contusions, intuitively it would seem reasonable to use TXA to stabilise these lesions and prevent their expansion. However, because of the way the data has been presented, clinicians could easily be misled into thinking that that TXA has been proven to be beneficial for all patients with TBI which is clearly not the case. Administration of the drug is highly time dependent in a specific subset of patients whose clinical characteristics have yet to be definitively determined. The absolute reduction in mortality was small (1.7% [5.8% vs. 7.5%]) with the number of patients needed to treat to prevent one death being 59. This should not detract from what is potentially a particularly important finding; however, it should not make clinicians prioritise administration of the drug above other well-established resuscitation and transfer procedures. No matter how tempting, a tendency to generalise a positive secondary outcome to increase a trial’s impact must be resisted by researchers as well as editors. In addition, there is the important issue of safety. All drugs that have a physiological effect have side effects, especially one that can possibly reduce mortality in the extraordinarily complex disease of TBI. If overall TXA provides no benefit, but an analysis of a subgroup shows an increased survival, then there must be another subgroup that is harmed (to balance out the data even though it might not have reached statistical significance). Indeed, although the CRASH 2 (investigating TXA in major trauma) and the WOMAN studies determined a small benefit if TXA is given within 3  h, data from the same studies showed that mortality is increased if TXA is given later than that [15, 17]. The results in the CRASH 3 were similar (RR1.31). This is an important finding that cannot be ignored, and it serves to emphasise that caution must be exercised before TXA is incorporated into routine clinical practice for all patients with TBI, regardless of its severity.

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However, notwithstanding these limitations, there would appear to be a very specific subset of patients for whom TXA may be indicated, and this must be the focus of future research. Overall, this was an excellent trial conducted in a difficult group of patients to study, and there is a tremendous amount of data which can be used to guide further research. The CRASH-3 collaborators should be commended on their efforts; however, the results have been presented in such a way as to possibly cause more confusion than clarity. It is certainly an important source of information on which to base further research; however, there is a danger that views regarding efficacy will become polarised. Further work is certainly required to define the subset of patients that may benefit as well as to evaluate the long-term outcomes in order to determine if there are certain patients who may be harmed.

30.4 Conclusion There is no doubt that the evidence gained from clinical trials will continue to provide evidence to inform practice. However, it is becoming increasingly apparent that there are limitations to this approach. Background scientific information gained from knowledge of basic pathology, combined with clinical experience, are required, not only to interpret the data but also to consider the clinical application to an individual patient. In addition, it is increasingly recognised that there is an ethical imperative to consider patient preferences, especially in the context of traumatic brain injury where outcome cannot be simply dichotomised into only life or death. Rather than stratifying evidence according to a fixed hierarchy, the EBM movement probably needs to evolve such that each of its constituents and their overall consistency are included in the decision-making paradigm. Whether the overall approach to clinical trials needs to change remains to be seen, but given the increasingly complex nature of modern-day medicine, the time may have come for a more uniform approach to reporting that mandates publication and recog-

nises (as demonstrated here) the importance of negative trials. Conflict of Interest  None declared. Funding: None.

References 1. Ioannidis JP.  Why most published research findings are false. PLoS Med. 2005;2:e124. 2. Roberts I, Yates D, Sandercock P, et  al. Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial. Lancet. 2004;364:1321–8. 3. Clifton GL, Miller ER, Choi SC, et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med. 2001;344:556–63. 4. Hutchison JS, Ward RE, Lacroix J, et al. Hypothermia therapy after traumatic brain injury in children. N Engl J Med. 2008;358:2447–56. 5. Clifton GL, Valadka A, Zygun D, et  al. Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study:Hypothermia II): a randomised trial. Lancet Neurol. 2011;10:131–9. 6. Adelson PD, Wisniewski SR, Beca J, et  al. Comparison of hypothermia and normothermia after severe traumatic brain injury in children (Cool Kids): a phase 3, randomised controlled trial. Lancet Neurol. 2013;12:546–53. 7. Andrews PJ, Sinclair HL, Rodriguez A, et  al. Hypothermia for intracranial hypertension after traumatic brain injury. N Engl J Med. 2015;373:2403–12. 8. Cooper DJ, Nichol AD, Bailey M, et al. Effect of early sustained prophylactic hypothermia on neurologic outcomes among patients with severe traumatic brain injury: the POLAR randomized clinical trial. JAMA. 2018;320:2211–22. 9. Vahedi K, Hofmeijer J, Juettler E, et al. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol. 2007;6:215–22. 10. Jüttler E, Unterberg A, Woitzik J, et  al. Hemicraniectomy in older patients with extensive middle-cerebral-artery stroke. N Engl J Med. 2014;370:1091–100. 11. Cooper DJ, Rosenfeld JV, Murray L, et  al. Decompressive craniectomy in diffuse traumatic brain injury. The DECRA Trial Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group. N Engl J Med. 2011;364:1493–502. 12. Hutchinson PJ, Kolias AG, Timofeev IS, et al. Trial of decompressive craniectomy for traumatic intracranial hypertension. N Engl J Med. 2016;375:1119–30.

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13. Chesnut RM, Temkin N, Carney N, et  al. A trial of 1 6. CRASH-3 Trial Collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events intracranial-pressure monitoring in traumatic brain and other morbidities in patients with acute traumatic injury. N Engl J Med. 2012;367:2471–81. brain injury (CRASH-3): a randomised, placebo-­ 14. Bratton SL, Chestnut RM, Ghajar J, et al. Guidelines controlled trial. Lancet. 2019;394:1713–23. for the management of severe traumatic brain injury. J 17. CRASH-2 Trial Contributors. Effects of tranexamic Neurotrauma. 2007;24(Suppl 1):S14–20. acid on death, vascular occlusive events, and blood 15. WOMAN Trial Collaborators. Effect of early transfusion in trauma patients with significant tranexamic acid administration on mortality, hysterhaemorrhage (CRASH-2): a randomised, placebo-­ ectomy, and other morbidities in women with post-­ controlled trial. Lancet. 2010;376:23–32. partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017;389:2105–16.

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31

Aakanksha Rana, Caroline M. W. Goedmakers, and Timothy R. Smith

31.1 Introduction

this unprecedented growth of data and emergence of related data technologies (i.e., machine learnThere is massive potential for healthcare to ben- ing, artificial intelligence, and robotics), there is a efit from the two largest technological innova- growing reliance on computer algorithms to tions of the twenty-first century: big data and interpret and analyze this data. In fact, historical artificial intelligence (AI). Backed by machine statistical approaches are not capable of managlearning algorithms, AI has opened multitudi- ing this volume and variety of data, making us nous opportunities of knowledge generation from increasingly reliant on artificial intelligence to big data. Machine learning, a fundamental driver help discover meaningful signals from an otherof current-generation AI, feeds on big data to wise impossibly noisy and expanding universe of improve its performance and identify underlying data. The increased utilization of machine learnpatterns to accomplish predefined goals. ing and artificial intelligence raises a host of ethiWith an explosion of healthcare data ranging cal healthcare issues. With the gradual decline of from basic science, clinical, numerical, language-­ direct human participation and supervision of based, and imaging data to vast amounts of data utilization, and the automation of processes, administrative and economic data, artificially pathways, and algorithms that were historically intelligent computer programs are well posi- curated by natural intelligence, several issues tioned to harvest, manage, analyze, and interpret have emerged. this data to optimize healthcare delivery. In fact, This chapter will attempt to frame the ethics there are some tasks already, in which machines of artificial intelligence within framework of might outperform clinicians. It is now claimed autonomy, justice, non-maleficence, and benefithat AI can more accurately diagnose skin cancer cence, proposed by Beauchamp and Childress. than a board-­certified dermatologist and predict breast cancer better than a radiologist [1]. With

31.2 Background

A. Rana · T. R. Smith (*) Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA e-mail: [email protected] C. M. W. Goedmakers Department of Neurosurgery, Leiden University Medical Center, Leiden, Netherlands © Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_31

The development of the Internet of things (IoT), ranging from personal computers and the Internet itself to smart devices such as smartphones, occurred with amazing speed. It took nearly 450  years for technology to advance from the printing press to the telephone. It took 70 years 315

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for more than 90% of American homes to have a television. Today, it is estimated that more than five billion people have mobile devices. First introduced in 2007, the smartphone is the fastest, most widely adopted technology ever developed. By 2020, 90% of world’s population older than 6 are estimated to have a smartphone. From the dawn of human civilization till the turn of the century, humans created about 5 exabytes of data. We now produce 5 exabytes of data every day. Recording digitized observations for optimal outcomes has become the norm in every sphere of human life, be it legal, medical, commercial, political, or academic. Over the last few decades, this unprecedented growth of data from the IoT has helped create an entirely new field of “data science.” Data science, which combines the fields of statistics, epidemiology, applied mathematics, engineering, and computer science, seeks to derive meaning from this burgeoning and complex world of data. With billions of devices connected across the world via the Internet, global digital data alone is approximated to be over 90 zeta-bytes (zeta-byte: one sextillion byes) by the end of 2025. The burgeoning scale of data growth can also be seen in Google’s massive $13B investment, to expand its cloud-based capacity in the USA and Europe. Data commercialization has followed closely with the rapid expansion of data creation. The four largest companies in the world in 1969 were General Motors, Exxon, Ford, and General Electric, all representing transportation and energy sectors. In 2020, the four largest companies in the world are data and technology corporations: Apple, Microsoft, Amazon, and Alphabet. These companies have a combined worth of approximately $4T, which is more than every country’s GDP except for the top three (USA, $21.5T; China, $14.1T; and Japan, $5.1T). The capacity to generate wealth from data, and the incentives this creates, has made the need to examine the ethics of data utilization even more pressing. Healthcare has also seen an exponential growth of data. The advent of the electronic health record (EHR) has contributed to this, and as more people are getting enrolled into EHR

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across the globe, both the volume and velocity of health data are increasing commensurately. This logarithmic growth in healthcare data not only is a result of active clinical data collection in the form of EHR but also encompasses data from varied sources including administrative data, hospital data, payer records, wearable and other mobile health devices, geographical positioning systems, and social media accounts. This highlights the immense variety of health data, which introduces uncertainty into attempts to measure it. Healthcare practitioners have always paid special attention to uncertainty around data, its collection, building proper standards, and validation protocols. Most medical journals quantify uncertainty and give confidence intervals in their research projects involving patient cohorts. This comes under the broader definition of veracity of healthcare data. In summary, volume, velocity, variety, and veracity are the big data pillars upon which meaningful health data science can be performed. Understanding and analyzing such expansive longitudinal data for the purpose of improving patient outcomes requires both clinical and technical knowledge. This knowledge comes at a cost, including building infrastructure, acquiring technical know-how, as well as the development of novel analyses. This complex data apparatus is unwieldy for the typical physician and has led to a major increase in development and deployment of big data analytic tools to analyze and interpret granular datasets. In addition to data analytics infrastructure, there have also been spectacular advancements in artificial intelligence/machine learning (AI/ML) tools that can better aid clinicians in real time, to take informed decisions regarding the health of their patients. By AI, we mean the branch of science which aims to develop and study the intelligence demonstrated by machines, unlike the intelligence demonstrated by humans or animals. Researchers have long been studying the development of machine intelligence complex enough to understand its environment and optimize decision-making. Machine learning (ML) which is a subset of AI uses training data to build mathematical models which can effectively

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p­ redict or take decisions without explicitly being programmed to do so. After a breakthrough in the field of computer vision and robotics, AI has been actively investigated and deployed in a variety of domains including manufacturing, defense, aerospace, pharmaceutics, and fashion. In the last few years, data scientists within the healthcare space have also been exploring its potential for better patient outcomes. For example, several AI, or rather ML, tools have been deployed for a wide variety of tasks in neurosurgical care, ranging from predicting tumor margins on cerebral MRIs, detecting intracranial hemorrhage on CT scans, or even detecting lesions in different organs. More recently, the COVID-19 pandemic has seen a plethora of projects that have shown the effectiveness of AI tools in either estimating the extent by segmenting consolidations, pulmonary nodules, or pleural effusions in lung CTs or automatically assessing the pulmonary disease severity in COVID-19 patients and predicting whether these patients would require intensive care in the future.

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their surrogates. As the publication rate for new medical research articles is now estimated at one million each year, AI-based “speed-readers” can offer computational help to healthcare providers so that they can keep up with advances in their own disciplines. This can be done using commercial artificial intelligence (AI) search engines, i.e., IRIS.AI, or other free AI-powered tools such as Microsoft Academic, Semantic Scholar, or non-commercially developed deep learning algorithms. With AI systems helping guide clinical decision-making, it will still be the responsibility of the treatment team to safeguard a patient’s autonomy. One of the roles that physicians will increasingly assume is that of interpreter of algorithmic treatment pathways. Even more revolutionary is the idea of a so-called autonomy algorithm that proposes the use of machine learning technologies to integrate data mined from EHRs and social media in order to estimate the confidence of the prediction that a patient would consent to a given treatment. However, patient outcomes are rarely binary, and higher-dimensional data introduces computational complexity that multiplies existing treatment complexity, 31.3 Ethical Outlook especially in the case of neurosurgical care. As treatment decisions become more complex, and AI has the potential to revolutionize healthcare, more opaque, informed consent for these decibut there are a growing number of concerns sions becomes much more taxing for patients and regarding the inherent ethical pitfalls. Several their families. recommendations and guidelines are being disBeneficence and non-maleficence can be seen cussed dealing with pressing issues ranging from as closely related in the context of the usage of transparency, reliability, responsibility to respect technological advancement in medicine. While for human rights, among many others. All such beneficence stands for balancing the benefits healthcare AI guidelines must be discussed while against the risks and costs involved, non-­ considering the fundamental principles of ethics maleficence means avoiding the causation of in medicine: autonomy, beneficence, non-­ harm. To closely adhere to these principles, the maleficence, and justice. technology needs to be primarily accurate and Medical ethics believes in a patient’s (or their reliable. AI algorithms, in general, are trained surrogates’) right to have autonomy of thought, from large databases of patient data to predict intention, and action when making decisions the probabilities for individual patient diagnosis regarding their healthcare. However, a sufficient and prognosis. The algorithmic data dependence understanding of the medical information is makes it essential to question the following essential for patients or their surrogates to make a properties of the data: i) source, ii) purpose, iii) truly autonomous decision. Clinicians and the consistency (namely, frequency and formats), healthcare providers have a responsibility to dis- and iv) relation to testing environment. Training seminate this information by building a strong on an unsuitable dataset could result in a high relationship of trust and care with patients and false positivity and false negativity rates as well

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as high uncertainty. One such example is observed when International Classification of Diseases (ICD) codes from the EHRs are directly used as labels (or ground truths) for training. This may lead to a poor diagnostic prediction because their primary purpose is for billing. Some of the data-­related bias can be corrected during the training phase of the model; however, in general, an awareness is required to delve deeper into data curation procedures to recognize any potential threats to reliability. In addition, modelling algorithm awareness of individual patient circumstances with longitudinal data, i.e., by developing personalized prediction modelling, is one potential solution that performs risk/benefit evaluation in the context of long-term patient care [2]. In elective spine surgery, this kind of personalized prediction modelling has been used to predict nonroutine discharge after elective spine surgery [3]. The ethical principle of justice stands for sharing the burdens and benefits of any technological advancement equally among all groups in society. Practically however, inequalities in medicine are systemic and closely intertwined with social inequalities. Data collected from most healthcare systems also reflect many such inequalities that exist due to race, sex, and other socioeconomic disparities. Racial and gender biases have already been a pressing concern in several AI systems deployed in non-medical domains. In facial recognition algorithms, this was shown by a high misclassification of darker females as compared to a high accuracy for the classification of lighter males. Moreover, image searches for highly paid positions such as CEO produce fewer images of females, and job search ads for these positions are less likely to be presented to women [4]. AI healthcare prediction systems trained on such datasets potentially bring unintentional injustice to individuals that are under-represented due to systemic socioeconomic disparity. For example, algorithms may predict that an individual should receive surgery just because the model is trained on a dataset which is biased toward the group that is well insured. In the reverse scenario, models may even predict a low survival rate to financially marginalized patients. To protect against algo-

rithmic bias due to under or over data representation, there is a need for build-in checkpoints to ensure more representative databases are used for training AI systems.

