Critical Care Update 2019 [1 ed.] 9789389776140, 9789352709106

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Critical Care Update 2019

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Critical Care Update 2019 Editors Subhash Todi MD MRCP Director Department of Critical Care Advanced Medicare Research Institute Kolkata, West Bengal, India

Subhal Bhalchandra Dixit MD IDCCM FICCM FCCM Consultant Critical Care and Director ICU  Sanjeevan and MJM Hospitals  Pune, Maharashtra, India

Kapil Zirpe MD FICCM FCCM Director Neuro Trauma Unit Ruby Hall Clinic Pune, Maharashtra, India

Yatin Mehta MD MNAMS FRCA FAMS FIACTA FICCM FTEE Chairman Institute of Critical Care and Anesthesiology Medanta The Medicity Gurugram, Haryana, India

JAYPEE BROTHERS MEDICAL PUBLISHERS The Health Sciences Publisher New Delhi | London | Panama

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Jaypee Brothers Medical Publishers (P) Ltd Headquarters Jaypee Brothers Medical Publishers (P) Ltd 4838/24, Ansari Road, Daryaganj New Delhi 110 002, India Phone: +91-11-43574357 Fax: +91-11-43574314 Email: [email protected]

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Website: www.jaypeebrothers.com Website: www.jaypeedigital.com © 2019, Jaypee Brothers Medical Publishers The views and opinions expressed in this book are solely those of the original contributor(s)/author(s) and do not necessarily represent those of editor(s) of the book. All rights reserved. No part of this publication may be reproduced, stored or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission in writing of the publishers. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. Medical knowledge and practice change constantly. This book is designed to provide accurate, authoritative information about the subject matter in question. However, readers are advised to check the most current information available on procedures included and check information from the manufacturer of each product to be administered, to verify the recommended dose, formula, method and duration of administration, adverse effects and contraindications. It is the responsibility of the practitioner to take all appropriate safety precautions. Neither the publisher nor the author(s)/editor(s) assume any liability for any injury and/or damage to persons or property arising from or related to use of material in this book. This book is sold on the understanding that the publisher is not engaged in providing professional medical services. If such advice or services are required, the services of a competent medical professional should be sought. Every effort has been made where necessary to contact holders of copyright to obtain permission to reproduce copyright material. If any have been inadvertently overlooked, the publisher will be pleased to make the necessary arrangements at the first opportunity. The CD/DVD-ROM (if any) provided in the sealed envelope with this book is complimentary and free of cost. Not meant for sale. Inquiries for bulk sales may be solicited at: [email protected] Critical Care Update 2019 / Subhash Todi, Subhal Bhalchandra Dixit, Kapil Zirpe, Yatin Mehta First Edition: 2019 ISBN: 978-93-5270-910-6

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Contributors EDITORS Subhash Todi MD MRCP

Kapil Zirpe MD FICCM FCCM

Director Department of Critical Care Advanced Medicare Research Institute Kolkata, West Bengal, India

Director Neuro Trauma Unit Ruby Hall Clinic Pune, Maharashtra, India

Subhal Bhalchandra Dixit MD IDCCM FICCM FCCM

Yatin Mehta MD MNAMS FRCA FAMS FIACTA FICCM FTEE

Consultant Critical Care and Director ICU  Sanjeevan and MJM Hospitals  Pune, Maharashtra, India

Chairman Institute of Critical Care and Anesthesiology Medanta The Medicity Gurugram, Haryana, India

CONTRIBUTING AUTHORS A Hari Prasad DNB FNB

Abhinav Gupta MD DNB FNB EDIC

Ajith Kumar AK MD DNB EDIC FICCM

Fellow Registrar Critical Care Department of Critical Care Medicine Care Hospitals Hyderabad, Telangana, India

Senior Fellow, Critical Care King's College Hospital Brixton, London, UK

Senior Consultant Department of Intensive Care Manipal Hospitals Bengaluru, Karnataka, India

Aakanksha Chawla MD IDCCM

Abhishek Vishnu MD IDCCM IFCCM

Akhil Taneja MD IDCCM IFCCM EDIC

Attending Consultant, Respiratory Medicine, Critical Care and Sleep Medicine, Indraprastha Apollo Hospitals New Delhi, India

Aashish Jain DNB EDAIC FIACTA

FICCM

Senior Consultant BLK Center of Excellence for Critical Care BLK Superspeciality Hospital New Delhi, India

Consultant Medanta Institute of Critical Care and Anesthesiology, Medanta The Medicity Gurugram, Haryana, India

Aditya Bang DNB

Abdul Rauf MD

Ajeet Singh MD IDCCM FNB EDIC

Fellow, Department of Pediatrics Institute of Child Health Sir Ganga Ram Hospital New Delhi, India

Consultant Department of Critical Care Medicine Manipal Hospital New Delhi, India

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Emergency Medicine Resident Jehangir hospital Pune, Maharashtra, India

Senior Consultant Department of Critical Care Max Super Speciality Hospital New Delhi, India

Akshaykumar A Chhallani FNB DNB Consultant Intensivist and Physician Sterling Wockhardt Hospital Navi Mumbai, Maharashtra, India

Alok K Sahoo MD IDCCM Assistant Professor Department of Anesthesiology and Critical Care Medicine All India Institute of Medical Sciences Bhubaneswar, Odisha, India

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Critical Care Update 2019

Amitava Ghosh DA

Anshul Sood PhD Scholar

Ashutosh Garg MD IDCCM

Consultant Department of Anesthesiology and Critical Care Ayursundra Superspecialty Hospital Guwahati, Assam, India

Department of Medical Microbiology Postgraduate Institute of Medical Education and Research Chandigarh, Punjab, India

Senior Consultant Department of Critical Care Medicine Max Super Speciality Hospital New Delhi, India

Amit Omprakash Sharma MD

Anuj M Clerk MD IDCCM EDIC FNB

Asif Ahmed DNB IDCCM

Director Intensive Care Services Sunshine Global Hospital Surat, Gujarat, India

Consultant and In-charge Department of Critical Care Medicine Tata Main Hospital Jamshedpur, Jharkhand, India

Anup Jyoti Dutta DA IDCCM

Atul P Kulkarni MD FISCCM PGDHHM FICCM

Consultant, Department of Critical Care Ayursundra Superspecialty Hospital Guwahati, Assam, India

Professor and Head Department of Anesthesiology Critical Care Medicine and Pain Tata Memorial Hospital Mumbai, Maharashtra, India

Consultant Jigyasa Foundation Regen Hospitals Jaipur, Rajasthan, India

Amit Varma MD FCCM Executive Director Critinext New Delhi, India

Anand Shah MD Clinical Assistant Hinduja Hospital Mumbai, Maharashtra, India

Anil Sachdev MD

Assistant Professor Department of Medical Microbiology Postgraduate Institute of Medical Education and Research Chandigarh, Punjab, India

Director Department of Pediatric Emergency Critical Care and Pulmonology Institute of Child Health Sir Ganga Ram Hospital New Delhi, India

Arghya Majumdar MD DNB MRCP

Anirban Hom Choudhuri MD FICCM

Head Department of Medical Microbiology Postgraduate Institute of Medical Education and Research Chandigarh, Punjab, India

PGDMLE FIAMLE

Professor and ICU In-charge Department of Anesthesiology and Intensive Care, GIPMER New Delhi, India

Anish Gupta MD FNB EDIC Associate Consultant Department of Critical Care Medicine Max Super Speciality Hospital New Delhi, India

Anjul Dayal DNB Fellowship Pediatric Critical Care

In-charge and Senior Pediatric Intensivist, Pediatric Intensive Care Unit Continental Hospitals Hyderabad, Telangana, India

Anshu Joshi MBBS PGDM PGDGM

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Archana Angrup MD

Senior Manager Medical Affairs Scientific and Medical Affairs ANI-India Mumbai, Maharashtra, India

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Director and Head Department of Nephrology AMRI Hospitals Kolkata, West Bengal, India

Arunaloke Chakrabarti MD

Arun Bansal MD FCCM FRCPCH

Avadhesh Pratap DA DNB FNB Consultant, Department of Critical Care Medicine, Continental Hospitals Hyderabad, Telangana, India

Avash Pani MD Fellowship Pediatric

Critical Care

Consultant Pediatric Intensivist Pediaric Intensive Care Unit Continental Hospitals Hyderabad, Telangana, India

Ayesha Sunavala DNB FNB Consultant Department of Infectious Diseases PD Hinduja National Hospital and Medical Research Centre Mumbai, Maharashtra, India

Professor Department of Pediatrics Advanced Pediatrics Centre Postgraduate Institute of Medical Education and Research Chandigarh, Punjab, India

Babu K Abraham MD MRCP (UK) FICCM

Arup Roy MD Fellow in Clinical Microbiology Tata Medical Center Kolkata, West Bengal, India

Chief Consultant Critical Care and Anesthesia Apollo Hospitals Bhubaneswar, Odisha, India

Ashit Hegde MD MRCP

Bharat G Jagiasi DA, MD, IDCCM

Consultant, Department of Medicine and Critical Care PD Hinduja National Hospital and Medical Research Centre Mumbai, Maharashtra, India

Head Department of Critical Care Terna Speciality Hospital and Research Centre Navi Mumbai, Maharashtra, India

Senior Consultant Department of Critical Care Medicine Apollo Hospitals Chennai, Tamil Nadu, India

Banambar Ray MD FICCM

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Contributors

Bharath Kumar Tirupakuzhi Vijayaraghavan MD EDIC Fellowship in

Critical Care (NUHS, Singapore and University of Toronto, Canada)

Consultant Intensivist Department of Critical Care Medicine Apollo Hospitals Chennai, Tamil Nadu, India

Bhuvna Ahuja MD Senior Resident Department of Anesthesiology and Intensive Care GIPMER New Delhi, India

Binila Chacko MD DNB FCICM DM Professor Medical Intensive Care Unit Christian Medical College Vellore, Tamil Nadu, India

Camilla Rodrigues MD Consultant Microbiologist Hinduja Hospital Mumbai, Maharashtra, India

Chandrashish Chakravarty MD(AIIMS) MRCP(UK) SCE-Resp Med (UK) EDIC MAMS Fellow in CCM(USA)

Consultant Critical Care Apollo Hospital Kolkata, West Bengal, India

Chitra Mehta DNB FNB Associate Director Medanta Institute of Critical Care and Anesthesiology Medanta The Medicity Gurugram, Haryana, India

Davy Cheng MD MSc FRCPC FCAHS CCPE

Dean (Interim) and Distinguished University Professor Anesthesia and Perioperative Medicine, Schulich School of Medicine and Dentistry Western University London, Ontario, Canada

Deb Sanjay Nag MD Consultant Department of Anesthesiology Tata Main Hospital Jamshedpur, Jharkhand, India

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Deepak Govil MD EDIC FICCM FCCM

Ganshyam M Jagthkar MD FNB

Director Institute of Critical Care and Anesthesia Medanta The Medicity Gurugram, Haryana, India

Head, Department of Critical Care Maxcure Hospitals Hyderabad, Telangana, India

Deeksha Singh Tomar DA IDCCM IFCCM

COO and Head, Clinical Services Health Care at Home India Noida, Uttar Pradesh, India

EDIC

Consultant, Critical Care Narayana Superspeciality Hospital Gurugram, Haryana, India

Deepak R Jeswani MD DNB IDCCM EDIC Director, Critical Care Unit Criticare Hospital and Research Institute Nagpur, Maharashtra, India

Deven Juneja DNB FNB EDIC FCCP FICCM FCCM

Associate Director Department of Critical Care Medicine Max Super Speciality Hospital New Delhi, India

Devi Prasad Samaddar MD FICCM FICA Director Medical Affairs, Critical Care, Academics and Q Control, Ruby General Hospital Kolkata, West Bengal, India

Dhruva Chaudhry MD DNB DM Professor and Head Department of Pulmonary and Critical Care Medicine Post Graduate Institute of Medical Sciences Rohtak, Haryana, India

Dilip Kshirsagar MBBS Dip Chest & TB Intensivist and Pulmonologist Criticare Hospital and Research Institute Nagpur, Maharashtra, India

Diptimala Agarwal DA PG DHA FICCM Director Department of Anesthesia and Critical Care, Pushpanjali Hospital and Research Centre Agra, Uttar Pradesh, India

Farhad Kapadia MD FRCP Consultant Physician and Intensivist Department of Intensive Care and Medicine, Hinduja Hospital Mumbai, Maharashtra, India

Gaurav Thukral DNB

Geetarth Gogoi MBBS CCCM Associate Consultant Department of Critical Care Ayursundra Superspecialty Hospital Guwahati, Assam, India

Gouri Ranade DNB FRCA EDIC Consultant, Department of Critical Care and Emergency Medicine Deenanath Mangeshkar Hospital and Research Center Pune, Maharashtra, India