31.4 Pathway for Ethical Healthcare 31.4.1 Transparency, Responsibility, and Reproducibility Transparency, reproducibility, and responsibility are the three most consistently discussed factors with regard to contemporary discourses around AI. Transparency, intricately linked with reproducibility and responsibility, is a multifaceted concept in various domains such as psychology and governance. In the context of AI, transparency is often conceived as algorithmic explainability (with reference to interpretability) and trust in the model for its decision-making ability. It is the foundation for the assessment of risks and benefits involved in the decision-making process while maintaining disclosures of procedures involved in data collection, curation, and usage. One of the greatest challenges with the use of AI is its un-interpretable nature. Often referred to as a “black box,” the predictive mechanism with logical reasoning is hidden not only from the users who don’t understand the underlying sophisticated computations but also to the system developers. In healthcare, explainability and interpretability of the system are essential. Transparency in the decision-making process can not only help to build trust in the patient-­ healthcare personnel relationship but also improve the quality, safety, and efficiency of the overall system. Conversely, the inexplicable nature of the underlying algorithmic decision-­ making process can undermine confidence and trust between physicians and patients. Arguably, understanding the complex mathematics behind the predictive modelling is not important; however, the interpretation and justification of decisions made by such models are essential. Let’s reflect on the decision-making

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criterion in clinical and machine learning setting. To date, clinicians and care providers provide recommendations for their patients combining their knowledge, critical thinking, and experience. There exists a logical and explainable reasoning based on the principles of causal reasoning, i.e., “What if?”. For example, a clinician would recommend a certain treatment or a pathway for their patient, by critically and logically analyzing multiple possible routes, as in why treatment X is better than treatment Y. The current learning paradigm, on the contrary, is based on classical machine learning algorithm designed to learn a unique relationship between disease D and output X.  Unable to explore the causal inference learning while exploring multiple decision routes, these algorithms may not answer why treatment Y is a bad option. It may be that building explainable solutions in healthcare by incorporating causal reasoning could help to provide a more robust explanation to unanticipated predictions. Responsibility is yet another challenging facet of AI development that goes hand in hand with its interpretability. Responsibility can be seen from multiple viewpoints ranging from individual to institutional level. Generally, it is understood in terms of “holding accountable” and requires that reasons are provided for the actions taken, so as to justify those actions in accordance with some set of rules or standards for evaluation. Accountability becomes especially important whenever the exercise of certain actions has the capability to cause harm. Recognizing the potential power and scale of the actions that AI systems can exert in the socio-technical affairs in real world only serves to highlight the need for accountability. However, given that legal systems consider humans as the only responsible agents, the question arises as to who should be blamed if an AI system causes the harm? Serious concerns over AI’s “algorithmic accountability” emerged within the AI community after a woman was killed after she was struck by an autonomous vehicle in 2018. Imagining a similar situation in a clinical setting would be equally dangerous. With no or limited understanding of the functionality and specification of

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AI models, how much responsibility would a medical professional take if a model fails to provide a correct analysis? Moreover, seeking multiple contributions from individuals, institutions, servers, machines, software developers, and the end users/institutions makes algorithmic accountability a difficult problem. Algorithmic accountability, after all, depends on answerability of their model. Some positive actions to develop better protection can be observed by FDA’s new guideline draft for clinical decision support for software systems that are using machine learning algorithms while laying foundations for model reliability. These guidelines detail some well-established risk management and best-practice guidance while considering the challenges and opportunities in AI modelling such as incorporating real-world evidences in training and validation feedback loops. Alternatively, current legal frameworks within national boundaries comprise data protection law, consumer protection law, and constitutional law to protect human rights. These laws should also play a significant role in drafting algorithmic accountability guidelines by examining the implications of advanced AI algorithmic solutions. Reproducibility generally refers to the ability to reproduce the results of a previous study. Though this term is often used interchangeably with concepts like “replication” and “repetition,” reproducibility aims at reproduction of computational results alone, where a sufficient amount of annotated data and code sharing is provided. Recently, the increase in rates of scientific paper retractions has highlighted the staggering reproducibility crises of results in several scientific subdomains including science and biomedicine [5]. The field of AI has not been untouched. Due to its bigger scope and scale of effect in real-­ world application setting, reproducibility of AI system has become critical, and a number of machine learning-based models have been developed to create clinical tools for diagnosis and prognosis. In neurosurgery, machine learning has also been developed to conduct research more easily and efficiently by automating chart review and

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systematizing analysis of pathology reports [6]. However, clinical models have shown reproducibility challenges; indeed, one commonly observed phenomenon in clinical setting is that a doctor at a different hospital might observe an entirely different set of results when using the same AI model [7]. Such reproducibility errors in healthcare stem from lack of clinical or biomedical data. Healthcare datasets are primarily protected due to privacy concerns, which is not a concern in non-healthcare domains such as computer vision or natural language processing. There is also less tendency for code release, preprocessing specifications, and cohort descriptions in computational clinical studies, thereby making reproduction of results more difficult. Shared data repositories, such as biobanks in the UK and Japan, stand as a unique solution in such situations. These national biobanks de-­ identify the personal data and provide datasets under strict guidelines for several serious and life-threatening disease research including cancers, heart diseases, eye disorders, and other forms of dementia. Prospective data collections such as NIH’s “All of Us” research program, Evidation’s DiSCover Project, and institution-level efforts such as MIMIC are promising steps in the direction of protected data sharing. Such national- and international-level databases can also be utilized to ensure social inclusivity in training models with diversity of gender, race, color, ethnicities, and social status. In addition, a research drive for some advanced and periodic statistical procedures to ensure fair comparison between the datasets and models can pave the way for better reproducibility. An alternate solution to combat the problem of data sharing is by developing new techniques such as federated learning, distributed learning, and split learning which eliminates the need for data sharing. Regulations in peer-reviewed conferences and journals for code and data release would help elevate the barriers of reproducibility of results, by promoting fair research practices for creating a verification-friendly environment. Publication

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guidelines need to be established to address validation of models specifically designed to reproduce or replicate index model results. Finally, the establishment of governing data science bodies could help form universal standards for overseeing data capture, curation, and modelling. In healthcare, transparency, responsibility, and reproducibility are not only the steppingstone for a model’s technical integration, but they are also pivotal for developing trustful relationships between these systems and their users, be it patients or providers.

31.4.2 Autonomy in AI (Scope of Human Intervention) Autonomy refers to person’s independence over individual thoughts and action while considering notions of self-control, free will, governance, and responsibility. In medicine, it stands as a shared principle between patient and their treatment team, who carry responsibility for adequately informing their patient and surrogates. For AI and related fields such as robotics, autonomy has been debated at the functional level of a model. It often means algorithmic autonomy which can only be obtained with respect to human control to a certain functional degree. With AI technology that runs a million times faster than a human brain, efficient solutions are coming at the cost of the less and less human intervention, thereby increasing algorithmic autonomy. AI led to the Amazon Go shopping experience, autonomous driving vehicles by Google and Tesla, and voice-operated personal assistants such as Siri and Google Home. In the clinical world, the FDA approved its first fully autonomous diagnostic AI tool in 2018, a tool for diagnosing diabetic retinopathy. The tool, known as IDx-DR, provides a screening decision without any need for a clinician to interpret images or results. Another example is iRhythm which is an assistive device for on arrhythmia detection. However, notwithstanding the AI’s impressive performance, several questions in regard to autonomous decision-making capability have been raised.

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• How much control is required in autonomy? • How do we define the ability to interrupt the technology (control or switch off)? • What should we thrive for, an assistive AI or an autonomous AI? Answers to such basic questions are required in order to understand the scope of human intervention in an AI-led digital era. Non-interruptibility, loss of privacy, lack of responsibility and legal aspects of algorithmic design, as well as the potential for unemployment are some bigger challenges originating from AI’s autonomous footprint. The benefit of using assistive methodology is that it places a human in charge of the final decision-making, whereas fully autonomous AI systems, such as diagnostic AI, replace the human element, and this raises several level of concerns regarding: • Interpretability flaws • Susceptibility to technical malware attacks • Liability

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AI in healthcare is still considered to be in its early phase where its potential is being explored from assistive to fully autonomous setting. Therefore, identifying objectives with appropriate control setting (assistive/autonomous) becomes a primary step. An ideal AI model should be able to demonstrate both high sensitivity and high specificity to ensure a balance between safety and efficiency. Aiming at such a balance requires guidelines to be examined by ethicists, clinicians, and ML scientists in order to determine an acceptable and safe degree of autonomy. It may be useful to compare human graders with deep learning-incorporated AI systems in randomized controlled clinical trials in order to validate the use of AI systems into clinical practice.

31.4.3 Privacy and Security

The world’s digitization has led to talks of privacy and security rights aimed at safeguarding and controlling the usage of personal informaAnother major concern in AI autonomy is to tion. Privacy concerns regarding how the data is determine the degree to which the technology stored, processed, or transmitted with consent can be interrupted, thereby retaining a degree of from its owner. Security deals with ensuring that control. For example, if robots are used in chil- sensitive data is protected from breaches, leaks, dren therapy sessions, should they be super- or any kind of security threats. vised? If so, what would be the stages of With machine learning algorithms exploiting supervision and how would these be imple- big data more than ever before for various tasks, mented? All of this would need substantial plan- privacy and security regulatory research has ning. Another important concern of driving gained momentum. Emergence of real-world autonomy in AI system is quantifying the per- controversies relating to breach of human privacy formance. For instance, diagnostic convolu- using AI models has further verified the potential tional neural networks (CNN) for intrinsic brain challenges that this technology can bring. Facial tumors have been shown to provide near-real- recognition used by Chinese governments for time, intra-operative brain tumor diagnosis for authoritarian control, facial imaging-based AI all four major WHO histopathologic brain tumor models to determine sexual orientations even categories. However, while these networks are when individual’s consent is not required, and promising, there is currently no governing stan- Amazon’s failed hiring algorithm which discrimdard for CNN accuracy. inated against the women applicants are just a There is little doubt that AI is going to serve as few examples. a third contributor in a healthcare provider-­ In healthcare, privacy and security of digitized patient relationship in the near future; however, patient data is at the core of the ethical principles unchecked autonomy of AI (which is still a of justice and autonomy. It ensures the protection “black box”) could be a potential threat to the of individuals against any harms that could be patient-provider relationship. caused by sharing of information with any

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to a patient by the algorithm because certain attributes of patient (such as gender, race, or other information) do not qualify for the model’s selection criterion. Such unchecked data sharing could lead to algorithmic biases which can finally lead to racial discriminations, enhancing issues such • Data anonymity, accessibility, and security as social disparity. Hence, secure data sharing • Protection against any form of bias post-data guidelines also need to learn what should be and sharing should not be shared with such advanced technology. To guarantee a certain level of data anonymity, To overcome such failures, strong privacy and accessibility, and security, European countries security audit policies are required to assess have made one universal privacy law that applies potential risks and analyze retrospective outthroughout the entire European Union: the new comes of algorithms to reduce the risk of unfair General Data Protection Regulation (GDPR). results. More work is required to maintain priIn the USA, the Privacy Rule in the Health vacy and security of AI systems along with subInsurance Portability and Accountability Act jective (human-level) analysis to ensure justice (HIPAA) protects, among other things, the stor- and non-maleficence. As an alternative to mitiage of individuals’ medical records and other gate the risk of sharing data, models could be personal health information. On processing and designed to provide possible solutions, using storing medical data, HIPAA states the require- record simulation via generative adversarial netment of a HIPAA-compliant business associate works (GANs) [9]. For instance, working with contract or agreement (BAA) between the con- data generated by GANs offers the opportunity to troller (hospital) and the processor or sub-­ avert maleficence with EHR data and preserves processor (cloud provider). Recently, however, patient autonomy by allowing them to opt out of findings demonstrate that AI models can re-­ EHR data sharing. Such privacy protection modidentify the individuals by observing the underly- els based on the AI-driven generative models ing patterns obtained from daily data collected by could be used to rework current legislations. activity trackers, smartphones, and other handheld devices and correlating those patterns with the demographic data [8]. Several forms of spe- 31.4.4 Social Impact cific attacks to breach security codes of such data using cryptic, influential, and algorithmic design AI has the potential to take over tasks from spetechniques have also been observed, and this con- cific groups of healthcare workers, therefore posfirms that current legislations do not fully ensure sibly eliminating jobs. A similar phenomenon data anonymity, accessibility, and security. was observed during the Great Depression when Privacy and security laws worldwide aim to agricultural innovation led to a decreased necesprotect data providers from malicious activities; sity for workers in food production. The automahowever, little is known regarding the potential tion that is made possible by AI is often discussed threats that can indirectly arise by sharing a so-­ because of its ability to replace workers; howcalled “secure and privacy protected” databases ever, it may create jobs or fight unemployment by with powerful AI tools. The previously cited aiding job seekers in their search for work. A Amazon hiring algorithm is a classic example 2018 report by the Word Economic Forum predemonstrating how the algorithm exploited the dicted that AI would create 133 million new jobs gender attributes implicitly from its secure data- while simultaneously eliminating 75 million jobs base to reject women candidates. Imagine such by 2022, which would result in a total increase of scenarios in a clinical setting, where a treatment 58 million new jobs. However, it is possible that or extra medical help for a disease is not offered a mismatch will occur between the fraction of human, organization, or technology, thus invoking the principle of non-maleficence. However, assurance of privacy and security has become challenging as current standards might not consider all challenges such as:

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workers losing their jobs to AI and the ideal candidates for jobs created by AI, because of the relevant skills required to fill these new positions. In a report from the National Bureau of Economic Research, economists Anton Korinek and Joseph E. Stiglitz state that unemployment is one of the ways through which artificial intelligence will increase economic inequality [10]. In the past decade, life expectancies have diverged significantly for the poor and wealthy, and this has been attributed in part to disparity in access to healthcare and costly technological innovation. Korinek and Stiglitz speculate on how AI might augment wealth for the wealthy by harnessing AI as an economic advantage. As can be seen now to a lesser extent in how ownership of a computer, a car, or a smartphone creates more economic possibilities. If AI is used to augment human capability, it is probable that the wealthiest become the most enhanced. This could increase their productivity significantly, further increasing the gap between rich and poor. AI can magnify existing healthcare inequalities. Disparities are reflected in healthcare data, and untrained AI can propagate those disparities into biased predictions. This phenomenon was illustrated in a 2019 article on racial bias in algorithms, where the authors sought to investigate the performance of a widely used algorithm across racial categories. They demonstrated that for every risk score, black patients were considerably sicker than corresponding white patients, which was confirmed by increased blood biomarkers indicating uncontrolled chronic illnesses in black patients. This form of racial bias occurred because the algorithm predicted healthcare costs rather than illness. Unequal access to healthcare resulted in less money spent on care for black patients as compared to white patients [11]. Averting such biases in initial input data, and therefore the algorithms built on this data, is essential to maintain social justice. Biased algorithms are not a problem that is exclusively encountered in medicine. Racial and gender biases have also been identified in algorithms used in criminal justice decision-making. A popular tool to automate risk assessment in criminal justice cases is COMPAS (Correctional

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Offender Management Profiling for Alternative Sanctions). Its reoffending risk scales assess age, criminal history, employment history, drug problems, and vocational and educational problems, such as grades and suspensions. COMPAS was found to overpredict the risk for women to reoffend, therefore leading to unfair sentencing of female offenders. Additionally, COMPAS overpredicted high risk of reoffending for black offenders, illustrated by a much higher false positive rate for black offenders as compared to white offenders [12]. Possible solutions to these challenges can be found with the use of subsidies. To prevent an employment mismatch based on skills, subsidizing re-education in relevant areas can contribute to reintegrating workers onto the job market that have been unemployed because of technological innovation. Even though code is often shared online for free on websites such as GitHub, subsidizing AI tools that have been developed with this code, in order to make them publicly available, could help battle the economic disparity in access to AI tools. Fully eliminating bias in algorithms might not be possible, but analyzing data sources and creating awareness can help mitigate some of the biases that are inherent with big data collection.

31.4.5 Machines with Morality Ethics and morality are two closely related terms, where ethics is often used to refer to the psychological processes of ethical decision-making and morality focuses on the normative aspects or content of a decision. Discussing ethics and morals involves decisions and actions. In judging whether a decision or action is right or wrong, judgment of its normative aspects is essential. Good and bad do not exclusively follow from actions and decisions but also from natural phenomena. The difference between nature and humans lies in the concept of choice. The question that arises is whether algorithms that are making decisions based on learned experience, without being explicitly programmed to do so, possess this ability to choose. Can an algorithm

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choose not to decide? And how justifiable is a decision from a black box deep learning algorithm if it remains unclear what the decision is based upon? These questions center around the process rather than the content of decision-­ making. Precisely, the process is what seems to be the biggest challenge for an algorithm. Therefore, it seems like we could potentially create moral machines, but teaching ethics may turn out to be too complex. There is ongoing debate on whether humans are born with an innate sense of morality; however, whether innate or learned behavior, a moral sense further develops through interaction with the environment and experience. Morality is therefore not static but instead heavily dependent upon these interactions. Untrained AI algorithms have no inherent morality, and to train such algorithms, data from large research studies inculcated with cultural mores need to be extracted and curated. In healthcare, however, for providers to draw ethical conclusions from models, some awareness is needed regarding quantifiable definitions of normative values (from both ethicist, clinicians, and AI developers). Defining morality is a difficult task and programming morality potentially even more problematic, especially given the widely varying cultural norms and moral values. AI algorithms are “data hungry” by nature, and this limitation could be exploited to embed ethical values. Curating ethically sound data is a challenging task. In an attempt to do so, researchers at the Massachusetts Institute of Technology have created an online platform to explore the moral dilemmas faced by autonomous vehicles. Their “Moral Machine” uses crowdsourced data to train AI models to take moral decisions for self-driving cars [13]. Whether society is willing to employ such “Moral Machines” is questionable, as research shows that people currently still oppose the idea of autonomous machines making moral decisions [14]. A project like MIT’s “Moral Machine” with focus on healthcare decision-­ making has yet to be developed. Ultimately, creating policy for AI developers on how quantified ethical values should be incor-

porated into model designs is a necessary step in creating machines with morality.

31.4.6 Deployment and AI Safety AI safety debate has got enough attention lately to access its near-term and long-term risks. A $10 million grant to the Future of Life Institute, for focus on risks from advanced AI while aiming a deployment in ways that do not harm humanity, is one among the several steps taken in this direction worldwide. Deployment of AI technology within a real-world setting is a much more difficult task than developing it in a well-curated experimental environment due to several technical aspects such as improper or imbalanced datasets. In addition, an effective deployment of safe AI models needs to be necessarily carried out from an ethical, legal, and moral responsibility standpoint. Conventional deployment of safe technical robust model requires several phases of testing to ensure the three important stages as shown in Table 31.1, namely: • Specification • Robustness • Reliability A step-wise approach is required to check an application’s functionality and to understand the objective and user compatibility (specification). Thereafter, performance with respect to response time, traffic, and security against attacks is investigated (robustness). And lastly its usability (assurance) is determined. While this represents an ideal method of deployment, such technical safety measures in the healthcare environment might not be straightforward. For specification, the first stage could be a functionality check, where the model output would be simply observed by clinicians but will not be used in clinical decision-making. During this stage, the model would be rewarded for correct decisions and penalized for incorrect decisions in a reinforcement learning framework. In

31  Artificial Intelligence and Healthcare Ethics Table 31.1  The three stages of AI deployment Stage Specification Robustness

Reliability

Definition The objective of the technology and the specific aims it targets The model’s ability to withstand any perturbation that can happen due to possible internal or external factors Ensures that system or technology can be understood and can be controlled during their operative time

addition, a compatibility check should aim to calibrate the decision models in terms of their objective and design. Understanding model compatibility to the applied environmental settings is necessary in order to address very basic questions such as: • What is the best way integrate the designed model with the healthcare provider’s workflow? • Who are the real users at the application end, a nurse, an allied health professional, a physician, or a surgeon? To address the design-related challenges, model re-optimization strategies that are easy to plug in should be formulated while addressing plausible environmental and data bias. Data and technology are mostly de-centralized in healthcare, i.e., models trained on images of one domain (imaging devices which can also vary in institutions or hospitals) are subsequently deployed on different domain images which can introduce “distribution shifts” [15]. Adversarial attacks are another special form of machine learning security threat which can cripple the training (poisoning) and inference (evasion) of the model by adding small carefully crafted (unnoticeable) perturbation into the actual input samples [16]. Another form of volatility due to unsafe exploration can result from a system that seeks to maximize its performance and attain goals without having safety guarantees. To combat these unforeseen events and various forms of malicious adversarial attacks, the robustness of the AI models in all such conditions should be

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well-determined, and this is an active area of research in the field of AI safety. Healthcare leaders should stimulate research-driven solutions by investing in infrastructure for developing robust evaluation systems for AI models in medicine. Though several risks can be mitigated using specification and robustness checks, continuous monitoring and enforcing control are still pertinent for reliability of AI systems. Monitoring is usually carried out using both subjective (human judgment) and objective (statistical decision metrics) to inspect functioning of the model. Control enforcement is performed by designing tools to restrict actions of the system while observing its behavior. The ability to interpret the function of the AI system is important; however, ensuring a fair monitoring and control can be challenging. For example, doctors can only examine reasoning or behavior of the model before approving its decision if the model is able to provide some added explanation with predicted diagnosis. To build such systems, an augmented approach could be designing an automated behavioral analysis model using machine theory of mind.

31.5 Conclusions There is little doubt that AI will have a considerable impact on the way healthcare is provided in years to come, and there is also little doubt that there will be significant challenges to overcome. Machine learning algorithms can continue to learn from data to improve system performances over time. Hence, safety measures should evolve in concert with these advances being continuously checked until a satisfactory quantitative level is reached. Recent steps undertaken in this direction by the US Food and Drug Administration to investigate guidelines for regulatory practices for AI systems ensuring their safe deployment are promising moves in the right direction and should be adopted worldwide. Conflict of Interest  None declared. Financial support: No financial support has been required for this research.

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Ethical Issues in Paediatric Traumatic Brain Injury

32

Ahmed Ammar and Stephen Honeybul

32.1 Introduction Understanding clinical ethics is important in the complex field of acute paediatric neurotrauma, and many of the issues encountered are similar to those seen in adult patients. However, there are inherent differences between children and adults because the circumstances under which these issues need to be considered are constantly evolving as the child develops both physically and intellectually. In the early years of a child’s development, parents are the sole decision-makers and will often be required to make decisions which they believe are in the child’s best interests. However, as a child develops through infancy and then into early adolescence, discussions regarding their medical care and the attendant ethical issues will need to reflect the child’s physical and intellectual maturation. As a child approaches adulthood and begins to develop opinions and self-interests, the “child” must have a more significant role

A. Ammar (*) Department of Neurosurgery, King Fahd University Hospital, Imam Abdulrahman Bin Faisal University, Al Khobar, Saudi Arabia e-mail: [email protected] S. Honeybul Department of Neurosurgery, Sir Charles Gairdner and Royal Perth Hospitals, Perth, WA, Australia e-mail: [email protected] © Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_32

regarding health-care decisions, and the clinical management must become more patient centred and reflect and respect the child’s or early adult’s developing values and sense of identity. Over recent decades, the field of surgical paediatrics has evolved considerably for several reasons not least of which has been because of advances in surgical techniques, but also because of changes in societal attitudes regarding quality-­ of-­ life issues and survival with disability. Reviewing some of the historical aspects of paediatric medicine serves to highlight how this has occurred and the relevance these changes have to the contemporary management of neurotrauma.

32.2 Background Information In 1954, a book entitled Neurosurgery of Infancy and Childhood outlined the management strategies available for neural tube defects [1]. At the time, surgical treatments available were extremely limited, and many children either died early due to infection or survived with extensive disabilities, such that there were negligible prospects of anything approaching a normal life. Because of this, the authors advised that treatment should be withheld, and at the time, this view was widely accepted as being ethically justifiable. However, over subsequent years, as surgical techniques improved, it became increasingly apparent that many infants could benefit from surgical closure 327

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of the defect and go on to make a good recovery all be it with some degree of disability. As surgical treatments continued to advance and social attitudes to disability changed, clinicians began to acknowledge that there were significant ethical problems when intervention is withheld, based on a somewhat paternalistic notion of unacceptable disability and a perceived poor quality of life [2]. These changes in attitude were reflected in government legislation, and in 1973, the US federal government had passed the Rehabilitation Act prohibiting discrimination against handicapped individuals. Some years later, another case that reflected further changes in societal attitude was that of Baby Doe. On April 9, 1982, he was born in Bloomington, Indiana, with Down’s syndrome and a tracheoesophageal fistula. At the time, it was felt that the defect could be corrected and there was every chance that he would be able to eat normally after surgery. Arrangements were made for the surgery to be performed at a nearby hospital; however, Baby Doe’s obstetrician advised the parents that instead of surgery they could simply do nothing, which would result in death of the infant due to dehydration or starvation after a few days. The doctor’s advice was based on the belief that he thought survival with Down’s syndrome was unacceptable. The parents agreed; however, the family’s physician and a local paediatrician strongly opposed this plan. Their concern was based on their belief that the prognosis for a good medical outcome after surgical repair of an abnormal oesophagus was much better than the family had been led to believe. These physicians enrolled several attorneys, and the case was presented to local courts, appealing for a declaration of neglect under Indiana’s Child in Need of Services statute. The courts chose to follow contemporary precedent, deferring to the parents’ decision. The Indiana Court of Appeals denied an immediate hearing to review the decision, and the Indiana Supreme Court denied a petition for emergency relief to order medical treatment. Baby Doe died of dehydration and pneumonia at 6 days of age on April 15. At the centre of the ethical debate was whether the life of a child with Down’s syndrome and

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hence some degree of disability should be valued any less than that of other people. The Surgeon General of the USA, at the time of this incident, Doctor C.  Everett Koop, argued the boy was denied treatment (and food and water) not because the treatment was unreasonably risky but rather because he was intellectually disabled (which would be impossible to know at the baby’s age, since some individuals with Down’s syndrome can develop near-normal or even normal-­ range intellect). Koop commented publicly that he disagreed with such withholding of treatment, and a subsequent amendment to the Child Abuse Law, namely, the Baby Doe Law, was passed in 1984. This sets out specific criteria and guidelines for the treatment of seriously ill and/or disabled newborns, regardless of the wishes of the parents. It mandates that states receiving federal money for child abuse programmes develop procedures to report episodes of medical neglect, which the law defines as the withholding of treatment unless a baby is irreversibly comatose or the treatment for the newborn’s survival is “virtually futile”. Assessments of a child’s quality of life are not valid reasons for withholding medical care. There were a number of amendments to this legislation over subsequent years; however, the fact that this case and a number of similar cases provoked such controversy does in some ways serve to highlight the progress that had occurred in the field of paediatric bioethics in what is a relatively short period of time.