Gunchan Paul MD IDCCM Associate Professor Department of Critical Care Medicine Dayanand Medical College and Hospital Ludhiana, Punjab, India

Gunjan P Chanchalani MD FNB IDCCM IFCCM EDIC

Chief Intensivist, Department of Critical Care, Nanavati Super Speciality Hospital Mumbai, Maharashtra, India

Hans Albert Lewis Bachelors in Mass Media Master in Philosophy

CEO, Department of Critical Care SL Raheja Hospital (A Fortis Associate) Mumbai, Maharashtra, India

Harsh Sapra DA Fellowship Neuroanesthesia (UK)

Director Neuroanesthesia and Neurocritical Care Medanta The Medicity Gurugram, Harayana, India

Hasan M Al-Dorzi MD Intensive Care Department College of Medicine, King Saud bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center King Abdulaziz Medical City Riyadh, Saudi Arabia

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Janet Martin BSc PharmD MSc (HTA and M)

John Victor Peter MD DNB MAMS FRACP

Kiran Bada Revappa MD DNB

Associate Professor Department of Anesthesia and Perioperative Medicine and Department of Epidemiology and Biostatistics Western University London, Ontario, Canada

FJFICM FCICM FICCM

FNB Critical Care Trainee Columbia Asia Referral Hospital Bengaluru, Karnataka, India

Janice L Zimmerman MD MACP MCCM Head, Critical Care Division Department of Medicine Houston Methodist Hospital Houston, Texas, USA

Javed Ismail MD DM Senior Resident Department of Pediatrics Postgraduate Institute of Medical Education and Research Chandigarh, Punjab, India

Javier D Finkielman MD Assistant Professor of Clinical Medicine Department of Cardiology Houston Methodist Hospital Houston, TX, USA

Jean-Louis Teboul MD PhD Professor of Therapeutics and Critical Care Medical ICU Bicêtre Hospital Hôpitaux Universitaires Paris-Sud Le Kremlin-Bicêtre Paris, France

Jean-Louis Vincent Department of Intensive Care Erasme Hospital Université libre de Bruxelles Bruxelles, Belgium

Jhuma Sankar MD IAP-ISCCM Fellowship in

Director Christian Medical College Vellore, Tamil Nadu, India

JV Divatia MD FCCM FICCM Professor and Head Department of Anesthesiology Critical Care and Pain Tata Memorial Centre Mumbai, Maharashtra, India

Jyoti Goyal DNB IDCC EDIC Senior Consultant and Head Department of Internal Medicine Nayati Medicity Mathura, Uttar Pradesh, India

Kamal Lashkari MD IDCCM EDIC Critical Care Specialist and Incharge ICU Thumbay Hospital Ajman, UAE

Jignesh Shah MD IFCCM EDIC

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Associate Professor Department of Critical Care Medicine Bharati Vidyapeeth (Deemed to be University) Medical College Pune, Maharashtra, India

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Consultant Intensivist Intensive Care Services Sunshine Global Hospital Surat, Gujarat, India

Lata Bhattacharya MD Senior Consultant Department of Anesthesiology and Critical Care, JLN Cancer Hospital and Research Centre Bhopal, Madhya Pradesh, India

Lokendra Gupta MD FNB(CCM) MRCEM(UK) A and E, Registrar, KGH NHS,UK

Maitree Pandey MD

Director and Head Critical Care, Deep Hospital Ludhiana, Punjab, India

Director and Professor Department of Anasthesiology and Critical Care Lady Hardinge Medical College New Delhi, India

Kavitha TK MD

Manisha Biswal

Kanwalpreet Sodhi DA DNB EDIC IDCCM

Senior Resident Pediatric Critical Care Unit Department of Pediatrics Postgraduate Institute of Medical Education and Research Chandigarh, Punjab, India

Khalid Ismail Khatib MD Professor Department of Medicine Smt Kashibai Navale Medical College and General Hospital Pune, Maharashtra, India

Pediatric Critical Care

Assistant Professor Department of Pediatrics All India Institute of Medical Sciences New Delhi, India

Krunal J Patel MD IDCCM

Khusrav Bajan MD EDIC Consultant Critical Care Head, Department of Emergency Medicine, PD Hinduja National Hospital and Medical Research Centre Mumbai, Maharashtra, India

Kingshuk Dhar MD Fellow in Clinical Microbiology Tata Medical Center Kolkata, West Bengal, India

Department of Medical Microbiology Postgraduate Institute of Medical Education and Research Chandigarh, Punjab, India

Manish Gupta MD IDCCM Consultant, Department of Critical Care RJN Apollo Spectra Hospital Gwalior, Madhya Pradesh, India

Manish Munjal MD FICCM FCCM Chairman, Jigyasa Foundation Medical Director, Regen Hospitals Jaipur, Rajasthan, India

Manoj K Goel MD Diploma in Interventional Pulmonology (France) FISM (Australia) FICM (Belgium) FCCP FIAB FISDA FICCM Certified Training in Ultrasound EBUS Bronchoscopy (Australia) Director and Head Department of Pulmonology, Sleep Medicine and Critical Care Fortis Memorial Research Institute Gurugram, Haryana, India

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Contributors

Manoj Singh MD DTCD DNB FNB

Monika Raghuwanshi MD

Omender Singh MD FCCM

Consultant Chest and Critical Care Department of Critical Care Apollo Hospitals International Limited Gandhinagar, Gujarat, India

Intensivist and Anesthesiologist Criticare Hospital and Research Institute Nagpur, Maharashtra, India

Director Department of Critical Care Medicine Max Super Speciality Hospital New Delhi, India

Manu Varma MK MD DM PDCC Assistant Professor Department of Critical Care Medicine St John's Medical College Hospital Bengaluru, Karnataka, India

Marin H Kollef MD Professor of Medicine Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine St Louis, Missouri, USA

Mansi Gupta MD DNB DM Assistant Professor Department of Pulmonary Medicine Sanjay Gandhi Postgraduate Institute of Medical Sciences Lucknow, Uttar Pradesh, India

Martin Jose Thomas MD DNB Registrar (CICM Trainee) Department of Intensive Care Medicine Tamworth Rural Referral Hospital Tamworth, NSW, Australia

Meena Sonone DTCD IDCCM Fellowship in Diabetology

Junior Consultant, Critical Care Medicine Ashoka Medicover Hospitals Nashik, Maharashtra, India

Mohan Gurjar MD PDCC Additional Professor Department of Critical Care Medicine Sanjay Gandhi Postgraduate Institute of Medical Sciences Lucknow, Uttar Pradesh, India

Mohit Kharbanda MD IDCCM FNB Director, Department of Critical Care Desun Hospital and Heart Institute Kolkata, West Bengal, India

Mohit Mathur MD IDCCM EDIC Consultant and Incharge Critical Care Medicine, Max Hospital Gurugram, Haryana, India

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Mozammil Shafi MD FNB Consultant, Department of Critical Care and Anesthesia, Medanta The Medicity Gurugram, Haryana, India

Nagarajan Ramakrishnan AB (Int Med, Crit Care, and Sleep Med) MMM FACP FCCP FCCM FICCM FISDA

Director Department of Critical Care Medicine Apollo Hospitals Chennai, Tamil Nadu, India

Narendra Rungta MD FICCM FISCCM FCCM

Senior Consultant Critical Care Medicine Rajasthan Hospital Limited Jaipur, Rajasthan, India

Narmada Aluru DA IDCC EDIC Senior Consultant Department of Critical Care Virinchi Hospitals Hyderabad, Telangana, India

Natesh Prabu R MD DNB DM EDIC Assistant Professor Department of Critical Care Medicine St John's Medical College Hospital Bengaluru, Karnataka, India

Neha Gupta Consultant Infectious Diseases Department of Internal Medicine Medanta The Medicity Gurugram, Haryana, India

Nimita Deora MSc

Palepu B Gopal MD FRCA FCCM FICCM Head Department of Critical Care Medicine Continental Hospitals Hyderabad, Telangana, India

Pallab Ray MD DNB Professor Department of Medical Microbiology Postgraduate Institute of Medical Education and Research Chandigarh, Punjab, India

Pankaj R Shah MD DNB Professor Department of Nephrology, IKDRC-ITS Ahmedabad, Gujarat, India

Parmee V Gala Masters in Clinical Pharmacy

Assistant Manager Department of Clinical Pharmacy PD Hinduja Hospital and Medical Research Centre Mumbai, Maharashtra, India

Parshotam Lal Gautam MD DNB

MNAMS FICCM

Professor and Head Department of Critical Care Medicine Dayanand Medical College and Hospital Ludhiana, Punjab, India

Pooja R Murthy MD FNB EDIC Consultant, Critical Care Medicine Manipal Hospitals Bengaluru, Karnataka, India

Clinical Research Assistant Department of Anesthesiology and Critical Care, Chirayu Medical College and Hospital Bhopal, Madhya Pradesh, India

Pradeep D’Costa MD Dip Criti Care

Niraj Tyagi EDIC Attending Consultant Department of Critical Care and Emergency Medicine Sir Ganga Ram Hospital New Delhi, India

Pradeep Rangappa DNB FJFICM EDIC FCICM PGDipECHO MBA (HCS) FICCM PGDMLE (NLSUI)

ICU In-charge King’s Edward Medical Hospital Physician, Sahyadri Hospital Pune, Maharashtra, India

Consultant Intensivist Columbia Asia Referral Hospital, Bengaluru, Karnataka, India

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Pradip K Bhattacharya

Rajesh Chandra Mishra MD FNBCCM

Professor and Head Department of Anesthesiology Director, Critical Care and Emergency Services, Medical Superintendent Chirayu Medical College and Hospital Bhopal, Madhya Pradesh, India

EDICM FCCM FICCM FCCP

Prasad Rajhans MD FICCM Chief Intensivist Department of Critical Care and Emergency Medicine Deenanath Mangeshkar Hospital and Research Center Pune, Maharashtra, India

Prasanna Marudwar MD FNB Consultant Intensivist Department of Intensive Care Medicine Deenanath Mangeshkar Hospital and Research Center Pune, Maharashtra, India

Rajesh Chawla MD FCCM Senior Consultant Respiratory Medicine Critical Care and Sleep Medicine Indraprastha Apollo hospitals New Delhi, India

Roopa Karanam DNB IDCCM

Rajesh Pande MD PDCC FICCM FCCM

Attending consultant Respiratory Medicine Critical care and sleep Medicine Indraprastha Apollo hospitals New Delhi, India

Director BLK Center of Excellence for Critical Care BLK Superspeciality Hospital New Delhi, India

Rajeshwari Nataraj DNB IDPCCM Consultant Pediatric Intensivist Apollo Children’s Hospital Chennai, Tamil Nadu, India

Prashant Kumar MD IDCCM FNB EDIC

Raj Kumar Mani MD MRCP ACCP FICM

ADHCA DOA

Senior Consultant Department of Critical Care Medanta The Medicity Gurugram, Haryana, India

Medical Director Chairman Critical Care and Pulmonology Batra Hospital and Medical Research Centre New Delhi, India

Pravin Amin MD FCCM

Ranvir Singh Tyagi MD FICCM FCCM

Head Department of Critical Care Medicine Bombay Hospital Institute of Medical Sciences Mumbai, Maharashtra, India

Director, Department of Anesthesia and Critical Care, Synergy Plus Hospital Agra, Uttar Pradesh, India

Rahul Chauhan MD FNB Fellow Medanta Institute of Critical Care and Anesthesiology Medanta The Medicity Gurugram, Haryana, India

Rahul Pandit MD FJFICM FCICM EDIC FCCP DA

Director Department of Intensive Care Fortis Hospital and Healthcare Mumbai, Maharashtra, India

Rajeev Soman

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Consultant Intensivist and Internist Ahmedabad, Gujarat, India

Consultant Infectious Diseases Department of Infectious Diseases Jupiter Hospital Pune, Maharashtra, India

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Rishabh Kumar MD FNB Consultant Department of Critical Care Medicine Fortis Escorts Heart Institute New Delhi, India

Ritesh J Shah MD IDCCM Director Critical Care Unit, Sterling Hospitals Vadodara, Gujarat, India

Ritoo Kapoor FCARCSI DNB DA Consultant Anesthetist and Intensivist Department of Anesthetics and Intensive Care East Kent Hospitals University NHS Foundation Trust Kent, England, UK

Ritu Singh MD PDCC Assistant Professor Trauma Critical Care Apex Trauma Center Sanjay Gandhi Postgraduate Institute of Medical Sciences Lucknow, Uttar Pradesh, India

Consultant, Department of Critical Care SL Raheja Hospital (A Fortis Associate) Mumbai, Maharashtra, India

Roseleen Kaur Bali DNB IDCCM

Ruchira Khasne DA DNB IDCCM EDAIC &

EDIC

Consultant and Head Department of Critical Care Medicine Ashoka Medicover Hospitals Nashik, Maharashtra, India

Sachin Gupta MD IDCCM IFCCM EDIC FCCM FICCM

Head, Department of Critical Care Narayana Superspeciality Hospital Gurugram, Haryana, India

Samaresh Das MD DESA (Brussels) Specialist Anesthetics and Intensivist Yeovil District Hospital, NHS Foundation Trust, Higher Kingston, Yeovil Somerset, UK

Sameer Jog MD EDIC IDCCM Consultant Intensivist Department of Intensive Care Medicine Deenanath Mangeshkar Hospital and Research Center Pune, Maharashtra, India

Samir Sahu MD FICCM Director Department of Critical Care and Pulmonology, AMRI Hospitals Bhubaneswar, Odisha, India

Sandeep Dewan DA DNB IDCCM Director and Head Department of Critical Care Medicine Fortis Memorial Research Institute Gurugram, Haryana, India

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Contributors

Sanjay Bhattacharya MD DNB

Shivakumar Iyer MD DNB EDIC

Sunitha Binu Varghese DNB IDCCM

DipRCPath FRCPath

Professor and Head Department of Critical Care Medicine Bharati Vidyapeeth (Deemed to be University) Medical College Pune, Maharashtra, India

Head Department of Critical Care Niramaya Hospital Pune, Maharashtra, India

Senior Attending Consultant Department of Critical Care and Emergency Medicine Sir Ganga Ram Hospital New Delhi, India

Shivakumar Shamarao DCH DNB IDPCCM

Supradip Ghosh DNB EDIC

Consultant Pediatric Intensivist Manipal Hospital Bengaluru, Karnataka, India

Director and Head Department of Critical Care Medicine Fortis Escorts Hospital Faridabad, Haryana, India

Sanjith Saseedharan DA (Univ, CPS)

EDIC FICCM

Consultant in Microbiology Tata Medical Center Kolkata, West Bengal, India

Sanjeev Mittal MBBS

IDCCM EDIC FNNCC FIMSA

Teacher and Head Department of Critical care SL Raheja Hospital (A Fortis Associate) Mumbai, Maharashtra, India

Saswati Sinha MD IDCCM EDIC Consultant Department of Critical Care AMRI Hospitals Kolkata, West Bengal, India

Satish Kumar Anumala MD DM Consultant Hematologist Columbia Asia Referral Hospital, Bengaluru, Karnataka, India

Saroj Kumar Pattnaik DNB IDCCM IFCCM Senior Consultant Department of Anesthesiology Apollo Hospitals Bhubaneswar, Odisha, India

Shalini Singh MBBS Registrar Department of Medicine Lilavati Hospital Mumbai, Maharashtra, India

Sharmili Sinha MD DNB EDIC Senior Consultant Department of Critical Care Apollo Hospitals Bhubaneswar,Odisha, India

Sheila Nainan Myatra MD FCCM FICCM Professor Department of Anesthesia Critical Care and Pain Tata Memorial Hopital Mumbai, Maharashtra, India

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Shrikanth Srinivasan MD DNB FNB Consultant and Head Department of Critical Care Medicine Manipal Hospital New Delhi, India

Shruthi Kamble MD FNB Consultant Intensivist Department of Intensive Care Medicine Deenanath Mangeshkar Hospital Pune, Maharashtra, India

Shweta Ram Chandankhede MD IDCCM Consultant, Department of Critical Care Medicine, Care Hospitals Hyderabad, Telangana, India

Simantika Ghosh DNB Fellowship in Oncoanesthesia and Critical Care Fellowship in Liver Transplant Anesthesia and Critical Care Consultant Anesthesiologist Department of Anesthesia Nayati Medicity Mathura, Uttar Pradesh, India

Srinivas Samavedam MD FRCP DNB FNB EDIC DMLE MHA

Head, Department of Critical Care Virinchi Hospitals Hyderabad, Telangana, India

Subho Banerjee MD DM Assistant Professor Department of Nephrology IKDRC-ITS Ahmedabad, Gujarat, India

Sunil Karanth MD FNB EDIC FCICM Chairman Critical Care Services Manipal Health Enterprises (P) Ltd Manipal, Bengaluru, India

EDIC

Suresh Ramasubban AB (Internal Medicine,

Pulmonary and Critical Care

Senior Consultant Department of Respiratory, Critical Care and Sleep Medicine Apollo Gleneagles Hospital Kolkata, West Bengal, India

Surojit Das PhD Scientific Officer in Microbiology Tata Medical Center Kolkata, West Bengal, India

Sushma Gurav DNB IDCCM Intensivist Neuro Trauma Unit Department of Neuro Trauma Unit Grant Medical Foundation Ruby hall Clinic Pune, Maharashtra, India

Swagata Tripathy MD DNB IDCC EDIC Associate Professor and In-charge Central ICU Department of Anesthesia and Intensive Care All India Institute of Medical Sciences Bhubaneswar, Odisha, India

Swati Chandra MBBS Practising Physician Delhi, India

Sweta J Patel MD IDCCM Senior Consultant Department of Critical Care Medicine Medanta The Medicity Gurugram, Haryana, India

Tulsi Modi DNB Clinical Associate Department of Medicine, Lilavati Hospital Mumbai, Maharashtra, India

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Critical Care Update 2019

Umang Agrawal DNB MRCP DipUKMP

Vasudha Singhal MD

FNB Fellow Department of Infectious Diseases PD Hinduja National Hospital and Medical Research Centre Mumbai, Maharashtra, India

Neuroanesthesiology and Critical Care Medanta The Medicity Gurugram, Harayana, India

Vaishali Solao MD FNB Head Department of Intensive Care Global Hospital Mumbai, Maharashtra, India

Vandana Agarwal MD FRCA Professor Department of Anesthesia Critical Care and Pain Tata Memorial Hospital Mumbai, Maharashtra, India

Vandana Sinha MD Medical Director and Director Department of Critical Care Ayursundra Superspecialty Hospital Guwahati, Assam, India

Vasant C Nagvekar MD Fellowship in ID Consultant ID, Department of Infectious Diseases, Lilavati/Global Hospital Mumbai, Maharashtra, India

Venkat Raman K MD DNB IDCCM EDIC Head, Department of Critical Care Care Hospitals Hyderabad, Telangana, India

Victor D Rosenthal MD CIC MSc Founder and Chairman, INICC Buenos Aires, Argentina

Vignesh Chandrasekara MD FNB Consultant, Department of Critical Care Medicine, Apollo Hospitals Chennai, Tamil Nadu, India

Vinay Amin MBBS PG Student, Registrar Bombay Hospital Institute of Medical Sciences Mumbai, Maharashtra, India

Vinod K Singh MD EDIC MRCP Senior Consultant, Department of Critical Care and Emergency Medicine Sir Ganga Ram Hospital New Delhi, India

Vishal Agarwal DRM Dip CBNC FASNC FANMB

Consultant and Head Nuclear Medicine and PET-CT Nayati Medicity Mathura, Uttar Pradesh, India

YP Singh MD FICCM FCCM Senior Director and Head Department of Critical Care Medicine Max Super Speciality Hospital New Delhi, India

Yaseen M Arabi MD FCCP FCCM Intensive Care Department College of Medicine King Saud bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center King Abdulaziz Medical City Riyadh, Saudi Arabia

Yash Javeri DA IDDCM FICCM Director Apex Healthcare Consortium New Delhi, India

xii

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Preface Dear Friends, New Year Greetings from the Editors of Critical Care Update 2019, the Annual Congress book of ISCCM. The latest edition of Critical Care Update will be released during the Silver Jubilee Conference of ISCCM to be held in Mumbai on 1st February 2019. Similar to previous two editions (2017, 2018) this edition comprises of 101 Chapters divided across 13 Sections with a coverage of all the major subspecialties of critical care. The ratio of chapter distribution is in keeping with the relative scientific work done in the respective field. ISCCM has allocated a substantial space to the Quality, Research and Organizational aspect keeping in mind the growing importance of these often neglected areas of critical care. Most of the chapter topics will be covered during the annual congress and will be a ready reckoner for the attendees. The topics have been carefully selected by the ISCCM National Scientific Committee and the contributors are mostly national and international faculty in the congress. Young talents in the field have been encouraged to contribute to the book and the trend will increase in future. Best Wishes

Subhash Todi Subhal Bhalchandra Dixit Kapil Zirpe Yatin Mehta

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Acknowledgments It is with great pleasure that I write this message for the book. I must congratulate the co-editors for doing a stupendous work for bringing this about; a lot of the credit obviously goes to Dr Todi. The Critical Care Update 2019 has 101 chapters divided across 13 sections, written by the faculty for our Silver Jubilee Conference in Mumbai, where this book will also be released. This book by and large covers the full spectrum of critical care from clinical management to ethics to end of life issues. This book is a must read for students and practitioners of this complex specialty, particularly in this subcontinent.

Yatin Mehta

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Contents Section 1: Hemodynamic Monitoring and Resuscitation 1. Balanced Crystalloid Use in ICU: Current Status

3

Rajesh Pande, Abhishek Vishnu, Maitree Pandey

2. Saline Resuscitation: Does the Dose Matter?

7

Sameer Jog, Shruthi Kamble, Prasanna Marudwar

3. Negative Fluid Balance: Beneficial or Harmful?

12

Binila Chacko, John Victor Peter

4. Angiotensin II: The New Vasopressor

19

Yatin Mehta, Aashish Jain

5. Inotropes in Septic Shock: Which One and When?

24

Subhal Bhalchandra Dixit, Khalid Ismail Khatib

6. Integrating Hemodynamic Variables at the Bedside

27

Avadhesh Pratap, Palepu B Gopal

7. Using the Ventilator to Determine Fluid Responsiveness

31

Sheila Nainan Myatra

8. The Gray Zone of Fluid Responsiveness

35

Ashit Hegde

9. Are Static Measures Still Useful?

37

Sunil Karanth

10. Should We Target SBP/DBP/MAP in Shock?

43

Srinivas Samavedam, Ganshyam M Jagthkar, Narmada Aluru

11. Weaning-induced Cardiac Dysfunction

46

Sushma Gurav

12. Critical Appraisal of Surviving Sepsis Guidelines on Hemodynamic Resuscitation

52

Jean-Louis Teboul

13. Mini-fluid Challenge

55

JV Divatia

14. Monitoring the Quality of Cardiopulmonary Resuscitation

60

Prasad Rajhans, Gouri Ranade

15. Postcardiac Arrest Care in ICU

63

Javier D Finkielman, Janice L Zimmerman

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Critical Care Update 2019

Section 2: Respiratory/Airway/Ventilation 16. Tracheostomy Care in ICU

69

Manish Munjal, Samaresh Das, Amit Omprakash Sharma

17. Airway Management in ICU: Current Guidelines

77

Pradip K Bhattacharya, Lata Bhattacharya, Nimita Deora

18. Recruitment Maneuver in ICU: Is it Out?

84

Rajesh Chawla, Aakanksha Chawla, Roseleen Kaur Bali

19. Mechanical Ventilatory Support in Failing Heart

89

Mohit Mathur, Yash Javeri

20. Lessons Learnt from Lung Safe Study

93

Ajeet Singh, Shrikanth Srinivasan, Rishabh Kumar

21. Lung Protective Ventilation: Not So Protective

95

Sachin Gupta, Deeksha Singh Tomar

22. Positive End-expiratory Pressure Titration: Current Status

98

Yash Javeri, Bharat G Jagiasi, Gunjan P Chanchalani

23. Spontaneous or Assisted Breathing on Mechanical Ventilation: Which Way to Go?

103

Dhruva Chaudhry, Mansi Gupta

24. Noninvasive Ventilation-induced Acute Lung Injury

110

Supradip Ghosh

25. Ventilation-induced Lung Injury: Ergotrauma

114

Suresh Ramasubban

26. Apneic Oxygenation

118

Khusrav Bajan

27. CAP, HAP, HCAP and VAP: How Should Intensivists Approach this Alphabet Soup?

124

Marin H Kollef

28. Adverse Effects of Oxygen Therapy in ICU

131

Deepak Govil, Mozammil Shafi, Sweta J Patel

29. Venous Thromboembolism in Critically Ill Patients: Risk Stratification and Prevention

135

Hasan M Al-Dorzi, Yaseen M Arabi

30. Mean Systemic Filling Pressure: Physiology and Applicability

141

Mohit Kharbanda

Section 3: Infection/Antibiotic/Sepsis/Infection Control 31. Colistin Resistance: A Growing Threat

149

Vasant C Nagvekar, Tulsi Modi, Shalini Singh

32. When to Suspect and How to Detect Carbapenemase Production? A Review

155

Sanjay Bhattacharya, Surojit Das, Kingshuk Dhar, Arup Roy

33. Antibiotic within One Hour: Is it for Everyone?

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161

Martin Jose Thomas, Vandana Agarwal

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Contents

34. Dysbiosis and Probiotics in ICU

165

Anshu Joshi

35. MALDI-TOF: Utility in ICU 169 Anand Shah, Camilla Rodrigues

36. Therapeutic Drug Monitoring for Beta-lactams and Colistin: Is it Ready for Prime Time?

173

Ayesha Sunavala, Umang Agrawal, Parmee V Gala

37. Steroids in Septic Shock: What do the Recent Studies Tell Us?

178

Narendra Rungta

38. Role of Vitamin C in Septic Shock

181

Anirban Hom Choudhuri, Bhuvna Ahuja

39. Vitamin C in Septic Shock: Is it the Holy Grail?

186

Khalid Ismail Khatib, Kapil Zirpe, Subhal Bhalchandra Dixit

40. Candida auris: The Emerging Threat

189

Arunaloke Chakrabarti, Manisha Biswal

41. Cryptococcal Meningitis: Current Treatment Strategy

193

Rajeev Soman, Neha Gupta

42. Management of Severe Dengue: Are WHO Guidelines Relevant?

198

Pravin Amin, Vinay Amin

43. Scrub Typhus: When to Suspect and How to Manage?

203

Khalid Ismail Khatib, Subhal Bhalchandra Dixit

44. Epidemiology and Prevention of HAIs Worldwide in ICUs with Limited Resources: Experience of the International Nosocomial Infection Control Consortium Global Network

206

Victor Daniel Rosenthal

45. Daily Chlorhexidine Body Wash: Is it Helpful?

211

Venkat Raman K, Shweta Ram Chandankhede, A Hari Prasad

Section 4: Quality/Ethics/Organization/ICU Research 46. How to Create an ICU Checklist Manifesto?