32.3 Current Evidence In the field of paediatric neurotrauma, there are similar ethical issues that need to be considered; however, there is limited evidence to inform the decision-making, and this is a common problem in many aspects of paediatric surgery. Clinical research using children requires more rigorous standards than research using competent adults. In addition, children are in a potentially vulnerable position that requires protection. Many trials of surgical techniques that are frequently performed on children have either excluded children

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from participation or include an insufficient number of children to draw strong conclusions. Finally, those trials that have been conducted often have difficulty with recruitment such that they are insufficiently powered to provide substantive conclusions, and these limitations were demonstrated in one of the few paediatric trials in neurotrauma. Taylor et  al. randomised children with elevated intracranial pressure following head trauma to either early decompressive craniectomy or medical management alone [3]. The study demonstrated that the intracranial pressure (ICP) was consistently (but not significantly) lower in patients randomised to surgery, and it was also concluded that functional outcomes were better in children randomised to surgery. It has to be acknowledged that the number of patients in the trial was very small and the results of subsequent studies in adults have confirmed that surgical intervention reduces mortality at the expense of an almost direct increase in the number of survivors with dependency [4]. However, this raises another problem, and that is the utility or otherwise of extrapolating evidence from adult trials to paediatric practice, because the context in which the ethical issues need to be considered is quite different in the paediatric population. These issues are clearly demonstrated in the following illustrative case. Illustrative Clinical Case 1 A 4-year-old boy falls 3 m from a balcony whilst playing with his three older siblings. He sustains a severe traumatic brain injury, and the initial CT scan of the brain shows severe cerebral swelling with effacement of the basal cisterns with patchy areas of ischaemia in the left hemisphere. He is admitted to the paediatric intensive care for intracranial pressure (ICP) monitoring, and the initial pressures are consistently above 30 mmHg despite aggressive medical management. Four hours after admission, his pupils become fixed and dilated, and a repeat CT scan shows areas of ischemia in the left hemisphere. The attending neurosurgeon is doubtful that surgical intervention is indicated based on her

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perception of an acceptable long-term functional outcome. She has a discussion with all family members present, and she requests that a second opinion be obtained from an intensive care colleague and one of her neurosurgical colleagues. Because of the respectful manner in which the discussions are conducted and despite the time constraints, there is no animosity, and the atmosphere is, given the circumstances, relatively calm. Opinion is obtained from all family members, and there is great care not to apportion blame regarding the cause of the accident. The medical team made it very clear that the family were not being asked to make the final decision regarding surgical intervention but rather they were being asked what they would feel to be in the best interests of the child based on the strong possibility of severe neurocognitive disability. The family accepted the neurosurgeon’s reservations but requested that all measures be taken to preserve the boy’s life. The boy is taken to theatre for a decompressive hemicraniectomy. Ten years later, the neurosurgeon receives an invitation to a school play in which the now 14-year-old boy is performing. It is a relatively minor role, but he performs it well and to the obvious admiration of his parents and siblings. He has an obvious right-sided hemiparesis and a moderate dysphasia, but he is in mainstream schooling and making good progress. After the show, the neurosurgeon meets the family and observes the close bonds the boy has with his siblings, who seem not to notice his disability, and they seem to argue and squabble like any teenagers. This case serves to illustrate the difficulties of extrapolating evidence obtained from adult studies to the paediatric population. It also demonstrates the limitations of making what may be interpreted as being an overly paternalistic assessment of acceptable outcome. This young man and his family have never really known him to be anything other than the person who he is, and if you asked him if he regretted having had surgery that had saved his life but had left him with some degree of disability, the most likely answer would be “as opposed to what?, not being alive at all?” In addition, judging quality of life

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based on abilities can be inherently problematic especially in the paediatric population, and this is reflected in the ethical concept of the “Disability Paradox”. This is the observation that many people with serious and persistent disabilities report a good or excellent quality of life when to most observers they would appear to live in a very undesirable state [5, 6]. Of course, this is by no means always the case, and it does not mean that every child with a serious head injury should be aggressively treated. Further research will be required to establish appropriate clinical indications, and whilst there is unlikely to be any more randomised controlled trials for decompressive craniectomy, it may be that, as is the case with ventriculoperitoneal shunts, the establishment of registries and clinical outcome databases may form the basis of comparative effectiveness research (CER). This is a rapidly developing field that recognises that not all types of neurosurgical interventions are best examined by clinical trials. It aims to directly compare existing health-care interventions in order to determine which provide the greatest benefit for patients and, perhaps just as importantly, which may provide minimal benefit. The illustrative case no. 2 is a good example of the latter point. Illustrative Clinical Case 2 (Part 1) A 15-year-old girl sustained an isolated severe blow to the vertex of the skull with a blunt instrument. Her initial GCS is 11 (E2, M5, V2), her pupils are equal and reactive, and she is extremely agitated. On examination, there is an open wound with an obvious midline skull depression in the region of the anterior aspect of the posterior third of the sagittal sinus. She is intubated and ventilated and taken to the CT scanner which confirms a badly comminuted fracture that is depressed approximately 2  cm directly in the midline, with an underlying large extradural haematoma which is causing significant mass effect. As she is taken out of the scanner, it is noted that her right pupil is fixed and dilated. The decision is made to proceed straight to the theatre for emergent evacuation. The attending neurosurgeon is told that the girl’s

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father has arrived in the emergency department, and he hurries to meet him. The neurosurgeon explains the seriousness of the situation, the need for urgent surgery and the possibility of an injury to the sagittal sinus. It is at this point that the father states that they are Jehovah’s Witnesses and he refuses point blank to provide consent. Jehovah’s Witnesses believe that the Bible prohibits ingesting blood and that Christians should not accept blood transfusions or donate or store their own blood for transfusion. The belief is based on an interpretation of scripture that differs from that of other Christian denominations and teaches that their refusal of transfusions of whole blood or its four primary components (red cells, white cells, platelets and plasma) is a non-­ negotiable religious stand. In the adult population, it must be acknowledged that in the eyes of the law, a mentally competent individual has an absolute moral and legal right to refuse consent for blood transfusion. Many Jehovah’s Witnesses carry an advance directive or have executed a detailed Health Care Advance Directive (Living Will). Copies are usually lodged with their general practitioner, family and friends, and case law is clear that such directives are legally binding. For children, the ethical and legal issues require careful navigation. Depending on the age at which a child is deemed a minor (e.g. 16 in the UK, 18 in the USA), parents have the right to provide or refuse consent by proxy, based on the belief that they are safeguarding the best interests of the child. In the current circumstances, the surgeon must explain that every attempt will be made to minimise blood loss. However, it must also be emphasised that the surgeon would not allow the child to let die for lack of blood transfusion. If there were time available, it is important to recognise that there are strong recommendations in most jurisdictions to obtain agreement or assent from the child. This differs in a relatively subtle way from obtaining formal consent which (depending on the family dynamics) could place the child in conflict with their parents. In the current situation, it is important to recognise that at 15 years of age, this girl/young adult may have matured sufficiently such that she has formed her

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own opinions regarding consent for blood transfusion. In the UK, the so-called Gillick competence states that the parental right to determine whether or not their child below the age of 16 will have medical treatment terminates if and when the child achieves sufficient understanding and intelligence to understand fully what is proposed. This was decided by the House of Lords in Gillick v West Norfolk and Wisbech AHA [1986] where a mother of girls under 16 objected to Department of Health advice that allowed doctors to give contraceptive advice and treatment to children without parental consent. Unfortunately, there will always be situations where all avenues of discussion have been exhausted and consent for transfusion from either the parents or a competent child is refused. If the situation was not so time critical and if it was thought to be unreasonable to go ahead with surgery without the freedom to transfuse, a request to the appropriate courts for “specific issue order” can be made. This allows transfusion without removing all parental authority, and this serves to emphasise that a doctor’s final legal and ethical obligation rests with the child and not the wishes of the parents. Courts throughout the world generally recognise parental rights, but also recognise that these rights are not absolute and exist only to promote the welfare of children. In the current situation, where time does not permit application to the courts, if need be, blood should be given. Failure to give life-saving treatment in these circumstances could render the doctor vulnerable to criminal prosecution. Illustrative Clinical Case 2 (Part 2) The child is taken to theatre, and a bifrontal craniotomy is performed over the middle third of the sagittal sinus. The extradural haematoma is removed, and a laceration across the sinus is repaired primarily using a small muscle patch. An ICP monitor is inserted and the patient taken back to the intensive care unit. She is initially stable, but over the following 24 h, her ICP progressively increases despite maximal medical management. Both pupils became fixed and dilated, and a repeat CT scan reveals that she has

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developed extensive bilateral venous infarcts. A family meeting is called to discuss the situation, and it turns out that the patient’s parents are recently separated and there was no documentation regarding guardianship. There is a great deal of tension in the air, and at the mention of a possible poor outcome, the father storms out of the room. The mother is silent. Following further discussion, it was decided to desedate the patient with a view to assessing her neurological function. A further meeting was planned in 48  h. During that time, the girl showed no signs of any neurological progress and was failing to trigger the ventilator. The second meeting was no better, and at the mention of possible brain death, the father again stormed out. A third meeting was planned, and prior to this meeting, the neurosurgeon met privately with the father. During the conversation, it was emphasised politely but firmly that discussions had to progress. The neurosurgeon asked specifically if there was anyone the father could bring to provide him with support, and he was surprised when the father told him that he had not thought that would be possible. He asked if he could bring his brother, and he also asked if he could bring a specific intensive care nurse who seemed to be particularly attentive to his daughter. The following meeting could not have been anymore different. He had spent the evening with his brother and his estranged wife, who had remained on good terms with his brother. The brother led most of the discussions and the father sat quietly. As it turned out, up until then, the father had not told his family about his daughters’ accident because he had felt responsible for her injury. At the time, the daughter had been staying with him, and she had gone out with friends, without telling him. This was in part because he had fallen asleep whilst intoxicated, and he admitted he had been drinking excessively since his separation. It also became apparent that the father failed to understand that his daughter could be brain dead as he believed whilst the heart was beating there was always hope. In fact, it was his brother, who was a vet, who had spent the previous evening explaining this issue and its implications.

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occur as in the second illustrative case, it is important to explore the cultural and religious backgrounds, in order to navigate and hopefully resolve these issues. This leads on to the issue of consent in the context of acute paediatric neurotrauma. It is often noted that children are a potentially vulnerable population that require protection; however, it is equally noteworthy that parents can be vulnerable especially when called upon to provide consent in situations where their capacity may be impaired because of emotional distress. The first illustrative case serves to illustrate that the family 32.4 Communication and Consent are not being called on to make a decision regarding surgical intervention. Indeed, to do so in these in Paediatric Neurotrauma circumstances would be seen as abandoning them Paediatric neurotrauma can present unique ethi- to make decisions that they may later regret or cal dilemmas given the potential difficulties in that they are not necessarily qualified to make. dealing with families in what can be an emotion- The case demonstrates that a far better approach ally charged atmosphere, especially when they is one that involves collaborative communication are called on to participate as surrogate decision-­ and an exchange of information between the makers in complex management issues. These medical team and the family, which hopefully difficulties can be compounded when there is can lead to a shared family-centred decision, and disagreement with family members or there are this is an increasingly preferred approach in the cultural values or religious beliefs that conflict field of paediatrics [7]. with a clinician’s management strategy. The second case serves to illustrate that in The first illustrative case demonstrates the most jurisdictions it is a legal and ethical duty for importance of a collaborative approach that paediatric health-care providers to provide a staninvolves all stakeholders and acknowledges the dard of care that meets the child’s needs and not uncertainty inherent in neurotrauma outcome. necessarily what the parents’ desire or request. The second case illustrates the need for conflict Parental decision-making does not imply a right mitigation especially when there are underlying for parents to make their own autonomous choices; issues of guilt which are not uncommon in the instead, it should primarily be understood that the context of trauma. Rightly or wrongly, parents parents’ responsibility is to support the best interwill often feel a sense of responsibility when ests of their child [8]. This applies in all decisions their child is injured, and this can be manifested not just those based on religious beliefs such as in in any number of negative emotions that can be the case of Jehovah’s Witnesses [9]. As a rule, directed towards medical staff and make effective medical decision-making in children is centred and productive communication problematic. In on the best-interest standard for the child, not on these circumstances, early recognition of poten- the interests of the caregiver. The parents or surtial conflict is essential to prevent these behav- rogate should be advised that the aim of clinical iour patterns becoming entrenched and leading to care is to maximise benefits and minimise harms breakdowns in communications. Involvement of to the minor and prevent neglect of the child, as nursing staff can be invaluable because they often would be the case if the child died because of spend many hours with the patients and their failure to give blood [10]. families, and they are well placed to notice potenA final consideration in this case is the need to tial areas of conflict either between family mem- consider the developmental maturation of the bers or with medical staff. When conflict does child because this allows for increasing At the end of the meeting, the father thanked everyone and apologised for his previous behaviour. The neurosurgeon accepted the apology but made it clear that this was not necessary. The daughter subsequently underwent brain death tests, and she proceeded to organ donation. These illustrative cases serve to illustrate several important issues regarding communication, consent and brain death that are frequently encountered in the management of neurotrauma in children.

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l­ongitudinal inclusion of the child’s opinion in medical decision-making. At 15  years of age, depending on the jurisdiction, she is approaching an age where she may have at least in part developed an opinion regarding the acceptability or otherwise of consent for a blood transfusion. In the context of acute neurotrauma, where there are significant time constraints, it would be reasonable to proceed as has previously been outlined and transfuse blood as required. However, in less time-constrained circumstances and especially if documentation were available that confirmed a mature child’s refusal to accept blood products, the ethical and legal issues will require careful navigation, and early recourse to legal counsel may be required.

32.5 Brain Death The main indication of formal brain death determination in a child is for that person to serve as a potential organ donor. However, as demonstrated in the second illustrative case, in certain jurisdictions, the diagnosis of brain death may require clarification. The father failed to accept that his daughter was dead because to him she appeared to him to be alive and, more specifically, her heart was still beating. Indeed, this belief was shared by the ancient Egyptians and Greeks who also regarded the absence of a heartbeat as the primary criterion for death. They believed that the heart created the vital spirits, so that without cardiac pulsation, life was impossible. By contrast, traditional Jewish sources focused on respiration as the primary criterion for life. The Old Testament contains several references to this idea, beginning in Genesis where god “breathes life” into Adam via his nostrils. These beliefs were held for many years; however, in the early 1960s, the development of the modern-day intensive care and the possibility of positive pressure ventilation, coupled with the invention of cardiac defibrillation and cardiopulmonary resuscitation, meant that life could be maintained, potentially indefinitely, in the absence of spontaneous breathing, whilst the absence of a heartbeat

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became a medical emergency rather than a sure sign of death. This led to the difficult issue of withdrawing life support, and in 1968, a special committee was set up by the Harvard Medical School with the aim of defining brain death [10]. They proposed that irreversible coma might be defined as a new kind of death for medical and legal purposes and that this definition could be used to justify the withdrawal of life support. A further statement from the combined Royal Colleges of the UK in 1976 further endorsed the position that the criteria proposed for the diagnosis of brain death should be accepted as amounting to the death of the individual [11]. Whilst these concepts are now very widely accepted, it should be recognised that there remains jurisdiction with views that are counter to this position. For example, Romania and Pakistan still do not recognise brain death as a valid criterion for the death of the individual. These observations serve as a reminder that death is not simply a medical phenomenon but a philosophical and sociocultural one, and they point to the need for further discussion and debate about what death means and how it may be shaped by political imperatives and transformed by science and technology.

32.6 Conclusions The field of paediatric surgery has come a long way in a relatively short time. The ethical issues that need to be considered have evolved as surgical techniques have improved and societal attitudes have changed. It is becoming increasingly apparent that the best approach to clinical decision-­making is through collaborative communication and the exchange of information between the medical team and the family. This leads to shared family-centred decision-making that place the best interests of the child at the centre of the discussion. Conflict of Interest  None declared. Financial support: No financial support has been required for this research.

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References 1. Ingraham FD, Matson DD. Neurosurgery of infancy and childhood. Springfield, IL: Charles C Thomas; 1954. 2. McLone DG. The diagnosis, prognosis, and outcome for the handicapped newborn: a neonatal view. Issues Law Med. 1986;2:15–24. 3. Taylor A, Butt W, Rosenfeld J, et  al. A randomized trial of very early decompressive craniectomy in children with traumatic brain injury and sustained intracranial hypertension. Childs Nerv Syst. 2001;17:154–62. 4. Honeybul S, Ho KM, Gillett GR. Long-term outcome following decompressive craniectomy: an inconvenient truth? Curr Opin Crit Care. 2018;24:97–104. 5. Ubel PA, Loewenstein G, Schwarz N, et  al. Misimagining the unimaginable: the disability paradox and health care decision making. Health Psychol. 2005;24:S57–6.

A. Ammar and S. Honeybul 6. Albrecht GL, Devlieger PJ.  The disability paradox: high quality of life against all odds. Soc Sci Med. 1999;48:977–88. 7. McDonald P, Gupta N, Peacock W. Ethical issues in pediatric neurosurgery. In: Albright AL, Adelson PD, Pollack IF, editors. Principles and practice of pediatric neurosurgery. 2nd ed. New York: Thieme; 2008. 8. Katz AL, Webb SA.  Committee on bioethics. Informed consent in decision-making in pediatric practice. Pediatrics 2016;138(2). 9. Conti A, Capasso E, Casella C, et  al. Blood transfusion in children: the refusal of Jehovah’s Witness Parents’. Open Med (Wars). 2018;13:101–4. 10. A definition of irreversible coma. Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. JAMA 1968;205:337–40. 11. Diagnosis of brain death. Statement issued by the honorary secretary of the Conference of Medical Royal Colleges and their Faculties in the United Kingdom on October 1976. BMJ 1976;2:1187–8.

Withholding and Withdrawing Treatment

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Tamra-Lee McCleary and Stephen Honeybul

33.1 Introduction Over the past 50 years, there have been considerable advances across all aspects of medical treatment. Increasingly sophisticated medical and surgical interventions have been introduced and rapidly incorporated into everyday clinical practice. Many of these advanced have significantly increased the capability of doctors to extend a patient’s lifespan; however, there will always come a time when a disease has progressed to such an extent or an injury is so severe that consideration must be given to either withholding treatment that may be perceived to be overly burdensome or withdrawing treatment that is no longer providing clinical benefit. In these circumstances, policy makers and medical guidelines make it very clear that doctors are under no obligation to provide treatment that they feel is providing no benefit, and they also clearly state that there is no ethical distinction between withholding treatment and withdrawing medical

T.-L. McCleary (*) Department of Critical Care and Respiratory Care, Integrated Ethics in Cancer Care, The University of Texas MD Anderson Cancer Center, Houston, TX, USA e-mail: [email protected] S. Honeybul Department of Neurosurgery, Sir Charles Gairdner and Royal Perth Hospitals, Perth, WA, Australia e-mail: [email protected] © Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_33

treatment once it has already been started [1]. Indeed, it could be argued that there is a strong ethical imperative to introduce the concept of withdrawal or withholding of life-sustaining treatment, rather than instigate or continue treatment when it is no longer providing any clinical benefit. On face value, the need to make these decisions would appear obvious; however, societal complexities are such that a number of ethical issues need to be considered. In the context of severe traumatic brain injury, the issues that require consideration range from relatively simple tasks, such as identifying the appropriate surrogate decision-maker, to more complex tasks such as determining what are the acceptable parameters of quality of life for patients with disorders of consciousness. Further difficulties arise when the doctors charged with making these decisions feel uncomfortable withdrawing a life-sustaining therapy because they feel some degree of responsibility for the patient’s eventual death. These difficulties are compounded when there is pressure from family members who “want everything done” and may see withdrawal of therapy as “giving up” on their loved one. In these situations, doctors may not always feel empowered to do what is ethically correct, and this may in part be due to highly publicized medicolegal cases in the United States and the United Kingdom. These cases serve to illustrate the problems that can occur when the ethical 335

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analysis has been deficient, and the courts have been called upon to consider the issues in the full glare of publicity.

33.2 Withdrawing Medical Therapy: Historical Aspects In the United States, the first, most widely known legal case regarding withdrawal of life-sustaining therapy was that of Karen Quinlan, which dealt with the issue of withdrawing ventilatory support in the relatively early days of modern intensive care (Quinlan 429 US 922, 1976). Subsequently, the Nancy Cruzan case dealt with the issue of removal of a feeding tube when the concept of enteral feeding in the care of patients with severe neurological conditions was in its relative infancy (Cruzan v Missouri 497 US 261 (1990)). In both cases, there was uncertainty about the legality and the ethics of withdrawal or continuation of therapy, despite withdrawal being requested by surrogate decision-makers. Both young women were kept alive by the medical and legal establishment in a condition that their next of kin thought the patients themselves would find unacceptable. Finally, in the case of Terri Schiavo who had suffered an anoxic brain injury, there was disagreement between her parents and her husband regarding withdrawal of therapy. This led to a protracted legal battle that lasted 15 years until her percutaneous gastrostomy tube was finally removed and she eventually died (Schiavo rel Schindler v Schiavo 403 F3d 1289, 2005). The final decision in this case was based on the assertion by her husband, Michael, that Terri had once remarked (and this therefore represented her known wishes) that she would never want to live in a vegetative state. In the United Kingdom, the leading case was that of Anthony Bland who was left in an unresponsive coma after he was crushed in the Hillsborough football stadium disaster (Airedale NHS Trust v Bland [1993] AC 789). Uncertainty about the legal position meant that the hospital authorities were not prepared to withdraw artificial nutrition and hydration without a supporting declaration of the court. The House of Lords held

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that treatment could be withdrawn or withheld when it was in the patient’s best interests and in apparent accordance with his previous attitudes and approach to life. This case highlights the slightly different approach to decision-making in the United Kingdom when compared to the United States. The best interests test requires a decision-maker to take into account the medical and social data regarding the proposed treatment and make a decision which best serves the interest of the patient. Substituted judgment requires the decision-­maker to use whatever is known about the patient’s wishes, desires, and values to make a decision which they believe the patient would have made. Both tests are based on common law, but historically the best interests test has had primacy in the United Kingdom (and also Ireland, New Zealand, Australia, and Canada), whereas substituted judgment has been the primary test in most of the United States. More recently, many jurisdictions have moved toward combining the tests so that a decision-maker should begin with subjective factors based on the patient’s known wishes and interests and then move toward more objective factors regarding the proposed treatment (Re G [1997] NZFLR 362).

33.3 Withdrawing and Withholding Medical Therapy: Traumatic Brain Injury These cases serve to illustrate that there were (and some cases still are) a number of key issues that could not be resolved. In the first instance, there is the issue consent for patients who have lost competency. Second, there was uncertainty regarding the benefit or perhaps, more importantly, the burden of ongoing supportive therapy. Finally, there was debate regarding the ethics and legality of withdrawing life-sustaining treatment. Notwithstanding the significant progress in ethical discussion over recent years, these problems have by no means been completely resolved and are encountered on a regular basis in patients

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with severe traumatic brain injury. The illustrative case serves as a good example. Illustrative Case A 46-year-old female was admitted with a severe traumatic brain injury following a high-speed motor vehicle accident. Her initial Glasgow Coma Score was recorded as 3, and her pupils were fixed and dilated. A CT scan confirmed a large, right-sided acute subdural hematoma with significant midline shift and obliteration of the basal cisterns. The attending neurosurgeon met with the husband of the patient to explain the seriousness of the situation. She was hesitant to surgically intervene given the likelihood of a poor neurological outcome, and she spent some time explaining her concerns. She tried to determine whether the patient had ever expressed a view about survival with severe neurocognitive disability; however, her husband was insistent that all measures be taken to prevent her death. The surgeon proceeded somewhat reluctantly, and the hematoma was evacuated. A primary decompressive craniectomy was performed as the brain was swollen. The patient was transferred back to the intensive care but made a very poor neurological recovery. At 3  weeks post-­ injury, she remained intubated and ventilated, and the only motor function was extensor posturing. Her pupils were now small and unreactive. She had no respiratory drive, and the intensive care team were considering the possibility of treatment withdrawal. They arrange to meet with the husband to discuss these options. When hearing of the prospect of treatment withdrawal and brain death, he is furious. He accuses the team of euthanasia and incompetence. He is clearly of the opinion that she must still be alive as her heart is still beating.

33.4 Treatment Decisions for Incapacitated Patients The issues encountered in this illustrative case are common in neurotrauma and require careful navigation of a number of interlinked ethical problems.

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33.4.1 Consent In this particular case, in a similar fashion to the aforementioned historical cases, the patient had been unconscious from the time of the injury and had consequently lost decision-making capacity. It was, therefore, not possible to determine her wishes regarding the acceptability or otherwise of her clinical condition. It was also not possible to determine whether she would have provided consent for the continuation or withdrawal of that therapy. While documentation such as advanced directives and living wills have been promoted as a solution for clearly establishing an individual’s values were they to lose capacity, these are most commonly encountered in the setting of chronic disease and increasing age. It is highly unlikely that these could be applied in the setting of an acute traumatic brain injury, given the unpredictable nature of the circumstances in which these injuries occur and the difficulty in predicting what defines an acceptable long-term outcome. In addition, it is empirically well known that patients may change their values and outlook on life when facing existential challenges, and philosophically one might argue that the advanced directive is given by a different person than the one affected by the decision especially in the context of a young person surviving with severe neurocognitive disability. The question remains regarding a workable framework with which to consider consent, and from a practical perspective, it is important to remember the two universal indications that need to be fulfilled prior to commencing or indeed continuing any form of medical intervention. In the first instance, the patient (or some form of surrogate) must provide consent. Secondly, the medical intervention must provide or be intended to provide some form of benefit. In the illustrative case, the issue of consent was based on the request of the husband for all measures to be taken in order to preserve her life. Notwithstanding the neurosurgeon’s reservations, the intention of surgical intervention was to provide benefit, by saving the woman’s life in the hope that she may make a good recovery. It would

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appear therefore that the two universal indicators for intervention have been satisfied. However, 3 weeks later, the situation is somewhat different. It is now no longer clear that the ongoing cardiorespiratory support is providing benefit. In these circumstances knowingly providing treatment that the patient has not agreed to and is arguably providing no benefit, and not only violates the ethical principle of non-maleficence, but in certain situations may provide grounds for a legal challenge. It is in these circumstances that concept of futility may be considered.

33.4.2 Medical Futility The possibility that life-sustaining therapy may be withheld or withdrawn happens more commonly when the medical team identifies the therapeutic interventions as futile. Unfortunately, modern medicine has struggled with this concept for many years, not only in its definition but also in its application. Previous definitions have included quantitative or physiological futility which are essentially clinical assessments. Other definitions have been based on either contextual or qualitative issues that are more patient centered. Finally, there is procedural futility which aims to introduce a third party in order to mitigate conflict (Table  33.1). Each of these approaches has their own advantages and potential applications in the context of severe traumatic brain injury, especially when considering an aggressive surgical intervention such as a decompressive craniectomy. However, notwithstanding these issues, one of their overriding limitations when considering the concept of futility is that it seems to imply a level of a certainty that in clinical practice is not only unrealistic but would appear to provide little room for discussion [2]. An alternative approach has been to combine various viewpoints and determine that an action or clinical intervention should be deemed futile if it does not achieve the goals of that action. The problem with this approach is that either the achievement of goals must be retrospectively evaluated which does not help with the actual decision or it must be a probabilistic assessment

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of the intervention not achieving the goals of therapy, in which case the argument disintegrates into the quantitative definition with the associated limitations. Further difficulties occur when the goals are not clearly defined, or the outcomes include states that a patient may regard as unacceptable. In these circumstances, it would be ethically unjustified to expose the patient to the risk of the outcome concerned [2]. For example, as demonstrated by clinical case, the attending neurosurgeon was well aware of the evidence that decompressive craniectomy reduces mortality. However, she was also aware that surgical decompression will not reverse the effects of the trauma and many survivors are left with severe neurocognitive disability. Prior to intervening she did attempt to determine that this outcome would be acceptable, but the results of the discussion with the husband highlight the difficulties involved in obtaining consent from surrogates in the emotionally charged atmosphere of acute neurotrauma. While the neurosurgeon made every effort to introduce the concept of severe disability, the husband (quite understandably in the circumstances) could only dichotomize outcome into life or death.

33.4.3 Medical Futility: An Alternative Approach More recently, the concepts of “proportionate” and “disproportionate” have been introduced in order to acknowledge that a specific treatment may not necessarily be futile, but may have progressively declining benefit and therefore increasing burden, in any one particular clinical situation. In the illustrative case, it could be argued that the initial surgical intervention was proportionate in that, notwithstanding the risk of dependency, there may be a small chance of a good outcome and people can learn to adapt to a level of dependency that they might previously thought to be unacceptable. However, as time goes by, it becomes increasingly apparent that continued therapy was disproportionate not only from an outcome perspective but also from the viewpoint of distributive justice. Maintaining patients with

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Table 33.1  Definitions of futility and application in the context of decompressive craniectomy Type of futility Description Physiological This is when the proposed futility intervention cannot physiologically achieve the desired effect. It is the most objective type of futility judgment Qualitative When the proposed futility intervention, if successful, will probably produce such a poor outcome that it is deemed best not to attempt it Quantitative When the proposed intervention futility is highly unlikely to achieve the desired effect

Contextual futility

When the treatment may be effective but the context in which it is provided is inappropriate

Procedural futility

When a process has been designed to determine whether the treatment is futile, which starts with the treatment team and family members but which may then involve the help of third parties to resolve differences

Application in the context of decompressive craniectomy Surgical decompression in a patient who has had fixed and dilated pupils for many hours and brain stem reflexes are absent

Comments Surgical decompression will not reverse the effects of the pathology that precipitated the neurological crisis

Surgical decompression in elderly patients with severe traumatic brain injury

Patients who survive will be left with severe neurocognitive disability and be fully dependent

Some patients survive following a decompressive craniectomy and make a good long-term recovery. There are outcome prediction models available that can stratify patients according to injury severity, and these have shown to have predictive value in the context of outcome following surgical decompression Surgical decompression in a patient with limited lifespan due to extensive malignancy

The CRASH and IMPACT models provide a percentage prediction of unfavorable outcome. However, there are limitations when applying population-based data to individual cases

Following surgical decompression, withdrawal of therapy may be considered if there is a poor neurological recovery

poor neurological outcome on prolonged cardiorespiratory support at the request of the family may mitigate conflict; however, resources are always finite and need to be allocated equitably. It is in this regard that consideration needs to be given to the societal value placed on an individual life.