219

Ajith Kumar AK, Pooja R Murthy

47. Standardized Mortality Ratio: Is it a Reliable Quality Indicator?

223

Banambar Ray, Saroj Kumar Pattnaik, Sharmili Sinha

48. Crisis Resource Management: Application in ICU

227

Abhinav Gupta

49. Challenges of Developing Critical Care in Resource Poor Settings

230

Parshotam Lal Gautam, Gunchan Paul

50. Value-based Critical Care Medicine: Evidence Reversal and Choosing Wisely Campaign in Critical Care

234

Janet Martin, Davy Cheng

51. Alarm Fatigue in ICU: How to Minimize? Anuj M Clerk, Krunal J Patel

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242

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Critical Care Update 2019

52. Structured Physician and Nursing Handover in ICU

246

Devi Prasad Samaddar, Asif Ahmed, Deb Sanjay Nag

53. Translating ICU Guidelines in Practice

251

Ranvir Singh Tyagi, Simantika Ghosh, Diptimala Agrawal

54. Withdrawal and Withholding of Life Support: Implications of Recent Court Judgments

255

Raj Kumar Mani

55. Limitations of Current ICU Trial Designs

260

Farhad Kapadia, Ritoo Kapoor

56. Home-based Critical Care—An Indian Experience

264

Gaurav Thukral, Amit Varma

57. End-of-life Practices in India: An Update

269

Shivakumar Iyer, Jignesh Shah

58. Patient-centered Structured Interdisciplinary Bedside Rounds in the Medical ICU

273

Babu K Abraham, Vignesh Chandrasekara

59. Availability and Applicability of Apps in the ICU: Digitalization in Critical Care

277

Sanjith Saseedharan, Roopa Karanam, Hans Albert Lewis

60. Physician Assistant and Advanced Nurse Practitioner

282

Subhash Todi

Section 5: Neurology 61. Multimodality Neuromonitoring

289

Prashant Kumar, Manish Gupta, Kamal Lashkari

62. Ischemic Stroke: Head Up or Head Down

295

Ritu Singh, Mohan Gurjar

63. Decompressive Craniectomy: Should It be Offered?

299

Harsh Sapra, Vasudha Singhal

64. Frailty in the ICU: Assessment, Implications and Management

303

Bharath Kumar Tirupakuzhi Vijayaraghavan, Nagarajan Ramakrishnan

65. Donation after Circulatory Death

308

YP Singh, Akhil Taneja, Ashutosh Garg

Section 6: Nephrology/Dialysis/Electrolytes 66. Chloride: The Neglected Ion

315

Sunitha Binu Varghese, Sushma Gurav

67. Contrast-induced Nephropathy: How to Prevent?

321

Vandana Sinha, Amitava Ghosh, Anup Jyoti Dutta, Geetarth Gogoi

68. Early versus Late Renal Replacement Therapy Initiation in ICU

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324

Rajesh Chandra Mishra, Kanwalpreet Sodhi, Pankaj R Shah, Subho Banerjee

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Contents

69. Augmented Renal Clearance: When to Suspect and How to Manage?

328

Khalid Ismail Khatib, Subhal Bhalchandra Dixit, Kapil Zirpe

70. Urine Output or Serum Creatinine: That is the Question!

330

Arghya Majumdar

Section 7: Trauma/Perioperative/Toxicology/Burns 71. Perioperative Care: Are Balanced Crystalloids Needed?

335

Rahul Pandit

72. Whole Body Ultrasound in Trauma

338

Pradeep D’Costa

73. Celphos Poisoning: Can We Save More Lives?

353

Omender Singh, Deven Juneja

74. Creation of Trauma Team

357

Chandrashish Chakravarty, Aditya Bang

75. Postoperative Peritonitis: Challenges in Diagnosis and Management

361

Ruchira Khasne, Meena Sonone, Atul P Kulkarni

Section 8: Gastroenterology/Pancreas/Nutrition/Hepatology 76. Stress Ulcer Prophylaxis: Is it Really Needed?

375

Samir Sahu

77. Extracorporeal Liver Support: Current Status

378

Vaishali Solao

78. Early Goal-directed Nutrition Delivery

382

Alok K Sahoo, Swagata Tripathy

79. Permissive Underfeeding: When, Why and How?

387

Subhal Bhalchandra Dixit, Khalid Ismail Khatib

80. Bedside Monitoring of Muscle Mass and Function

389

Ritesh J Shah

Section 9: Hematology/Oncology/Obstetrics/Pharmacology 81. Maternal Cardiac Arrest: How to Manage?

397

Yash Javeri, Lokendra Gupta

82. Age of Red Blood Cells and Outcome in ICU

403

Saswati Sinha

83. Individualizing Transfusion Threshold

408

Natesh Prabu R, Manu Varma MK

84. Role of Clinical Pharmacist in ICU

414

Bharat G Jagiasi, Akshaykumar A Chhallani

85. Infections in Hemato-Oncology Patients Pradeep Rangappa, Kiran Bada Revappa, Satish Kumar Anumala

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417

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Critical Care Update 2019

Section 10: Endocrine/Metabolic/Glucose Control 86. Hypoglycemia

427

Jyoti Goyal, Yash Javeri

87. Gut Microbiome in Critical Illness

432

Pallab Ray, Anshul Sood, Archana Angrup

88. Advances in Glucose Monitoring in ICU

437

Manoj Singh

89. Hypophosphatemia: Manifestations and Management

441

Manoj K Goel, Yash Javeri

90. Metabolic Care in ICU

445

Deepak Jeswani, Monika Raghuwanshi, Dilip Kshirsagar

Section 11: Transplant/Extracorporeal Support/Imaging 91. Utility of PET-CT in ICU

453

Vishal Agarwal, Yash Javeri, Swati Chandra

92. Mechanical Ventilation on Extracorporeal Membrane Oxygenation

460

Sandeep Dewan

93. Extracorporeal Organ Support: An Integrated Approach

464

Deven Juneja, Anish Gupta, Omender Singh

94. Role of Intensivists in Hematopoietic Stem Cell Transplantation

469

Chitra Mehta, Rahul Chauhan

95. Weaning and Withdrawing Extracorporeal Membrane Oxygenation Support

478

Niraj Tyagi, Sanjeev Mittal, Vinod K Singh

Section 12: Pediatrics 96. Advanced Modes of Ventilation

485

Arun Bansal, Kavitha TK

97. Fluid Resuscitation and Deresuscitation

491

Javed Ismail, Jhuma Sankar

98. Renal Replacement Therapy in Sepsis in Children

496

Rajeshwari Nataraj, Shivakumar Shamarao

99. Hypertension Management in Pediatric ICU

504

Anjul Dayal, Avash Pani

100. High-flow Nasal Cannula in Children: A Concise Review and Update

509

Anil Sachdev, Abdul Rauf

Section 13: Insights into Sepsis xxii

101. Ten Elements that can Improve Outcome in Sepsis

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519

Jean-Louis Vincent

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Section 1 Hemodynamic Monitoring and Resuscitation

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1

CHAPTER

Balanced Crystalloid Use in ICU: Current Status Rajesh Pande, Abhishek Vishnu, Maitree Pandey

INTRODUCTION Fluid resuscitation is a very important initial step in the management of hypovolemic critically ill patients. After the publication of starch trials, crystalloids have become the first-line resuscitation fluid for all critical patients unless blood is required for ongoing massive blood loss. Guidelines recommend initial crystalloid bolus of 20–30 mL/Kg to treat the hypovolemia in sepsis and septic shock patients.1 Four phases have been identified in the management of circulatory shock—salvage, optimization, stabilization and de-escalation (SOSD).2

SOSD PHASES OF RESUSCITATION Initial salvage phase focuses on restoration of vital organ perfusion by bringing hemodynamic parameters to acceptable levels and large volume crystalloid resuscitation is required in initial 0–24 hours, followed by optimization and stabilization phase lasting 24–72 hours where smaller volume are required to maintain fluid status and the focus is prevention of organ dysfunction after hemodynamic stability has been achieved and the last de-escalation or de-resuscitation phase after 96 hours, aims to achieve slight negative balance by either fluid restriction or induced diuresis.3 Intravenous fluids administration is important not only in the management of critically ill patients, but also in the patients undergoing major surgical procedures. Large volume crystalloid resuscitation has been identified as the cause of deterioration in some situations like acute respiratory distress syndrome (ARDS) and can lead to tissue edema due to increased interstitial volume, secondary abdominal compartment syndrome, decreased cardiac function, increased gastric mucosal permeability leading to bacterial translocation.

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WHAT ARE CRYSTALLOIDS? Crystalloids are sodium-based solutions which contain electrolytes in concentration similar to the plasma. Different crystalloids vary in several ways including chloride content, strong ion difference (SID) and osmolality. Traditionally crystalloids have been labeled as isotonic because the osmolality is similar to intravascular fluid and they can be infused fast in situations of ongoing intravascular fluid loss with few contraindications. They are cheap, do not require special storage, have extended shelf life and can be rapidly administered. Unlike colloids, they readily cross out of intravascular space to replenish fluid in the interstitial compartment. The interstitial fluid moves into the intracellular and intravascular spaces in shock, depleting the interstitial space. Crystalloids can affect the balance of body fluids in only these two compartments. The commonly used crystalloids are listed in Table 1.

TYPES OF CRYSTALLOIDS Normal Saline The most commonly used crystalloid solution is normal saline (saline, 0.9% NaCl or NS or isotonic saline solution, ISS). Saline contains 9 g of sodium chloride in 1 L of water (0.9%) and contains 154 mEq/L of sodium and 154 mEq/L of chloride. The chloride content is about 1.5 times higher than plasma, osmotic pressure is 286 mOsm/L (similar to intravascular and interstitial fluid) and has a strong ion deficit of zero.4 Aggressive fluid resuscitation with saline may cause dilution of circulating bicarbonate resulting in hyperchloremic acidosis proportional to volume infused. Saline is mainly distributed in the interstitium (75%) and to a lesser extent in the intravascular compartment (25%).

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SECTION 1: Hemodynamic Monitoring and Resuscitation TABLE 1

Composition of various crystalloids in comparison to plasma.

Features

Plasma

0.9% NaCl (normal saline)

Ringer lactate

Sterofundin

Plasma-Lyte® 148

Kabilyte

Osmolality (mOsm/kg H20)

290

286

256

290

294

294

Na (mmol/L)

142

154

131

145

140

140

K+

(mmol/L)

4.5

–

5.4

4

5

5

Ca++ (mmol/L)

2.5

–

1.8

2.5

0

0

Mg++

(mmol/L)

Cl─ (mmol/L)

HCO3─ (mmol/L)

1.25

–

–

1

1.5

1.5

103

154

112

127

98

98

24

–

–

–

–

–

Lactate (mmol/L)

1.5

–

28

–

–

–

Acetate (mmol/L)

–

–

–

24

27

27

Malate (mmol/L)

–

–

–

5

–

–

Gluconate

–

–

–

–

23

23

Therefore, the volume required to raise intravascular compartment is high.