It could equally be argued that it would be futile to offer decompressive surgery if the most likely outcome was severe disability and the patient had previously stated that they would feel this to be unacceptable Using a multidisciplinary team (doctors, nurses, social workers) to work with family members to determine the best course of action for the patient. In cases of dispute, using dispute resolution mechanisms to resolve differences (e.g., using a clinical ethics committee to give advice, involving independent specialists to confirm the prognosis, or going to a legal tribunal to seek resolution)

33.4.4 Medical Futility: Does Life Have Intrinsic Value? Given that technology is available that can prolong life in patients who will never regain consciousness, in this particular case, the futility debate rests on the assumption that life in itself

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provides no intrinsic value. This assumption is correct if life is determined to have instrumental value only and is a necessary condition to experience or perform other activities that provide value. In the previously mentioned UK court case relating to Tony Bland, Lord Goff wrote: I cannot see that medical treatment is appropriate or requisite simply to prolong a patient’s life when such treatment has no therapeutic purpose of any kind, as where it is futile because the patient is unconscious and there is no prospect of any improvement in his condition.

Many people will share Lord Goff’s view; however, a recent case served to illustrate the difficulties that can occur when this viewpoint is challenged. On December 9, 2013, Jahi McMath, a 13-year-old Californian girl, was admitted to Children’s Hospital Oakland for fairly extensive laryngeal surgery. She initially woke up well after the procedure, but then suffered a massive postoperative hemorrhage and subsequent cardiac arrest. She was resuscitated, but sustained profound hypoxic brain damage. Three days later, she was diagnosed as being brain dead by her physicians. However, her family refused to accept the medical declaration and initiated legal proceedings in an effort to require the hospital to continue treatment. They argued that according to their religious views, she was still alive because her heart was still beating. A Californian court supported the medical diagnosis of death, but the family continued to object to the discontinuation of life support. During a lengthy and acrimonious court battle, the hospital stated that it would be unethical and “grotesque” to require the hospital and its doctors to provide further medical care to a dead body. Jahi had been extensively investigated and found to have no activity on an electroencephalogram and no cerebral blood flow and made no respiratory effort when removed from the ventilator. Notwithstanding these findings, the family sought the opinion of Dr. Paul Byrne, a neonatologist who had campaigned against the widely accepted medical consensus of brain death. He stated in court documents that he had witnessed Jahi moving (Lazarus signs) and he therefore considered her to be alive.

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Eventually the family found a medical facility prepared to take over Jahi’s care, and she was transferred to an undisclosed location in New Jersey in January 2014. Her body was supported by a mechanical ventilator until she died a second and final time, from internal bleeding secondary to renal and hepatic failure, in June 2018. There is no doubt that this unfortunate case appears counter to contemporary, modern-day medical practice. However, several cultural and religious traditions consider life to have intrinsic value, i.e., to have value regardless of how a person can interact with the outside world or have conscious experiences [3]. Based on these values, some would argue that life should be preserved even in a chronic vegetative condition with full treatment which would have significant healthcare resource implications. However, notwithstanding these views, which are widely held among monotheistic cultures with Jewish, Roman Catholic, Islamic, or US religious convictions, there appears to be implicit agreement among most medical professionals that life cannot be viewed as intrinsically valuable under all conditions and even the most pro-life cultures seem to entertain a gray zone where maximum care is not offered or even discontinued if started [4]. This brings the discussion back to the ethical difference between withholding a treatment and withdrawing treatment that has already been started.

33.5 Withholding and Withdrawing Life-­ Sustaining Treatment: Is There a Difference? In a paper in a recent bioethical journal, the following comment was observed: The presumption that the distinction between withdrawing and withholding lifesaving treatment carries no moral weight is so commonplace that it is today rarely debated. [5]

However, from a clinical perspective, it is difficult to adopt this position given that studies have demonstrated that up to 50% of physicians felt there was an ethical difference between withholding treatment and withdrawing treat­

33  Withholding and Withdrawing Treatment

ment once it had been started. These views have been attributed to flawed moral reasoning, psychological factors, and social constructs. In addition, physicians may be influenced by issues such as the aforementioned perception of legal risk, prognostic uncertainty, the complexity or ambiguity of a clinical presentation, as well as their own personally held values and ethical viewpoints. In many clinical situations, withdrawing a treatment that is providing no clinical benefit should be relatively straightforward; however, the ethical tension rises considerably, when the most likely result of treatment withdrawal is the death of a patient. In the illustrative case, the neurosurgeon is being accused of euthanasia; however, is this a justifiable accusation? In these circumstances, a useful analogy can be drawn from the considerations of actions and omissions and a famous thought experiment proposed by the late James Rachels.

33.5.1 Acts and Omissions Two brothers, Smith and Jones, both stand to inherit a lot of money upon the death of their young nephew, so both want the nephew dead. Smith sneaks into the bathroom one night when his nephew is taking a bath and drowns him and then arranges things to make it look like an accident. In an alternative scenario, Jones sneaks into the bathroom one night when his nephew is taking a bath, prepared to drown him, but the boy slips, hits his head, and drowns all on his own. Jones is ready to push the boy’s head back down under the water, but he doesn’t have to.

Based on these circumstances and the collective responsibilities or intentions of the two uncles, Rachels reasoned that the only difference between the two cases is that one involves killing and the other involves letting die. What Jones omitted to do (save his nephew) was morally as bad as what Smith did (drowns the boy). Based on this reasoning, there would appear to be moral difference between the act and the omission, and therefore there is no moral difference between killing and letting die. Applying this reasoning to the act of euthanasia, if the only relevant difference between active and passive euthanasia is the

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killing/letting die distinction, it could be argued then that there’s no moral difference between active and passive euthanasia. There is no doubt that this is a pervasive argument; however, it was rejected by the US Supreme Court when ruling on the issue of physician-­ assisted suicide. The court ruled 9-0 that a New York ban on physician-assisted suicide was constitutional and stated that “the distinction between assisting suicide and withdrawal of life sustaining treatment is both important and logical; it is certainly rational” [6]. When considering the legal position in the thought experiment proposed by Rachels, Smith is guilty of murder and Jones isn’t guilty of anything!

33.6 The Equivalence Test Contemporary medical practice rejects the ethical importance of the action and omission distinction and judges the appropriateness of medical intervention in relation to purpose and boundaries of medical practice and the professional and ethical integrity of practitioners. In the field of neurosurgery, the act of treatment withdrawal and subsequent death of the patient is common, and neurosurgeons need to be familiar with the ethical distinction between withdrawing life-sustaining treatment and willfully ending a patient’s life. It is often assumed that the morally more acceptable action would be to continue to provide treatment even if it was deemed overly burdensome; however, it can equally be argued that from an ethical perspective, the default position is not to treat [7]. The Equivalence thesis is a useful way to navigate these challenging situations, and it rests on the assumption that “Other things being equal, it is permissible to withdraw a medical treatment that a patient is receiving if it would have been permissible to withhold the same treatment (not already provided) and vice versa” (Table 33.2). For those tasked with making these decisions, it is must be recognized that there are often strong psychological and social arguments for ­nonequivalence (and therefore to continue treatment). However, it is equally important that argu-

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342 Table 33.2  The Equivalence test and withdrawal of therapy in severe traumatic brain injury Clinical details on presentation when therapy is instigated The patient has sustained a severe traumatic brain injury (prognosis uncertain)

Clinical details when considering therapy withdrawal The patient has sustained a severe traumatic brain injury (prognosis more certain)

The patient requires intubation and ventilation for airway support The patient requires intravenous fluid supplementation to maintain cardiac output and vital organ function The patient is unable to feed themselves and will require either enteral or parenteral supplementation

The patient requires intubation and ventilation for airway support The patient requires intravenous fluid supplementation to maintain cardiac output and vital organ function The patient is unable to feed themselves and will require either enteral or parenteral supplementation

Comment There is much less prognostic uncertainty and the default position may now be considered to be not to treat No change in clinical indications

No change in clinical indications

No change in clinical indications

ments or perceptions are acknowledged as being psychological and social, in order to avoid perceiving these differences as ethical or legal reasons for nonequivalence, because this may lead to judgments that go against the best interests of the patient. In other words, the psychological reactions of medical personnel involved in the care of the patient can be acknowledged as real, but it must equally acknowledged that these reactions are not relevant and, indeed, may hamper clinical judgment. In the clinical case described, if the neurosurgeon was concerned that there may come a time when treatment has to be withdrawn, she may have considered not starting the treatment (surgical decompression) in the first place. Clearly,

judgment based on this reasoning (i.e., the neurosurgeon’s own feelings) cannot be in the best interests of the patient (who may be given the chance to benefit). Likewise continuing a treatment that a clinician feels is not providing a patient’s clinical benefit (notwithstanding the wishes of the husband) is clearly not in the patient’s best interests. When the time comes to consider withdrawing ventilatory support, the ethical indications to continue ventilation are the same as they were when ventilation was initiated (Table 33.2). Indeed, a closer examination of this case reveals why withdrawing treatment is a morally more defendable than withholding treatment (although it may not feel that way). It can be argued that notwithstanding the neurosurgeon’s initial reservations, an attempt was at least made at saving the patient’s life (hoping for a better neurological recovery). Now that it had become clear that the treatment has failed to provide the necessary benefit, withdrawal of treatment is not a new decision but termination of a treatment that has failed [7]. There are certainly no grounds for the accusation of euthanasia because the key difference between euthanasia and treatment withdrawal is intent. When a treatment is withdrawn, the intention is to discontinue treatment that is not providing benefit and recognize that the disease process will take its natural course. The patient will die as a result of the severe traumatic brain injury. In euthanasia, the intent is the death of the patient [8].

33.7 Practical Decision-Making There is no doubt that there is a strong moral imperative to understand and apply the academic ethical arguments appropriately; however, as demonstrated by the illustrative case, in these high-tension situations, clinical medicine is rarely straightforward, family dynamics are often complicated, and everyone involved in these decisions can find it challenging. One of the most important issues that must be clearly addressed early on in discussions is that families are not made to feel that they are actually

33  Withholding and Withdrawing Treatment Table 33.3  Geurts five-step approach for end-of-life decision • Collect the medical evidence regarding the diagnosis, prognosis, and treatment options • Share the information with the family and build rapport • Provide clinical appraisal • Make recommendations and share the responsibility of the decisions • Continuously assess the evolution of the patient’s status and follow up with the family

charged with the clinical decision. Clinicians with many years’ experience often find these situations challenging, so to abandon distraught relatives with no real clinical experience to make a decision based on limited information is not only unfair but can also promote a sense of guilt that can last for many years. Where possible, a process of shared decision-­ making should be employed, and the five-step approach for end-of-life decisions proposed by Geurts is a useful framework (Table 33.3) [9]. The proper identification of appropriate surrogate decision-maker is an important step in the shared decision-making process especially when interfamily conflict is encountered [10]. For adults, the hierarchy that is generally followed is spouses, adult children, parents, siblings, grandparents, or other reasonably available family members. For minors, the hierarchy is parents, adult siblings, grandparents, or other reasonably available family member. If the patient has appointed a medical power of attorney or a government appointed legal guardian, these are the decision-makers that take precedence over any family member. When discussing long-term outcome, especially in the context of treatment withdrawal, it is important to avoid value-laden statements such as “even if the patient survives, their life will not be a life worth living.” Adopting this position is not only overly paternalistic but is also open to misinterpretation [11]. In addition, it must always be acknowledged that in any decision there will be an element of uncertainty, and it is not uncommon that a patient in which a decision has been made to limit treatment recovers to a good outcome; hence, the patient’s best interests must include the possibility of recovery.

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33.8 Mitigating Conflict Where conflicts develop, every attempt must be made to avoid escalation; however, notwithstanding the aforementioned cases, there continue to be situations where there is a need to seek recourse to legal action in the courts. There will be obviously be some degree of regional variation in the legal position that is adopted; however, most court’s rulings have generally been based on a person’s “best interests” assessment, and legal decisions are usually based on a number of key considerations [12]. These include: • The medical evidence regarding the person’s diagnosis, prognosis, and treatment options • The degree to which the treatment may be viewed as overly burdensome • The known wishes of the person be it previously voiced or actually documented (and interestingly, to a much lesser extent, the views of family members) • The quality of life of the person if they receive treatment In most jurisdictions, courts also consider the process by which clinicians have decided that ongoing treatment should be withdrawn. These include: • Adherence to clinical guidelines • Consultation with other clinicians • Involvement with surrogate or substitute decision-makers It is also important to note that most courts have stated that organizational interests and availability of resources are not relevant to a best interests assessment. However, further guidance may be needed regarding this specific aspect. Global resource allocation difficulties such as those experiences during the SARS-CoV-2 pandemic have unveiled the need for clear policies during public health crisis where the need to consider resource allocation is unescapable. Overall, when these issues have been adequately addressed, the courts have usually ruled in favor

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of the clinician’s decision, even when there has been strong family opposition. It must be acknowledged that resorting to legal council must be seen as a failure of communication and a situation that benefits neither clinicians nor the families involved. Ironically, both parties usually feel that they are acting in the patient’s best interests, and clinicians certainly want to avoid public scrutiny of their clinical judgment, which are often reported unfavorably. However, in most jurisdictions, the clinician who acts with clearly stated objectives, having carefully considered the clinical and ethical aspects of what they are doing, will not be subjected to the “damned if you do and damned if you don’t” mentality that many clinicians fear the courts and the media will show in these emotionally challenging areas of decision-making. In fact, neither bioethicists nor the legal establishment are in the business of making reasonable care more difficult; they are only concerned that it be truly reasonable.

33.9 Conclusion Caregiving and delivering medical treatment are professional activities that are regulated by ethical canons. Medicine continues to advance, but we are yet to defeat death. There will always come a time when either a disease or an injury has progressed to such an extent that further treatment is providing no further benefit and may actually be becoming overly burdensome. While it is accepted that there is no ethical difference between withholding treatment and withdrawing treatment that has already started, it is important to acknowledge that there is a strong intuitive difference that may unconsciously influence clinical decision-making. Families must be involved in a shared patient-centered decision-making process that recognizes cultural, religious, and personal values. In these situations, there is a strong obligation to act in a patient’s best interests, and the

truly ethical decision is one that can be remembered in the narratives of those involved with honesty and integrity, so that for the person whose life may end and for those who are left grieving, there are closure and a sense of having done what is right in what can be a tragic situation. Conflict of Interest  None declared. Funding: None.

References 1. Gedge E, Giacomini M, Cook D.  Withholding and withdrawing life support in critical care settings: ethical issues concerning consent. J Med Ethics. 2007;33:215–8. 2. Honeybul S, Gillett GR, Ho KM.  Futility in neurosurgery: a patient-centered approach. Neurosurgery. 2013;73:917–22. 3. Ammar A. Influence of different culture on neurosurgical practice. Childs Nerv Syst. 1997;13:91–4. 4. Lobo SM, De Simoni FDB, Jakob SM, et  al. Decision-making on withholding or withdrawing life support in the ICU: a worldwide perspective. Chest. 2017;152:321–9. 5. Emmerich N, Gordjin B.  A morally permissible moral mistake? Reinterpreting a thought experiment as proof of concept. J Bioeth Inq. 2018;15:269–78. 6. Ursin LØ. Withholding and withdrawing life-­ sustaining treatment: ethically equivalent? Am J Bioeth. 2019;19:10–20. 7. Welie JV, Ten Have HA. The ethics of forgoing life-­ sustaining treatment: theoretical considerations and clinical decision making. Multidiscip Respir Med. 2014;9:14. 8. Wilkinson D, Savulescu J.  A costly separation between withdrawing and withholding treatment in intensive care. Bioethics. 2014;28:127–37. 9. Geurts M, Macleod MR, van Thiel GJ, et  al. End-­ of-­life decisions in patients with severe acute brain injury. Lancet Neurol. 2014;13:515–24. 10. Azoulay E, Timsit JF, Sprung CL, et al. Prevalence and factors of intensive care unit conflicts: the conflicus study. Am J Respir Crit Care Med. 2009;180:853–60. 11. Schaller C, Kessler M. On the difficulty of neurosurgical end of life decisions. J Med Ethics. 2006;32:65–9. 12. Carrier ER, Reschovsky JD, Mello MM, et  al. Physicians’ fears of malpractice lawsuits are not assuaged by tort reforms. Health Aff (Millwood). 2010;29:1585–92.

Long-Term Outcome Following Traumatic Brain Injury

34

Stephen Honeybul

34.1 Introduction The question of long-term outcome is one that needs to be considered at all stages and severity of traumatic brain injury (TBI). In cases of mild and relatively moderate head injury, patients and their families will often be concerned regarding issues such as restoration of neurocognitive function, social reintegration, and return to work. For the more severe injuries, the initial concerns may revolve around the issues of life and death and thereafter the possibility of survival with severe disability. The degree to which a patient recovers over time can be assessed with a variety of assessment tools that can be used to determine the influence or otherwise of various aspects of rehabilitation. Many of these tools incorporate a sophisticated evaluation of neurological, cognitive, psychiatric, and social function, and the overall aim is to determine a patient’s quality of life. However, notwithstanding the clinical value of these tools, the vast majority of clinical trials in TBI have continued to use either the Glasgow Outcome Score (GOS) or the Extended GOS (GOSE) to assess long-term outcome, and this is usually dichotomized into favorable or unfavor-

S. Honeybul (*) Department of Neurosurgery, Sir Charles Gairdner and Royal Perth Hospitals, Perth, WA, Australia e-mail: [email protected] © Springer Nature Switzerland AG 2021 S. Honeybul, A. G. Kolias (eds.), Traumatic Brain Injury, https://doi.org/10.1007/978-3-030-78075-3_34

able, the implication being that for a therapy to be considered beneficial, more patients in the intervention arm of a trial should achieve a favorable outcome, and from a research perspective, this is an entirely reasonable approach. However, for an individual patient and their families, adopting this position can be problematic. There is no doubt that some patients who have had a relative mild head injury go on to make a full recovery and they may make an uneventful return to normal life. However, the favorable outcome category also includes patients with moderate disability (and, in a recent trial, upper severe disability [1]), and this by definition includes patients whose work capacity is reduced and who have ongoing personality and interpersonal problems. The impact that these issues have on an individual and their families can be significant, and in certain cases, the term “favorable” may fail to adequately describe their perceived outcome. Likewise, there are certain patients who survive in the unfavorable outcome category who appear perfectly happy. The question remains as to how this should be approached from a clinical and ethical perspective such that patients and families can be counseled appropriately regarding realistic long-term outcome expectations. Overall, notwithstanding a considerable degree of variability, there would appear to be three broad outcome categories that require consideration. In the first instance, there are those patients who survive following a TBI 345

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and have ongoing neurocognitive issues which significantly impacts on their quality of life in a negative manner. Secondly, there are those patients who may survive with significant physical or neurocognitive disability but who have adapted in a positive manner. Finally, there are those patients who are either unable or are very restricted in their ability to communicate their opinion regarding their quality of life.

34.2 F  avorable Outcome but Not Necessarily Acceptable The effect that a traumatic brain injury has on a patient’s quality of life is by no means linear and may not necessarily correlate with either the severity of the injury or the subsequent outcome. Even patients with a relatively mild head injury can have subtle disturbance of cognitive function that can pose a significant barrier to social reintegration and return to work or study. For many individuals, these issues will resolve; however, for patients with a moderate or severe injury, there can be far-reaching repercussions. Certain patients may appear to have made a good physical recovery and may be adjudged to be in the favorable outcome category. However, there are many ongoing issues with which this group of patients must contend, and it is important that clinicians are aware of these issues in order to counsel patients and their families appropriately. Headache is one of the most common persisting symptoms with a reported incidence ranging from 30 to 90% [2, 3]. The mechanism of headache remains poorly understood; however, the presence of premorbid headaches appears significant. Indeed, the presence of a premorbid symptom is an important predictor of several posttraumatic symptoms, and the posttraumatic exacerbation of that symptom may merely reflect a reduced tolerance brought on by the injury [4]. Fatigue is another common problem that can have a significant effect on social, physical, and cognitive function; however, as with other posttraumatic symptoms, there is a wide range of reported prevalence from as low as 21% to as

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high as 73% [5]. This wide range is perhaps unsurprising given the difficulties inherent in defining “fatigue.” For example, “physiological fatigue” refers to a state of general tiredness due to physical or mental exertion which can be ameliorated by rest, whereas “pathological fatigue” refers to a weariness that is unrelated to previous exertion and is not ameliorated by rest. These difficulties in symptom definition are further compounded when considering the numerous possible causes of fatigue which may include any combination of neuroanatomical, functional, psychological, biochemical, or endocrine dysfunction [5]. Notwithstanding several comprehensive reviews into this topic, there remains relatively limited knowledge regarding specific clinical and pathophysiological factors that predispose to posttraumatic fatigue, its natural history, and the overall healthcare burden of this symptom. The same can be said of many other reported posttraumatic symptoms such as sleep dysfunction, depression, physical and cognitive impairment, and overall medical and neurological dysfunction all of which can have a significant negative impact on an individual’s long-term recovery [2, 4]. Finally, one of the most challenging aspects of recovery from moderate to severe TBI is the development of behavioral changes that can continue after the acute phase of recovery becoming chronic and thereafter persistent [6]. These so-­ called behaviors of concern (BoC) cover a broad spectrum ranging from apathy and social withdrawal through to more challenging behaviors such as disinhibition, sexually inappropriate, aggressive, and violent behavior patterns [6]. There are likely to be many factors that contribute to these BoCs, but it is becoming increasingly apparent that not only do these issues persist in many individuals but they can also worsen over time and may be exacerbated when individuals become frustrated as they attempt to reintegrate into family and community life. These individuals place a significant strain on community healthcare resources, and several studies investigating this issue have highlighted the lack of resources available among community-based

34  Long-Term Outcome Following Traumatic Brain Injury

adults who have survived many years with these issues. Overall, the long-term natural history of traumatic brain injury remains difficult to predict on an individual basis, and further work is required in order to gain consensus regarding issues such as precise symptom definition, timelines for assessment, and validated measures of outcome. It would also be useful to make any early determination regarding which individuals are likely to develop these problems. Early diagnosis and recognition that these symptoms are part of a “normal” recovery may remove some of the anxiety and frustration that can be associated with what may be perceived to be a poor recovery. It may also prompt individuals to seek early professional advice.

34.3 U  nfavorable Outcome but Not Necessarily Unacceptable Many patients who survive with severe disability and dependency exhibit high levels of dissatisfaction with their outcome and struggle to deal with many of the aforementioned issues. However, this is by no means always the case, and it has been shown on many occasions that people with serious and persistent disabilities report a good or excellent quality of life when to most observers they would appear to live in undesirable or unacceptable circumstances. It is important for clinicians to recognize this observation especially when considering an aggressive surgical intervention such as a decompressive craniectomy that increases the chance of survival with an “unfavorable” and by implication unacceptable outcome.

34.3.1 The Disability Paradox The obvious question is unacceptable to whom, and the inherent bias of this categorization probably originates from the common assumption that a good quality of life is associated with good health, subjective wellbeing, and life satisfaction

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[7]. Indeed, health and happiness are value judgments that everyone makes on a day-to-day basis especially in the field of medicine where the impact of the former would appear to have significant implications on the latter. Adopting this position is supported by the observation that people go to great lengths to achieve good health through lifestyle changes such as diet and exercise, and this may be predicated on the assumption that good health equates with happiness and ill health and disability are associated with a poor quality of life and unhappiness. However, the reality is that patients’ perceptions of personal health, wellbeing, and life satisfaction are often discordant with their objective health status [8]. This observation is reflected in the ethical concept of the disability paradox which seeks to describe how healthy individuals will often state that severe disability would have an extremely negative effect on their quality of life. Yet when those same individuals experience a severe illness or disability, a surprising number report a good or even excellent quality of life [8]. The precise reasons for this “paradox” are unknown. One suggestion has been that the reports of happiness and quality of life are inaccurate. However, an alternative explanation is that humans are resilient and may recalibrate their expectations in order to adapt and learn to live with a level of disability that they might previously have deemed to be unacceptable [8–10]. Survival with severe neurocognitive disability has been an issue in the neurosurgical community for many years especially in the context of decompressive craniectomy for life-threatening ischemic stroke and severe traumatic brain injury. There is now little doubt that surgical intervention can reduce mortality; however, it will not reverse the effects of the pathology that precipitated the neurological crisis, and the concern has always been that many survivors will find their eventual outcome unacceptable. In order to investigate this issue, a number of studies, initially in the context of “malignant” middle cerebral artery infarction, have asked survivors whether or not they were satisfied with their eventual quality of life and thereby obtained so-called “retrospective” consent. The relatively high number of

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p­ ositive responses in patients under 60 years of age seems to confirm the disability paradox [11] (however, for patients over 60  years of age, the number of positive responses was much less forthcoming [12]). In the context of severe traumatic brain injury, there have been relatively few studies that have addressed this issue; however, one small study explored the issue of retrospective consent among a small group of patients who had survived with severe disability for at least 3 years following a decompressive craniectomy for severe traumatic brain injury [13]. The rationale for this approach was that patients had had enough time to adapt to their disability. The patients were drawn from a cohort of 186 patients who had had had a decompressive craniectomy for severe traumatic brain injury in 1 of the 2 neurotrauma facilities in Perth, Western Australia. Among this cohort, 39 patients had been adjudged to be severely disabled or in a vegetative state at 18-month follow­up. Twenty patients or their next of kin agreed to participate in the study, 7 had died, and 12 were lost to follow-up. Several assessments were performed, the detailed results of which have been published elsewhere. During the semi-structured assessment, patients were asked their opinion regarding so-called retrospective consent. Specifically, they were asked: 1. At the time of your initial injury, you were unable to give any indication that you would or would not agree to what was considered “life-saving” surgery. In retrospect (looking back), would you have agreed to have the surgery performed knowing your eventual outcome? 2. How well can you remember what you were like prior to your injury? Among the 13 patients who could respond, 11 replied positively, and the implication of this response was that they were satisfied with their eventual outcome. Indeed, this finding was confirmed by the results of quality-of-life assessments that confirmed ongoing physical disability but near-normal scores for general health, vitality, and mental health. The responses were, at

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least to the senior investigators, surprising; however, they would seem to endorse the observation that health circumstances do not necessarily affect wellbeing as dramatically as people would expect and therefore confirm the “disability paradox.” However, before adopting this position, the limitations of the study must be recognized. Of the original cohort of 39 patients, 7 patients had died, and 12 were lost to follow-up. It may be that these patients had similar opinions to those expressed in the study, but this is unknown. Likewise, the opinions of those patients who remained in a vegetative state could not be established. Therefore, caution must be exercised when using these results not only to justify the initial surgery but also when using “retrospective consent” to validate an intervention that increases the possibility of a patient surviving with severe disability. Obtaining a positive response when asking a person whether they would retrospectively agree to an intervention that has enabled them to survive, albeit with a considerable loss of neurological functional, certainly demonstrates the human will to adapt to adversity. However, it would be injudicious and perhaps misguided to interpret this as a variation of the consenting process and therefore a validation of the surgical intervention no matter what the eventual outcome. In addition, many of the respondents stated that they were unable to remember a great deal about their lives prior to the injury, and it could be argued that these patients may have lost a great deal of their higher functioning, mental ability, and insight such that they are unable to fully appreciate their level of disability. However, this viewpoint would unfairly discriminate against people with neurocognitive disability. Just because a person has neurocognitive disability does not make their life any less valuable. Indeed, it is difficult to argue that it was not in a person’s best interest to surgically intervene if they are able to state that they are satisfied with the outcome. An alternative interpretation is that patients have indeed adapted to their disability, have recalibrated what they feel to be an acceptable quality of life, and do not feel that an “unfavorable” outcome is necessarily as unacceptable as is perceived by others.

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For many clinicians, this concept may be difficult to appreciate because so many methods of assessment focus on a patient’s disability and their inability to perform certain tasks such as feeding, attending to bodily needs, and mobilizing. However, this type of assessment may not necessarily capture what is important to patients and their families, and it is in this regard that a more holistic approach to quality-of-life assessment may be beneficial.