Balanced Crystalloids

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Crystalloids such as Ringer’s lactate (RL; Hartmann’s) solution, Plasma-Lyte, Normosol and similar solutions are currently labeled as “physiologically balanced” crystalloids, as their electrolyte contents are similar to the human plasma. These balanced crystalloids are nearly isotonic with a chloride concentration 6 hours, while serum chloride concentrations remained normal after Hartmann’s. Serum bicarbonate concentration was significantly lower after saline than after Hartmann’s. The same group compared 0.9% saline with PlasmaLyte (2 L within 1 h) in healthy volunteers on two separate occasions.11 The intravascular volume expansion was similar between Plasma-Lyte and 0.9% saline. But use of 0.9% saline was associated with sustained hyperchloremia, reduced SID, increased extravascular volume (edema) and lowered diuresis compared with Plasma-Lyte. Although there was difference in urinary NGAL, but renal artery flow velocity and renal cortical perfusion assessed with magnetic resonance imaging were significantly lower after 0.9% saline administration than after Plasma-Lyte. A data based observational study evaluating adult patients undergoing major open abdominal surgery who received either 0.9% saline (30,994 patients) or a balanced crystalloid solution (926 patients) on the day of surgery found higher in-hospital mortality in the saline group compared to balanced group (5.6% vs. 2.9%, p 7.5 L) in first 3 days was superior in reducing 90day mortality of patients with septic shock than those with 10% is associated with fluid responsiveness.7

Pulse Pressure Variation Pulse pressure (difference between systolic and diastolic pressure) is directly proportional to LV stroke volume and inversely related to arterial compliance. The respiratory changes seen in LV stroke volume determine changes in the peripheral pulse pressure during the respiratory cycle. Pulse pressure variation (PPV) can be expressed as a percentage using the equation PPV (%) = (PPmax − PPmin)/ PPmean. Measurement of PPV can be used to predict preload nonresponders in those with a PPV 12% indicates responders. ∆Vpeak can also be measured in the descending aorta using transesophageal Doppler.8

Superior Vena Cava Collapsibility Index and Inferior Vena Cava Distensibility Index The superior vena cava (SVC) diameter is measured using TOE and the SVC collapsibility index is calculated as (maximum diameter on expiration—minimum diameter on inspiration)/ maximum diameter on expiration. In hypovolemia, the increase in pleural pressure may be sufficient to completely collapse the vessel. An SVC collapsibility index >36% has been shown to predict fluid responsiveness with both excellent sensitivity and specificity. Inferior vena cava (IVC) measurement is obtained by transthoracic echocardiography using a subcostal approach. IVC diameter is affected by intra-abdominal pressure and right atrial pressure. An IVC distensibility index above 18% can predict fluid responsiveness and is calculated by maximal diameter at inflation-minimal diameter at expiration/maximal diameter. The major limitation of the IVC distensibility index is raised intra-abdominal pressure, due to various conditions.10

ASSESSING FLUID RESPONSIVENESS IN THE SPONTANEOUS BREATHING PATIENT Inferior Vena Cava Collapsibility Index Inferior vena cava collapsibility index is calculated as maximum diameter—minimum diameter/maximum diameter and threshold value of >12% or IVC variability (maximum diameter—minimum diameter/mean of the two diameters during the respiratory cycle) >50% predicts fluid responsiveness.

Passive Leg Raising Test Passive leg raising (PLR) can be performed in spontaneously breathing patient, arrhythmias and low tidal ventilation also. Provides autotransfusion of approximately 300 mL of blood from lower extremities.11 Cardiac output must be measured continuously and in real time. But it does not necessarily require invasive monitoring. Many studies have used nonin­ vasive or minimally invasive techniques to estimate the PLRinduced changes in cardiac output. Both the calibrated and uncalibrated pulse contour analysis techniques can be used. More than or equal to 10% increase in SV, ≥9% increase in PP, ≥8% increase in aortic blood flow predict fluid responsiveness.

End‑expiratory Occlusion Test Stopping ventilation for a few seconds stops the cyclic impediment in venous return causing a transient increase in cardiac preload. If cardiac output increases in response to

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SECTION 1: Hemodynamic Monitoring and Resuscitation this end-expiratory occlusion (EEO) test, it indicates preload responsiveness of both ventricles. The duration of the EEO must not be shorter than 15 seconds, because this lapse of time is required by the preload change to transit through the pulmonary circulation. Cardiac output >5% predicts fluid responsiveness with good sensitivity and specificity.12 The EEO technique does not have the technical constraints of PLR and is valid in patients with ARDS. The main limitation of the test being that the patient should be intubated and tolerate a 15 seconds respiratory hold.

Mini-fluid Challenge Mini-fluid challenge is performed with 100 mL of colloid, infused over 1 minute and the changes in the velocity time integral of the left ventricular outflow tract measured with echocardiography predicts preload responsiveness. The threshold value is >10%. The main disadvantage is that the test requires a very precise cardiac output monitoring system. Whether transthoracic echocardiography is precise enough is far from certain.13

Other Tests In a recent study in patients undergoing cardiac surgery, fluid responsiveness was assessed through CO2 elimination, which was used as a surrogate marker of cardiac output after a sudden increase in positive end-expiratory pressure from 5 to 10 cm H2O.14 The respiratory systolic variation test (RSVT) quantifies the decrease in systolic pressure in response to a standardized maneuver consisting of three consecutive mechanical breaths with increasing airway pressure. The main advantage of RSVT is that it is independent of tidal volumes.15 This test is now auto­ matically performed by some ventilators and the test appears to be as accurate as PPV and SVV.

FLIP SIDE OF SALINE RESUSCITATION

10

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Controversy regarding the use of salt-containing solutions in surgery and trauma has continued for most of the 20th century. The therapeutic value of a physiologic saline solution administered in large amounts either intravenously, hypo­ dermically, or by the intestinal tract in certain pathologic conditions characterized by changes, quantitative or qualitative, in the blood plasma, has been so abundantly demonstrated by clinical experience that it requires no emphasis here. Under certain circumstances, saline solutions can cause great harm to the tissues of the body and are even capable of causing death, is as true as it is of many other valuable therapeutic procedures (Evans, 1911). Traditionally fluid overload is defined as weight gain of 10% as compared to admission. Also, it can be defined in terms of symptoms and signs like development of pedal edema, crackles on auscultation or anasarca as compared to admission. Edema of gastrointestinal tract has been

well‑described in those resuscitated with crystalloids. It may lead to development of ileus. Increased nasogastric (NG) output may be falsely attributed to obstruction rather than aforementioned changes and increased crystalloid loads. The relationship between intestinal edema and absorptive function, diarrhea is less clear. Myocardial edema may be seen in conditions like septic shock requiring massive crystalloid resuscitation, showing depressed ventricular function. Edema of skin is associated with decreased oxygen tension resulting in impaired wound healing and increased risk of infections. Patients with hemorrhagic shock and surgical patients pose different problems such as adverse effects on coagulation due to dilutional effect leading to anemia, thrombocytopenia, reduced plasma and oncotic, clotting and opsonic proteins. Many studies have shown association between fluid overload and increased morbidity and mortality. Boyd et al.3 showed that in patients with septic shock who required vasopressors, higher mortality was found in those having greater positive fluid balance 12 hours and 4  ays after resuscitation. They also found direct relationship between CVP within first 12 hours and mortality. Of these, patients having CVP >12 mm Hg was associated with highest mortality. Vaara et al.16 showed a significantly higher 90-day mortality rate in patients who were volume-overloaded prior to the initiation of renal replacement therapy (RRT). Normal saline (0.9% saline) is still most commonly used crystalloid for resuscitation which has higher chloride content than plasma. Balanced crystalloids contain additional anions, such as lactate or acetate and acts as physiological buffers to achieve near physiological amounts of chloride. Though 0.9% saline is called as normal saline, it is neither normal nor physiological. It contains 154 mmol/L of sodium and 154 mmol/L of chloride and is in no way analogous to the complex composition of the extracellular fluid. Its higher chloride content (97–110 mmol/L), absence of other essential extracellular ions potassium, calcium, bicarbonate, magnesium, phosphorus, low pH (5.4) elicits different effects following resuscitation compared to balance crystalloid like Plasma-Lyte A. Resuscitation with normal saline has many detrimental effects can be explained by excess chloride resulting in intrarenal vasoconstriction, acute kidney injury (AKI), hyperchloremic metabolic acidosis, gastrointestinal dysfunction and the secretion of inflammatory cytokines.17 Saline induced adverse effects compared to balanced solution are: • Hyperchloremic acidosis: It can cause outflux of potassium in proportion to acidosis which can be clinically signi­ ficant. It can induce increase in production of circulatory inflammatory mediators and can result in reduction of cardiac and skeletal muscle performance by reduction of calcium sensitivity and maximal force generation. Reduced gastric blood flow and mucosal pH in elderly surgical patients, delayed recovery of gut motility, prolonged recovery and increased hospital length of stay in colonic surgical patients

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CHAPTER 2: Saline Resuscitation: Does the Dose Matter? • Symptoms like abdominal discomfort, abdominal distention and pain, nausea, drowsiness, decreased mentation and mental capacity • In cases of gastrointestinal hemorrhage, saline resusci­ tation was found to be associated with exacerbation of hemorrhage and need of more blood transfusion. No currently used resuscitation crystalloid fluid is evaluated formally regarding safety and efficacy. Two recent pragmatic randomized controlled trials have shown harmful effects of normal saline in terms of higher rates of death and kidney complications. The study by SALT-ED18 (Saline against Lactated Ringer’s or Plasma-Lyte in the Emergency Department) investigators randomly allocated 13,347 noncritically ill adults (median age 58 years) requiring IVF in the emergency department to treatment with either saline or balanced crystalloids (lactated Ringer’s solution or Plasma-Lyte A). The researchers included all patients admitted to the emergency department. The results showed no difference in the primary outcome of time to hospital discharge (the number of hospital-free days) between the two patient groups. However, treatment with balanced fluids was associated with a lower death rate than saline and the incidence of major adverse kidney events within 30 days was lower with balanced fluids than with saline. Other study by SMART (Isotonic Solutions and Major Adverse Renal Events Trial) investigators included 15,802 critically ill adult patients cared for in five intensive care units at the hospital. Use of balanced crystalloids was associated with a significantly lower rate of major adverse kidney events than saline infusion group. They also reported in-hospital mortality at 30 days was significantly lower with balanced fluids than with saline. Another cluster randomized blinded trial—0.9% Saline versus Plasma-Lyte 148 for ICU Fluid Therapy (SPLIT) trial has shown no difference in the incidence of AKI, need for RRT, or mortality between patients randomized to saline versus a balanced salt solution. But findings should be interpreted carefully as patients were less ill and majority of patients were surgical, average volume of fluid was approximately 2 L which may be insufficient to result in AKI in chloride restrictive group.

CONCLUSION Because of the risk of fluid overload and the inconsistent efficacy of volume expansion, the decision to administer fluid cannot be taken lightly. Fluids are drugs whose dose must be carefully titrated to the needs of the patient. Several methods and tests are currently available to identify preload responsiveness. All these techniques have some limitations, but they are frequently complementary. The choice between the techniques for assessing fluid responsiveness depends on the patient’s condition and the available monitoring techniques.

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It is important to stress that the decision of fluid administration should not be based solely on the presence of preload responsiveness, but also on the presence of hemodynamic instability (or peripheral hypoperfusion) and the absence of high risk for fluid overload. A reasoned fluid strategy estimating preload responsiveness to aid in the decision to administer fluid and to refrain from fluid administration will likely improve the quality of care delivered and patient outcomes. Newer dynamic measurements hold great promise for determining fluid status and bioimpedance and bioreactance techniques allow further refinement. Additional study of these methods is required to determine whether their use can improve morbidity and mortality in ICU patients.

REFERENCES 1. Smith S, Perner A. Higher vs. lower fluid volume for septic shock: clinical characteristics and outcome in unselected patients in a prospective, multicenter cohort. Crit Care. 2012;16(3):R76. 2. Levy MM, Evans LE, Rhodes A. The surviving sepsis campaign bundle: 2018 update. Intensive Care Med. 2018;44(6):925-8. 3. Sakr Y, Vincent JL, Reinhart K, et al. High tidal volume and positive fluid balance are associated with worse outcome in acute lung injury. Chest. 2005;128(5):3098-108. 4. Boyd JH, Forbes J, Nakada TA, et al. Fluid resuscitation in septic shock: A positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med. 2011;39(2):259-65. 5. Pinsky M. Assessment of indices of preload and volume responsiveness. Curr Opin Crit Care. 2005;11(3):235-9. 6. Diebel LN, Wilson RF, Tagett MG, et al. End-diastolic volume: a better indicator of preload in the critically ill. Arch Surg. 1992;127(7):817-21. 7. Hofer C, Senn A, Weibel L, et al. Assessment of SVV for predicting fluid responsiveness using the modified FloTrac and PiCCO plus systems. Crit Care. 2008;12(3):R82. 8. Michard F, Teboul JL. Using heart-lung interactions to assess fluid responsiveness during mechanical ventilation. Crit Care. 2000;4(5):282-9. 9. Tavernier B, Makhotine O, Lebuffe G, et al. Systolic pressure variation as a guide to fluid therapy in patients with sepsis-induced hypotension. Anesthesiology. 1998;89(6):1313-21. 10. Vincent JL. New echocardiographic parameters of fluid responsiveness in ventilated patients. Yearbook of Intensive Care and Emergency Medicine, 1st edition. Germany: Springer; 2005. pp. 553-60. 11. Jabot J, Teboul JL, Richard C, et al. Passive leg raising for predicting fluid responsiveness: importance of the postural change. Intensive Care Med. 2009;35(1):85-90. 12. Monnet X, Osman D, Ridel C, et al. Predicting volume responsiveness by using the end-expiratory occlusion in mechanically ventilated intensive care unit patients. Crit Care Med. 2009;37(3):951-6. 13. Muller L, Toumi M, Bousquet PJ, et al. An increase in aortic blood flow after an infusion of 100 mL colloid over 1 minute can predict fluid responsiveness: the mini-fluid challenge study. Anesthesiology. 2011;115(3):541-7. 14. Tusman G, Groisman I, Maidana GA, et al. The sensitivity and specificity of pulmonary carbon dioxide elimination for noninvasive assessment of fluid responsiveness. Anesth Analg. 2015;122(5):1404-11. 15. Preisman S, Kogan S, Berkenstadt H, et al. Predicting fluid responsiveness in patients undergoing cardiac surgery: functional haemodynamic parameters including the respiratory systolic variation test and static preload indicators. Br J Anaesth. 2005;95(6):746-55. 16. Vaara S, Korhonen AM, Kaukonen KM, et al. Fluid overload is associated with an increased risk for 90-day mortality in critically ill patients with renal re- placement therapy: data from the prospective FINNAKI study. Crit Care. 2012;16(5):R197. 17. Weinstein PD, Doerfler ME. Systemic complications of fluid resuscitation. Crit Care Clin. 1992;8(2):439-48. 18. Self WH, Semler MW, Wanderer JP, et al. Balanced crystalloids versus saline in noncritically ill adults. N Engl J Med. 2018;378(9):819-28.

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3

CHAPTER

Negative Fluid Balance: Beneficial or Harmful? Binila Chacko, John Victor Peter

INTRODUCTION The goal of fluid therapy in the critically ill patient is to maintain an adequate volume status, particularly in the intravascular and intracellular compartments without overloading the extracellular (interstitial) compartment. Optimizing fluid therapy in the critically ill is challenging and subject to much debate—not just with reference to the type of fluid but also with regards to the approach (timing and dose). Optimal fluid therapy is necessary to ensure adequate perfusion, which in turn would affect global oxygen delivery—if this is not done at the right time with the right amount, endothelial damage and microcirculatory dysfunction could ensue. Additionally, if fluids are used indiscriminately, increased microvascular hydrostatic pressures would subsequently increase interstitial fluid accumulation and have potential ill effects at the cellular level in the lungs and several other organs. This article will focus on answering the following questions based on the available evidence: • Should we aim for a negative fluid balance? What does the evidence say? • When is the right time? • How can I get my patient into a negative cumulative balance? • Will a more negative state be better? • If positive appears harmful and negative appears good, will “even” fluid balance be even better? If so what is the optimal balance?

WHAT IS NEGATIVE FLUID BALANCE? Daily fluid balance is generally calculated by subtracting the fluid output from fluid intake. This takes into account the actual intake through enteral and parenteral sources and the actual output through urinary and stool losses; the latter may be difficult to quantify accurately. It does not take into consideration fluid gained due to endogenous breakdown of

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protein in the positive side, and on the loss side, insensible losses that can be high in the critically ill. Third space sequestration also adds to the complexity of accurately determining fluid status as fluid shift from the intravascular compartment into the interstitial compartment depletes the intravascular volume. Fluid loss from insensible sources is generally estimated to be 500 mL per day. Adding the daily fluid balances generates the cumulative balance. Another definition of cumulative fluid balance, used more in the pediatric population, is given below: Cumulative fluid balance (%) =

(Cumulative daily input – Output ) in liters Admission weight in kg

× 100

Different definitions of negative fluid balance have been used in studies from the more simplistic negative daily balance of less than –500 mL/day to a more specific cumulative fluid balance of less than 0%.1 Additionally different levels of negative fluid balance have also been looked at ranging from 0 mL/kg/48 h to –60 mL/kg/48 h.2

WHY THE HYPE?

Given the reports of harm with positive fluid balance and the variable association of negative fluid balance3 on mortality and weaning, it is important to prescribe fluids only when necessary with the aim to avoid fluid overload following hemodynamic stabilization. Optimal fluid administration assumes much importance in the hemodynamically unstable patient where the quantum of fluids administered in order to minimize vasoactive agent use should be balanced with the consequences of fluid overload on organ function. Fluid overload could negatively impact organ function in the several compartments (head, chest, abdomen and extremities)4 while an underfilled state can result in the use of high doses of vasoactive agents that can affect both the macrocirculation (increased

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CHAPTER 3: Negative Fluid Balance: Beneficial or Harmful? TABLE 1

The Ebb and flow phase.

Phase

What happens in this phase?

What is recommended?

Ebb phase

• Metabolic response • Adequate filling to proinflammatory of the patient is cytokines with resultant recommended in order vasodilatory shock to avoid aggravation of microcirculatory • Drop in capillary oncotic dysfunction and pressure secondary to interstitial edema that albumin leak can compromise regional • Compensatory tissue oxygenation neuroendocrine reflexes • Positive fluid balance with potential renal is generally seen in this dysfunction phase

Flow phase

• Generally occurs when patient has been stabilized • Attenuation of inflammatory mediators and restoration of plasma oncotic pressure

• There may be spontaneous evacuation of excess fluids

cardiac afterload with increased oxygen demand) and microcirculation (endothelial damage and altered tissue perfusion with resultant increase in lactate). Maintaining this critical balance is important. This can be guided by the phase of the critical illness (ebb vs. flow; Table 1), the stage of fluid management (Table 2) as well as the nature and extent of each organ dysfunction. The ebb phase usually indicates the “first hit” response to an injury. Generally by the third day, if the underlying problem resolves, reduction in the cytokine response occurs with normalization of microcirculatory blood flow and decrease in capillary leak.5 If the flow phase does not take place by then, either because of persistent systemic inflammation or because of renal injury, fluid overload may occur. This can TABLE 2

result in global increased permeability syndrome (GIPS)6 and polycompartment syndrome due to increased venous resistance, interstitial edema, and decreased perfusion pressure (Fig. 1). Vincent and De Backer suggested four phases of fluid management7 in circulatory shock—the SOSD approach (salvage, optimization, stabilization and de-escalation) subsequently popularized as the ROSE approach (resuscitation, optimization, stabilization and evacuation) by Malbrain.8 This approach incorporated Cuthbertson’s ebb and flow phase with the different phases of fluid therapy. In the evacuation phase, negative fluid balance may occur because of either spontaneous diuresis or assisted with diuretics or ultrafiltration. This phase is also called late goal directed fluid removal or late conservative fluid management or deresuscitation. While it sounds intuitive that negative fluid balance could decrease interstitial edema and GIPS, there are several concerns that have been raised with reference to organ hypoperfusion as a result of hypovolemia.

SHOULD WE AIM FOR A NEGATIVE FLUID BALANCE? WHAT DOES THE EVIDENCE SAY? (TABLE 3) The concern with a positive cumulative fluid balance is a result of the reports of associated mortality and the possibility of compromised organ perfusion with increasing interstitial edema. A summary of the evidence looking at the impact of fluid balance on clinically relevant outcomes in critically ill patients can be found in Table 3.

Mortality, Ventilator-free Days and Length of ICU Stay Whilst most retrospective and prospective cohort trials (Table 3) detected a mortality benefit with a negative fluid

The ROSE approach to fluid therapy.

Phase

Time frame

Goal of fluid therapy

Fluid therapy

Caution

Resuscitation (Ebb phase)

Minutes

Rapid optimization of tissue perfusion to “preserve and protect” organ function

Early administration of fluid boluses guided by dynamic indices of fluid responsiveness

Optimization (Ebb phase)

Hours

Organ support and minimize secondary hits to— “prevent organ failure”

Fluid boluses guided by dynamic indices of fluid responsiveness

Inadequate resuscitation can result in microcirculatory dysfunction and can aggravate tissue hypoxia On the other hand, over aggressive fluid therapy can lead to increased interstitial edema and organ dysfunction

Stabilization (Ebb to flow phase)

Days

Organ function stabilization and Late conservative fluid therapy9 to maintain a supporting recovery of organ dysfunction and failure to— neutral to negative balance “support” recovery of organ dysfunction

Watch for fluid overload state—may need to induce diuresis with diuretics or ultrafiltration if AKI. There may be a role for albumin in this stage10

Evacuation or deresuscitation8 (flow phase)

Days

“Restore organ function”

Avoid excessive fluid removal as this could result in hypoperfusion

Late goal directed fluid removal8 to achieve negative fluid balance

(AKI: acute kidney injury; ROSE: resuscitation, optimization, stabilization and evacuation)

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SECTION 1: Hemodynamic Monitoring and Resuscitation

FIG. 1:  Ebb and flow phases and physiologic correlation. TABLE 3

Summary of trials in adult critically ill patients.

Study

Design/study period Randomized controlled trials Mitchell (1992) Single center

Exposure

Outcome

Pulmonary edema (n = 101) ALI (n = 37)

PCWP strategy vs. EVLW guided strategy

Trend toward decreased mortality in the conservative arm [RR 0.85 (0.62–1.17)]

Furosemide infusion titrated to weight loss of >1 kg/day and 25 g albumin q8h for 5 days Furosemide infusion and albumin 25 g q8h for 3 days vs. furosemide infusion alone Conservative vs. liberal fluid strategy

Trend toward decreased mortality in intervention arm [RR 0.78 (0.36–1.68)] this was not the primary outcome (main outcome—change in weight over a 5 days period)

Martin (2002)16

Single center (2002)

Martin (2005)17

Multicentric trial (2005)

ALI (n = 40)

Wiedemann (2006)18

Multicentric trial (2000–05)

ARDS (n = 1001)

Wang (2014)

14

Population (n)

Single center (2008–12) Chen and Kollef Single center (2015)19 (2014)

ARDS (n = 100) Septic shock (n = 82)

EVLW guided regimen vs. standard protocol Targeted fluid minimization vs. standard care

Hjortrup (2016)14

Septic shock (n = 151)

Fluid restrictive strategy vs. standard care

Multicentric CLASSIC trial (2014–15)

Primary outcome—oxygenation changes at 24 hours. P/F increased significantly in the albumin treated arm (43 vs. –24 p 5% after a MFC of only 150 mL is sufficient to predict fluid responsiveness, whereas the higher error of measurement of the COli did not allow sufficient diagnostic accuracy with the MFC.18 Mallat et al. investigated the effects of a MFC with 100 mL colloid (4% albumin) in 49 critically ill patients with circulatory failure, who were deeply sedated and ventilated with TV 6% induced by a MFC of 100 mL predicted fluid responsiveness with a sensitivity of 93% and a specificity of 85% and AUC 0.95. However, the change in PPV (AUC 0.65) was inferior to the change in SVI. SVI was measured by uncalibrated pulse contour analysis. In patients with septic shock who were mechanically ventilated, changes in end-tidal CO2 >5% after a MFC did not reliably discriminate responders for nonresponders.21

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SECTION 1: Hemodynamic Monitoring and Resuscitation In an observational study, an increase in SV more than 7% after a MFC with 100 mL crystalloid over 1 minute, accurately predicted fluid responsiveness during surgery under spinal anesthesia, with patients breathing spontaneously. SV was measured noninvasively using thoracic bioimpedance.22 In another study, Guinot et al. reported that in spontaneously breathing patients, an increase in SV >5% after a MFC with 100 mL lactated ringers solution over 1 minute accurately predicted a 15% or greater increase in SPV after volume expansion with 500 mL of fluid.23 A MFC of 50 mL over 10 seconds has been described.24 In this study 50 mechanically ventilated adults admitted to the intensive care unit (ICU) with hypovolemic shock, severe sepsis, or septic shock and at least one sign of tissue hypoperfusion were included. A 50-mL bolus of crystalloid solution was given to the patient over 10 seconds through a central venous catheter. VTI was recorded during and immediately after bolus administration. Patients with an

TABLE 2

58

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increase in CO after a 500 mL infusion over 15 minutes of 15% or more were classified as responders. An increase in CO >6%, measured by transthoracic echocardiography, and >9% increase in aortic blood flow VTI after the administration of 50 mL crystalloid solution over 10 seconds accurately predicted fluid responsiveness.24 The different methods of the MFC used are summarized in Table 2. Thus, the MFC of 100 mL fluid (colloid or crystalloid) given over 1 minutes appears to reliably predict fluid responsiveness. Since the changes in SV or CO produced in responders are of the magnitude of 5–7%, a CO monitoring technique with high degree of accuracy and precision is mandatory. Transthoracic echocardiography to estimate CO and aortic flow VTI appears to be reliable, but requires expertise. Surrogate endpoints for CO and fluid responsiveness such as PPV and end-tidal CO2 need further evaluation. It may not be accurate in patients with arrhythmias; in all studies, these patients were excluded. The

Summary of the different mini-fluid challenge techniques.