34.3.2 The Salutogenic Model The salutogenic model for health is an alternative approach to outcome assessment that focuses on factors that support a person’s health and wellbeing and may explain a person’s ability to adapt to circumstances that they may previously have thought to be unacceptable [14, 15]. It is a stress resource-oriented concept that seeks to explain why people can stay well despite stressful situations and physical hardships. In many ways, it is the opposite response to traditional assessments of disability that tend to focus on the pathological aspects of disability and the ability or otherwise of an individual to perform physical tasks. The model focuses more on resilience of the human spirit in the face of adversity, and there are two core concepts: the “sense of coherence” and the “generalized resistance resources.” The sense of coherence reflects a person’s view of life and their capacity to deal with difficult or stressful situations [14]. There are three core elements. • Comprehensibility embodies a belief that a person can understand events in their life. • Manageability is a belief that a person has the necessary skills or perhaps more importantly the necessary support such that they have some level of control of their lives. • Meaningfulness implies a belief that things in life are interesting and worthwhile and that there is good reason or purpose to care about what happens.

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In the context of survival following traumatic brain injury, it is perhaps the last element that is most important. If a person has no sense of meaning, they will not be motivated to comprehend and manage challenging events such as adapting to disability. The generalized resistance resources are factors such as money, self-confidence, and perhaps most importantly social support that help a person combat a range of psychosocial stressors [15]. It must be acknowledged that no assessment tool, in itself, will improve outcome. However, focusing on a person’s abilities to adapt and take value from their surroundings may improve their ability to cope with a level of disability that they might previously have deemed unacceptable, and this in some way helps explain the disability paradox. If a person has the necessary resources in terms of social and financial support, they can develop a strong sense of coherence such that they value their life and find it meaningful. If this can be achieved in those patients who survive with so-called unfavorable outcome, they themselves may not necessarily consider it to be “unacceptable.” Overall, there is unlikely to be a one-size-fits-­ all approach to the complicated issue of quality of life; however, adopting this more holistic approach may help certain patients and their families come to recognize their abilities and perhaps learn to accept their disabilities. In these circumstances, good communication is an important factor that can help optimize the often scarce rehabilitation resources, and it is in this regard that the final group of patients represents the greatest challenge because they have very limited ability to communicate and therefore to express their views regarding outcome.

34.4 Unfavorable and Unknown These patients fall into the broad category of disorders of consciousness which includes, but is not limited to, the minimal consciousness state (MCS) and the vegetative state (VS). The management of these patients presents several

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c­ hallenges. In the first instance, there are issues of accurate diagnosis and therefore long-term prognosis. Second, there is the use of experimental techniques on these patients that consumes considerable healthcare resources for limited or questionable benefit. Finally, there is the use of surgical intervention that increases the risk of an individual surviving in such a condition.

34.4.1 Disorders of Consciousness: Diagnosis The vegetative state was first described by Jennet and Plum in 1972. It is a state of wakefulness without awareness in which a patient does not respond to a variety of clinical stimuli and shows no appreciation or awareness of their surroundings. In the context of trauma, the term permanent is used if the patient remains unchanged at 12 months. It is an important diagnosis to determine because, by definition, the VS represents a total loss of cognitive function with no expectation of recovery. It would seem reasonable in these situations to consider withholding ongoing supportive care; however, this can be a contentious issue as was demonstrated by highly publicized cases such as that of Terri Schiavo and Karen Quinlan. Further difficulties arise when considering the possibility of a patient being in a minimally conscious state in which a low level of functional recovery suggests self or environmental awareness [16]. In these circumstances, there have been (admittedly uncommon) cases, where patients have made significant improvements, and this has occasionally been documented many years after the initial injury. The difficulty has always been making a quantitative analysis of cerebral function that can accurately predict those patients who have the potential to improve. Over the past three decades, there has been a large amount of work done on functional MRI and functional PET studies, some of which have suggested that certain patients may actually have higher levels of awareness than was previously realized and there may be potential for reestablishment of neural networks [17]. Some of these studies have gone as far as to demonstrate com-

S. Honeybul

munication with patients [18, 19]. By using healthy volunteers as controls, patients in a seemingly vegetative state have been asked to imagine one activity (such as playing tennis) for yes and another activity for no, when asked simple questions such as “Do you have any sisters?” and “Is your father’s name Alexander?”. In certain cases, there was a consistent and correct response which seems to suggest that these patients have relatively intact cognition. These findings were unexpected; however, what has yet to be determined is their clinical significance. It has been suggested that it may be possible to give some individuals a degree of autonomy. However, in what circumstances can this be applied? Presumably, one of the key questions is how patients perceive their quality of life and in what circumstance would it be feasible and indeed reasonable to ask whether ongoing supportive measures should continue or be withdrawn. The difficulties inherent in this type of approach are immense and involve ethical issues of competency of consent, reliability of the responses, and possible conflict between clinicians tasked to carry out the “wishes” of the individual and individual’s family members. Overall, the activation of neuronal networks in response to clinical stimulation may form the basis of a neurological recovery, and it would be clinically useful if this could predict those patients who are likely to make a progressive recovery. However, obtaining a fragmentary grasp of awareness and perhaps language in a small number of patients may not necessarily be perceived as a benefit. Indeed, increasing awareness of their situation may either promote a sense of belonging or may only serve to emphasize their social isolation. Likewise, complex neuroimaging may demonstrate neuronal activation that has no functional correlation with outcome let alone quality of life. More work will obviously be required to validate some of these findings and to continually develop rehabilitation strategies that may improve outcome. However, while this work represents an exciting field of research, complex neuroradiological imaging consumes considerable healthcare resources with relatively limited societal

34  Long-Term Outcome Following Traumatic Brain Injury

benefit. It is in this regard that the use of deep brain stimulation raises further ethical questions.

34.4.2 Disorders of Consciousness: Experimental Intervention The use of deep brain stimulation for patients in a VS or a MCS has been explored by a number of researchers dating back to the 1960s. The implanted electrodes deliver electrical pulses to specific areas of the brain, and it is an established and effective treatment for conditions such as Parkinson’s disease and essential tremor. However, in the context of severe TBI, the evidence supporting efficacy is much less robust. The target most commonly used has been the central thalamus, and this is based on the premise that the anterior forebrain mesocircuit plays a significant role in the spontaneous and medication-­ induced recovery of consciousness and cognitive function. Following TBI, undamaged neurons within the mesocircuit become downregulated to a low firing state, and this affects neuronal populations in the basal forebrain and reticular formation that are responsible for arousal. Targeting the central thalamus aims to restore function to the overall circuit. There is little doubt that this represents an area of considerable research interest; however, interpreting the literature can be difficult. There has been wide variation in timing of DBS, and in many of the earlier studies, the clinical improvement and emergence from either a VS or a MCS could be attributed to the natural history of TBI.  More recently a well-publicized case was published in Nature in 2007 by Schiff et al. [20]. The patient, who had been in a MCS for 6 years, was extensively investigated preoperatively with functional MRI in order to demonstrate the preservation of large scale, bihemispheric cerebral language networks. The preservation of these networks was interpreted as potential substrate for further recovery. Using a double-blind, alternating crossover design, it was possible to demonstrate modulation of behavior responses and improvement in functional limb control. The patient subsequently recovered the ability to

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interact consistently and meaningfully with others, and this was cited as the most important change by members of his family. He did, however, remain dependent, and the longer-term outcome is unknown. Overall, this was a landmark study which appeared to provide enough evidence for further research in this area. However, the following decade did not see a significant increase in cases reported, and this raises a number of ethical considerations. On the one hand, there would certainly appear to be enough clinical material given the increasing worldwide incidence of TBI and increasing numbers of patients who survive in either a VS or a MCS. There would also seem to be a strong incentive for industry involvement given the high cost of the equipment and the possibility of many eligible cases. However, notwithstanding the benefit to families who welcome a heightened level of awareness in their loved one, the clinical benefit has been relatively limited. This raises issues regarding resource allocation because the benefit provided to the individual patient and their families, combined with the scientific knowledge gained from these studies, must be balanced against the overall cost to the healthcare system. This is not insignificant given the extensive preoperative radiological investigations, the cost of surgery and the DBS equipment itself, and the intensive post-operative rehabilitation that is required. These types of conflicting issues are commonly encountered in the field of medicine and are encapsulated in the ethical concept known as the rule of rescue.

34.4.3 The Rule of Rescue This concept describes the powerful human proclivity to rescue a single identified individual regardless of cost or risk. The classic examples are heroic searches for a sailor lost at sea or daring attempts to rescue someone in a burning building. In such cases, while the chances of success may be small and either the cost to the community or the risk to those attempting the rescue is extremely high, the psychological and moral

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imperatives are difficult to resist. This rescue morality spills over into medical care and describes the ethical imperative to save or restore an individual life even when the money and resources might be more efficiently used in the wider community. In this example, if restoring lives is considered to have overriding importance, it is not difficult to invoke and justify the rule of rescue when considering DBS for patients in either a VS or a MCS.  However, by giving absolute priority to this type of therapy, the effect that this may have on resource availability for other patients, yet to be identified, requires careful consideration. Traditionally, cost-effectiveness dictates that the cost of a particular medical intervention should be divided by some measure of health benefit that is expected from the treatment. However, while there is general acceptance that healthcare resources must be financially justified, the fundamental difficulty is producing a cost-­ effectiveness analysis that is both socially and politically acceptable. One approach to these issues is to consider the utilitarian theories of value. These acknowledge that resources are scarce and must be allocated optimally to ensure that the overall performance of a healthcare system is maximized. An egalitarian assumption adds a further constraint of fairness to try and ensure universal access to adequate healthcare. From this standpoint, it is difficult to justify DBS in the context of TBI when the probable outcome is ongoing severe disability with that individual continuing to rely on long-term medical and nursing care. However, this position fails to recognize the considerable social value in caring for those most in need, especially if this is undiluted by considerations of cost. While attempts to restore meaningful consciousness may be incompatible with utilitarian resource allocation, conveying the message that communication with family, albeit somewhat limited, is precious and worth a great deal of effort to preserve can be a source of social utility. People obtain benefit from the belief that they are living in a caring and humane society, and attempts to restore an identified individual’s consciousness life serve to reinforce this belief. This can pro-

S. Honeybul

vide a feeling of security knowing that one lives in a compassionate society which cares for the needs of each constituent member and where those in most desperate need will not be ignored merely on the basis of resource allocation. However, this security is threatened if the rescue system is seen to be a juggernaut that is insensitive to the way people actually value their live. If use of DBS in the context of MCS or VS is to continue, longer-term outcome studies are required to determine the value provided to the individual, their families, and the wider TBI community. As with the use of complex neuroimaging, increasing awareness may not necessarily be perceived as a benefit, and this must be a focus of ongoing research. A final consideration is the ethical discussion regarding surgical procedures that increase the number of survivors with disorders of consciousness.

34.4.4 Disorders of Consciousness: Surgical Intervention It has been estimated that approximately 69 million patients suffer from TBI annually, and this is predicted to increase. Over recent years, advances in neurosurgery and intensive care have led to a reduction in mortality; however, this may result in an increase in the number of patients with disorders of consciousness. Indeed, the recent RESCUEicp trial demonstrated that use of decompressive craniectomy in the context of severe TBI led to a fourfold increase in the number of survivors in a vegetative state [1]. At 6  months, the number of vegetative survivors increased from 4 out of 188 patients (2.1%) randomized to the medical arm of the trial to 17 out of the 201 patients (8.5%) randomized to the surgical arm. This finding is even more ethically problematic when considering outcome findings at 12 months, because six of these patients subsequently died: five patients in the surgical arm and one patient in the medical arm. The psychological distress for families involved in these circumstances and the financial cost to society cannot be underestimated [12].

34  Long-Term Outcome Following Traumatic Brain Injury

There is little doubt that surgical intervention can reduce mortality, and many patients go on to make a good recovery. Certainly some survivors remain severely disabled, and the acceptability or otherwise of this outcome is a source of ethical debate [12]. However, notwithstanding these issues, most commentators would probably agree that converting death into survival in a VS is unacceptable. The difficulty has always been reliably predicting outcome and therefore knowing when to consider withholding surgical intervention. However, significant improvements in data gathering and statistical analysis have enabled researchers to develop sophisticated web-based prediction models such as the CRASH (Corticosteroid Randomization After Significant Head Injury) and IMPACT (International Mission For Prognosis And Clinical Trial) models [21, 22]. Both models provide a prediction of unfavorable outcome at 6 months, and several studies have used the percentage prediction to stratify patients according to injury severity [12, 23]. Comparing the predicted outcome with the

Good 100% Observed outcome at 18 months (GOS)

1

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5 1 3

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observed long-term outcome provides an objective assessment of the risk of survival either with severe disability or in a VS (Figs. 34.1 and 34.2). There will always be limitations when applying this type of data analysis to individual cases; however, once the prediction of unfavorable outcome exceeds 80%, the most likely outcome if the patient survives is long-term disability. In these circumstances, if everyone involved in the decision-making process is insistent that surgery proceed, clinicians (who may have their reservations) may derive some comfort from the disability paradox. However, a clinician’s obligation to a patient who has previously expressed a view, either voiced or documented, that they would find survival with severe disability unacceptable is quite otherwise. In these circumstances, proceeding with surgical intervention will significantly increase the chances of that outcome, and a surgeon could not assume that they would have obtained consent, even if it were possible. Even in the context of possible conflict, it would entirely be within a surgeon’s rights to withhold surgical intervention.

Severe 1 5 7

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Fig. 34.1  The CRASH collaborators prediction model. The prediction of an unfavorable outcome at 6  months (x-axis) and the observed outcome at 18  months among the 319 patients on whom 18-month follow-up was avail-

n = 319

able. Numbers within the bar chart represent absolute patient numbers. (Reproduced from Injury with kind permission by Elsevier)

S. Honeybul

354 Good 100% Observed outcome at 18 months (GOS)

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Fig. 34.2  The IMPACT investigators model. The prediction of an unfavorable outcome at 6 months (x-axis) and the observed outcome at 18  months among the 319 patients on whom 18-month follow-up was available.

Numbers within the bar chart represent absolute patient numbers. (Reproduced from Injury with kind permission by Elsevier)

34.5 Conclusions

Conflict of Interest  None declared.

The issue of long-term outcome in any disease process is complex, and discussions are needed on many levels. These range from the individual case through to use of institutional resources and thereafter societal issues such as the pursuit of scientific knowledge. In the context of TBI, the ethical tension is often intensified because of the time-dependent nature of the acute surgical decisions or the longer-term issues of research, resources, and realistic outcome expectations. Caution must certainly be exercised against an overly nihilistic attitude that would preclude further research into this vulnerable group of individuals. However, issues of quality of life and equitable use of healthcare resources must always be considered in the decision-making paradigm, especially when determining healthcare policy. Society has to determine the value we place on life and the financial, personal, and ethical burden we are willing to place on, not only those to whom we have a duty of care, but also the community as a whole.

Financial support: No financial support has been required for this research.

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