Author (reference)

Patients

Volume of fluid

Type of fluid

Time over which FC was given

Monitoring technique

End-points predicting fluid responsiveness

Muller17

39 patients with acute circulatory failure, sedated and ventilated with low TV

100 mL

Colloid (HES)

1 min

Transthoracic echocardiography

Increase in subaortic VTI ≥10%

Smorenberg18

21 postoperative cardiac surgical patients, mechanically ventilated

150 mL Colloid (HES) (50 mL boluses over 30 s × 3)

3 min

Pulse contour analysis with Modelflow®

Increase in CO >5%

Mallat19

49 critically ill patient circulatory failure, sedated, ventilated with TV 6%

Guinot22

73 spontaneously breathing patients under spinal anesthesia

100 mL

Crystalloid (lactated ringers)

1 min

Thoracic impedance cardiography (NICCOMO, Imedex, France)

Increase in SV>7%

Guinot23

34 spontaneously breathing patients under spinal anesthesia

100 mL

Crystalloid (lactated ringers)

1 min

Thoracic impedance cardiography (NICCOMO, Imedex, France)

Increase in SV>5% accurately predicted arterial pressure response

Wu24

50 mechanically ventilated critically ill patients with hypoperfusion

50 mL

Crystalloid

10 s

Transthoracic echocardiography

Increase in CO >6% Increase in aortic blood flow VTI >9%

(FC: fluid challenge; HES: hydroxyethyl starch; VTI: velocity-time integral; CO: cardiac output; TV: tidal volume; PBW: predicted body weight; PPV: pulse pressure variation; SVI: stroke volume index; SV: stroke volume; SVV: stroke volume variation)

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CHAPTER 13: Mini-fluid Challenge MFC can be used in patients with low-TV ventilation as well as spontaneosuly breathing patients, and without changing patient position. It can potentially be useful in situations in which the PLR cannot be performed, such as in patients with intra-abdominal hypertension, in the operating room, and those in the prone position. However studies are required in these patient subsets. It is likely that the mini-fluid bolus approach will result in smaller increases in cardiac filling pressures, less tissue oedema with a lower risk of fluid overload and cumulative positive fluid balance than large volume fluid resuscitation.25

CONCLUSION Both hypovolemia and excessive fluid overload are harmful. Patient’s response to fluid loading should be tested before giving fluids to prevent fluid overload. Test for fluid responsiveness are utilized to predict fluid responders. However limitations for these tests, especially the presence of spontaneous breathing and low-TV ventilation have necessitated development of preload challenge tests. The passive leg raising test is widely used and validated in these situations. The MFC, consisting of a rapid bolus of 100 mL fluid given over 1 minute is another preload challenge test that can be used. It requires a continuous CO monitoring technique with high precision, as small changes in SV and CO (>5%) need to be detected. Transthoracic echocardiography appears to be reliable, but requires expertise. The MFC may overcome some of the limitations of passive leg raising, with a negligible risk of fluid overload.



















REFERENCES

1. Acheampong A, Vincent JL. A positive fluid balance is an independent prognostic factor in patients with sepsis. Crit Care. 2015;19:251. 2. Michard F, Teboul JL. Predicting fluid responsiveness in ICU patients: A critical analysis of the evidence. Chest. 2002;121:2000-2008. 3. Osman D, Ridel C, Ray P, et al. Cardiac filling pressures are not appropriate to predict hemodynamic response to volume challenge. Crit Care Med. 2007;35(1):64-8. 4. Carsetti A, Cecconi M, Rhodes A. Fluid bolus therapy: Monitoring and predicting fluid responsiveness. Curr Opin Crit Care. 2015;21(5):388-94. 5. Weil MH, Henning RJ. New concepts in the diagnosis and fluid treatment of circulatory shock. Thirteenth annual Becton, Dickinson and Company Oscar Schwidetsky Memorial Lecture. Anesth Analg. 1979;58(2):124-32. 6. Vincent JL. “Let’s give some fluid and see what happens” versus the “mini-fluid challenge”. Anesthesiology. 2011;115:455-6.









7. Vincent JL, Weil MH. Fluid challenge revisited. Crit Care Med. 2006;34:1333-7. 8. Pierrakos C, Velissaris D, Scolletta S, et al. Can changes in arterial pressure be used to detect changes in cardiac index during fluid challenge in patients with septic shock? Intensive Care Med. 2012;38:422-8. 9. Cecconi M, Hofer C, Teboul JL, et al. Fluid challenges in intensive care: The FENICE study: A global inception cohort study. Intensive Care Med. 2015;41(9):1529-37. 10. Messina A, Longhini F, Coppo C, et al. Use of the fluid challenge in critically ill adult patients: A systematic review. Anesth Analg. 2017;125(5):1532-43. 11. Aya HD, Rhodes A, Chis Ster I, et al. Hemodynamic effect of different doses of fluids for a fluid challenge: A quasi-randomized controlled study. Crit Care Med. 2017;45(2):e161-8. 12. Monnet X, Marik PE, Teboul JL. Prediction of fluid responsiveness: An update. Ann Intensive Care. 2016;6:111. 13. Mahjoub Y, Lejeune V, Muller L, et al. Evaluation of pulse pressure variation validity criteria in critically ill patients: A prospective observational multicentre point-prevalence study. Br J Anaesth. 2014;112(4):681-5. 14. Myatra SN, Prabu NR, Divatia JV, et al. The changes in pulse pressure variation or stroke volume variation after a “tidal volume challenge” reliably predict fluid responsiveness during low tidal volume ventilation. Crit Care Med. 2017;45:415-21. 15. Monnet X, Rrienzo M, Osman D, et al. Passive leg raising predicts fluid responsiveness in critically ill. Crit Care Med. 2006;34:1402-7. 16. Bentzer P, Griesdale DE, Boyd J, et al. Will this hemodynamically unstable patient respond to a bolus of intravenous fluids? JAMA. 2016;316(12):1298-309. 17. Muller L, Toumi M, Bousquet PJ, et al. An increase in aortic blood flow after an infusion of 100 mL colloid over 1 minute can predict fluid responsiveness: The mini-fluid challenge study. Anesthesiology. 2011;115:541-7. 18. Smorenberg A, Cherpanath TGV, Geerts BF, et al. A mini-fluid challenge of 150 mL predicts fluid responsiveness using Model flow (R) pulse contour cardiac output directly after cardiac surgery. J Clin Anesth. 2018;46:17-22. 19. Mallat J, Meddour M, Durville E, et al. Decrease in pulse pressure and stroke volume variations after mini-fluid challenge accurately predicts fluid responsiveness. Br J Anaesth. 2015;115(3):449-56. 20. Biais M, de Courson H, Lanchon R, et al. Mini-fluid challenge of 100 mL of crystalloid predicts fluid responsiveness in the operating room. Anesthesiology. 2017;127(3):450-56. 21. Xiao-ting W, Hua Z, Da-wei L, et al. Changes in end-tidal CO2 could predict fluid responsiveness in the passive leg raising test but not in the mini-fluid challenge test: A prospective and observational study. J Crit Care. 2015;30(5):1061-6. 22. Guinot PG, Bernard E, Defrancq F, et al. Mini-fluid challenge predicts fluid responsiveness during spontaneous breathing under spinal anaesthesia: An observational study. Eur J Anaesthesiol. 2015;32(9):645-9. 23. Guinot PG, Bernard E, Deleporte K, et al. Mini-fluid challenge can predict arterial pressure response to volume expansion in spontaneously breathing patients under spinal anaesthesia. Anaesth Crit Care Pain Med. 2015;34(6): 333-7. 24. Wu Y, Zhou S, Zhou Z, et al. A 10-second fluid challenge guided by transthoracic echocardiography can predict fluid responsiveness. Crit Care. 2014;18(3):R108. 25. Marik PE. Fluid therapy in 2015 and beyond: The mini-fluid challenge and minifluid bolus approach. Br J Anaesth. 2015;115(3):347-9.

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14

CHAPTER

Monitoring the Quality of Cardiopulmonary Resuscitation Prasad Rajhans, Gouri Ranade

INTRODUCTION Cardiopulmonary resuscitation (CPR) was developed as early as 1960 and endorsed by the American Heart Association in 1963. The ILCOR, formed in 1992, produced the first international CPR guidelines in 2000. CPR has evolved over years. Before 2010, the CPR composed steps namely airway, breathing, and circulation (A-B-C). The 2010 guidelines changed the sequence to (C-A-B) that is circulation and then airway followed by breathing. This was done emphasize on compressions rather than on respiration. Guidelines today focus on compressions only CPR (COLS) so that rescue breaths are no longer recommended especially for lay people. This makes CPR simpler to administer as well as eliminates the aversion one may feel about exposure to communicable diseases while giving mouth-to-mouth breaths. Thus the focus is now mainly compressions and rightly so because studies have shown that good compressions increase the chances of return of spontaneous circulation (ROSC). Good quality compressions increase the aortic diastolic pressure and thus increase the coronary perfusion and thereby resulting in better outcomes. Good quality CPR has improved out of hospital cardiac arrest survival rates and thus it is necessary to monitor the quality of CPR and to implement changes so as to make sure that good quality CPR is administered. This chapter will review appraising quality of CPR.

HIGH-QUALITY CARDIOPULMONARY RESUSCITATION1,2 High-quality CPR is dependent on many factors: • Metrics of CPR performance: {{ Chest compression fraction (CCF) {{ Chest compression rate {{ Compression depth {{ Full chest recoil {{ Avoid excessive ventilation.

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• Monitoring and feedback: {{ Coronary perfusion pressure (CPP) {{ Arterial diastolic pressure {{ End-tidal carbon dioxide value. • Team-level logistics: {{ Training nontechnical skills such as team leadership {{ Maximize CCF {{ Consider mechanical CPR for patient transport. • Continuous quality improvement for CPR: {{ Debriefing {{ Frequent refresher training {{ Regular system review.

Metrics of CPR Performance The goal of CPR is to deliver oxygen and blood supply to the myocardium. The CPP is mainly responsible for myocardial blood flow and oxygen delivery during CPR and thus also determines ROSC. CPP is the difference between aortic diastolic and right atrial diastolic pressure during the relaxation phase.

Chest Compression Fraction Chest compression fraction is the proportion of time that chest compressions are performed during a cardiac arrest. Studies have shown that CCF of about 80% is achievable and thus it is recommended that CCF of above 80% should be aimed for high-quality CPR. Such can be achieved by minimizing interruptions in chest compressions. This was one of the main factors stressed in the 2010 American Heart Association (AHA) guidelines. So how can such interruptions be minimized? It is usually observed that such pauses occur for the following reasons: • Checking of pulse in spite of incompatible rhythm • Preshock as the defibrillator is charging • Postshock

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CHAPTER 14: Monitoring the Quality of Cardiopulmonary Resuscitation • During securing of definitive airway • During placement of backboard, mechanical CPR. The above can be minimized by: • Proper education and drills • Consider use of supraglottic airways rather than endo­ tracheal intubation; or continue with bag-mask venti­ lation—minimize pause to 6 cm. Achieving the right depth can be difficult and education and drills will again play an important role. A lot will also depend on the size of the patient, presence of a firm back surface and compression rate.

Monitoring Measuring the depth visually can be difficult. Feedback devices such as Zoll Pocket CPR, CPR plus or defibrillator inbuilt systems are based on force/pressure monitoring or accelerometers. The pressure sensors measure compression depth while the accelerometers can measure the rate. The Philips HeartStart MRx is the defibrillator with inbuilt systems based on pressure sense as well as accelerometer. In addition, it can also calculate thoracic impedance. Thus, it can also provide ventilation feedback.

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Pushing hard and pushing fast can be very tiring and thus administering high-quality CPR will vary from individual to individual, with some who are able do it for longer periods while others managing only up to a few minutes. It is very necessary for the team leader to recognize fatigue in the compressors and make sure that compressors are rotated. The switch over should be ideally accomplished within 3 second. Use of step stool especially in compressors of short stature will improve the depth of compressions and reduce fatigue. Hence paying attention to optimal positioning of the compressor is very essential.

Full Chest Recoil Coronary perfusion occurs during chest recoil or the relaxa­ tion phase of CPR. The most common cause of incomplete recoil is that the compressor leans on the patient’s chest. This leads to increased right atrial pressure, reduced venous return and ultimately reduced coronary perfusion. Tall compressors or those standing on a step-stool have the highest risk of leaning on the patient’s chest. Human observer or real time audiovisual feedback may help in reducing leaning.

Ventilation Providing adequate oxygenation without hampering blood flow is the main aim of ventilation in CPR. The time frame for providing oxygen in CPR may vary and is unclear with studies showing that in arrests due to arrhythmias, compressions only may be adequate. Chest interruptions to secure definitive airway can compromise CPP and should be limited to 20 mm Hg is necessary for achieving ROSC. When an arterial line is already in place, an arterial diastolic pressure of 25 mm Hg should be targeted in order to achieve the same.

End-tidal Carbon Dioxide End-tidal carbon dioxide (ETCO2) should be the physiologic parameter to monitor as this is especially easier to monitor in the absence of a central or arterial line. The EtCO2 reflects pulmonary blood flow and thus the cardiac output. If the EtCO2 is 85%. Hypoxemia is very common in critically ill patients, hence it may be that CPAP increases the functional residual capacity, and oxygenation prevents the collapse of alveoli. Aerophagia may occur with high pressure in noninvasive ventilation (NIV). Gastric distension may occur when airway pressure exceeds 20 cm H2O. High-flow nasal oxygenation (HFNO) at flows between 30–70 L/min can be an alternative. HFNO circuits interfere with the facemask seal and ventilation, and reduce the CPAP efficacy before and after induction. Preoxygenation may be difficult in agitated patients; small doses of a sedative such as ketamine are administered to enable effective preoxygenation. Prompt tracheal intubation is necessary when it becomes apparent that NIV, CPAP or HFNO are failing; delay is likely to lead to profound hypoxemia during intubation. Nasal oxygen can be kept applied during airway management with a facemask. The flow of oxygen through nasal cannula can be increased or decreased depending on the patient’s condition. HFNO may be beneficial in some patients with hypoxemia.

OXYGENATION DURING INTUBATION— PEROXYGENATION In view of the rapid alveolar derecruitment and hypoxemia that happens in critically ill patients after the onset of apnoea with the use of neuromuscular blocking agents, it is

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CHAPTER 17: Airway Management in ICU: Current Guidelines

(CPAP: continuous positive airway pressure; FONA: front-of-neck airway; NIV: noninvasive ventilation)

FLOWCHART 1:  Tracheal intubation of critically ill adult. Source: Higgs A, McGrath BA, Goddard C, et al. Guidelines for the management of tracheal intubation in critically ill adults. Br J Anaesth. 2018;120(2):323-52.

recommended to use either nasal oxygen at 15 L/min flow or HFNO during intubation attempts. Facemask ventilation with CPAP may improve oxygena­ tion. A “two-person” technique is always better. Adjuncts like oral airway/nasal airway may improve facemask ventilation. High respiratory rates and volume may cause hypotension or “breath-stacking” in cases of expiratory airflow limitation. If facemask ventilation between intubation attempts is unsuccessful, rescue oxygenation can be given using a second-generation supraglottic airway (SGA). The recommendation is to use facemask ventilational CPAP where manual ventilation is possible and where there is a high likelihood of hypoxemia. The recommendation is also in favour of CPAP before attempting intubation.

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INDUCTION OF ANESTHESIA Many sick patients are at risk of aspirating gastric contents, hence a “modified” rapid sequence induction (RSI) approach is recommended in these guidelines. The recommendation is optimal positioning, preoxy­ genation, and intravenous induction using a rapid-onset neuromuscular blocking agent (NMBA), precautions against pulmonary aspiration ( applying cricoid pressure by a trained assistant), facemask ventilation with CPAP, laryngoscopic technique to maximize first-pass success, and confirmation by waveform capnography. The risk of aspiration can be reduced by withholding enteral feeding, gastric tube suctioning and cricoid pressure

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SECTION 2: Respiratory/Airway/Ventilation application by a trained assistant. An existing gastric tube does not interfere with the protection offered by cricoid force and should not be removed. Gastric insufflation during mask ventilation can also be reduced by the application of cricoid force.

INDUCTION DRUG CHOICES Hemodynamic condition decides on the choice of drugs to be used. Ketamine is increasingly favoured in most circumstances. Induction with rapidly acting opioids enables lower doses of hypnotics. It provides cardiovascular stability and minimises the rise in intracranial pressure. It is recommended to use NMBAs during intubation, as this reduces intubation complications in the critically ill. NMBAs improves overall intubating conditions. The avoidance of NMBAs is associated with increased difficulty. Rocuronium may be a more rational choice over succinylcholine in the critically ill, providing similar intubating conditions to succinylcholine and lacking the side effects of succinylcholine. Sugammadex can be used as an antidote to rocuronium, but this does not guarantee resolution of an obstructed airway.

LARYNGOSCOPY

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Difficult laryngoscopy and intubation may lead to hypo­ tension, esophageal intubation, cardiac arrest and severe hypoxia. Our goal is to secure the tube in place before some traumatic intubation happens. Prolonged intubation and repeated attempts may lead up to a situation of failed intubation. The patient should be: • Positioned optimally • Preoxygenated • Anesthetized • Neuromuscularly relaxed. The operator should: • Have a primary plan and a plan in case of failure • Be trained and proficient in all the techniques they intend to use • Be supported by a trained and briefed team. If the first attempt of laryngoscopy fails, ensure that the FONA set is immediately available in hand and senior help is called for. The number of attempts should not be more than three. Following maneuvers are important to do following failed intubation—such as the use of a different blade, a different operator, suction and reduction or release of cricoid force. Many times laryngeal manipulations are also important. A bougie or stylet may be helpful when the laryngeal opening is poorly seen. Blind efforts should be avoided. Failed intubation should be declared after a maximum of three conventional attempts of laryngoscopy (Flowchart 1).

An immediate switch over to plan B/C is required if an expert feels he can go ahead for one further attempt.

VIDEOLARYNGOSCOPY IN THE CRITICALLY ILL10,11 Lewis SR et al. reported that videolaryngoscopes may reduce the number of failed intubations and may also reduce airway trauma.11 Evidence highlights the importance of training in success with videolaryngoscopy. The systematic review also identified that not all video laryngoscopes perform equally. There is uncertainty over the impact of videolaryngoscopy on intubation speed, but it is likely that hyperangulated (as opposed to MacIntoshshaped) blades prolong easy intubations. The recommendation is that a videolaryngoscope should be available and considered as an option for all intubations of critically ill patients. Those involved in critical care intubation should be appropriately trained in the use of the videolaryngoscope(s) they may be called upon to use. If difficult laryngoscopy is predicted in a critically ill patient (MACOCHA score ≥3),12 videolaryngoscopy should be actively considered from the outset (Table 2). If during direct laryngoscopy there is a poor view of the larynx, subsequent attempts at laryngoscopy should be performed with a videolaryngoscope. Where videolaryngoscopy is used as the first choice, it is logical to use a device that enables use both as a direct laryngoscope and as a videolaryngoscope (i.e. Macintosh-type blade). The blood and vomitus should be cleared before attempting videolaryngoscopy in a critically ill patient. TABLE 2

MACOCHA score.

Factors

Points

Factors related to patient: Mallampati class III or IV Obstructive sleep apnea syndrome Reduced mobility of cervical spine Limited mouth opening 25% of S. aureus isolates are methicillinresistant. The empiric gram-negative regimen employed in patients with septic shock should provide coverage for the majority of all likely gram-negatives within that ICU including Acinetobacter spp. and extended spectrum betalactamase (ESBL)-producing Enterobacteriaceae. Potential empiric combination regimens include an antipseudomonal β-lactam plus an aminoglycoside (gentamicin, tobramycin, and amikacin depending on local activity) or possibly an antipseudomonal quinolone (ciprofloxacin or levofloxacin) or colisitin. The antipseudomonal β-lactams include imipenem, meropenem, cefepime, piperacillin/tazobactam, ceftazidime and aztreonam. For ESBL-producing organisms, a third-generation cephalosporin is not reliable and preferred therapy is with a carbapenem as demonstrated by a recent randomized controlled trial.14 Moreover, with the increasing presence of carbapenem-resistant Enterobacteriaceae, consideration should be given to using one of the newer combination β-lactam β-lactamase combination drugs active against these pathogens (ceftazidime-avibactam and meropenem-vaborbactam with imipenem-relebactam, and cefiderocol as alternative agents in the future).

Flowchart 1 provides an algorithm for the empiric treatment of pneumonia based on the patient’s pneumonia classification and risk for mortality and infection with MDR pathogens. Note that this algorithm is a starting point and should be modified based on local predominant pathogens and their susceptibility patterns.

RECENT SUPPORTING DATA FOR PNEUMONIA CLASSIFICATIONS Given the changing patterns of infection and patient risk profiles, it is important to understand the recent data in support of pneumonia classification schemes. Corrado et al. reported their experience with 283,927 cases of pneumonia in New York City hospitals from 2010 to 2014.15 These investigators found that CAP was the most common type of pneumonia (54.3%) and VAP the least (1.6%). The low rates of VAP have been described by other authors.16,17 However, VAP was associated with the highest hospital mortality (21.6%) which may be due in part to the greater severity of illness in this grouping and the greater burden of comorbidities among patients with VAP.16,17 CAP also demonstrated a seasonal variation that was not seen in HCAP and patients with HCAP were more likely to require hospital readmissions compared

(CAP: community-acquired pneumonia; HAP: hospital-acquired pneumonia; HCAP: healthcare-associated pneumonia; ICU: intensive care unit; MDR: multidrug-resistant; MRSA: methicillin-resistant Staphylococcus aureus; VAP: ventilator-associated pneumonia)

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FLOWCHART 1:  Algorithm for empiric treatment of pneumonia based on the patient’s pneumonia classification, disease severity, and risk for infection with MDR pathogens.

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CHAPTER 27: CAP, HAP, HCAP and VAP: How Should Intensivists Approach this Alphabet Soup? to patients with CAP. This study reinforces the failure of simplistic pneumonia classification schemes that attempt to divide patients into community and hospital-based categories that are totally separable in terms of the presence of MDR pathogens.18 A recent study from Brazil, France, Italy, Russia and Spain was performed to assess the real-world treatment patterns and clinical outcomes associated with initial antibiotic therapy (IAT) of nosocomial pneumonia.19 Patients with HAP, VAP and HCAP were included. Overall, most patients (62.5%) were treated with antimicrobial monotherapy. Mean duration of IAT was 8.8 (7.2) days. MDR pathogens were identified in 52.4% and IAT failure was recorded in 72.5% of patients and was significantly associated with isolation of an MDR pathogen. Moreover, the presence of an MDR pathogen was found to be the most important predictor for IAT failure. Like the Corrado paper, this study highlights the similarities of HCAP to HAP and VAP. Similarly, a study from Jammu and Kashmir in India examined 318 consenting patients with HCAP (n = 165) or HAP (n = 153) presenting to a tertiary care hospital in North India from 2013 to 2015.20 These authors found that HCAP might not be as severe as HAP in term of patient outcomes, but patients with HCAP had comorbid characteristics and pathogen characteristics justifying this separate classification grouping. Patients with HCAP had more comorbidities and Escherichia coli and Acinetobacter baumannii were the most common bacteria in HCAP and HAP, respectively. Taken together these studies highlight the realworld problem that clinicians have when prescribing empiric antibiotics for patients either hospitalized for pneumonia or acquiring pneumonia in the hospital setting. The dilemma is whether to err on the side of over treating some patients with risk factors for infection with MDR pathogens upfront to improve clinical outcomes versus avoiding broad-spectrum therapy in order to minimize emergence of resistance.

POTENTIAL SOLUTIONS TO THE CLASSIFICATION PROBLEM Two main approaches exist to the intensivist for balancing the needs of the individual patient to receive appropriate therapy and the needs of society to minimize further emergence of antibiotic resistance by avoiding the use of broad-spectrum antimicrobials. The first is antimicrobial deescalation which can simply be seen as a clinical approach to empiric antibiotic treatment that attempts to balance the need for appropriate initial therapy with the need to limit unnecessary antimicrobial exposure to curtail the emergence of resistance. When specific risk factors for antibiotic resistance are identified in individuals with serious or life-threatening infection, e.g., patients at risk for HCAP admitted to the ICU, then broad-spectrum antimicrobials

would be prescribed. Once definitive microbiologic results become available (48–72 h) then the antibiotics would be either discontinued (for documented viral infection without concomitant bacterial infection) or narrowed based on the pathogen and its susceptibility pattern. The second approach for curtailing the use of broad-spectrum antimicrobials is the use of rapid microbiologic diagnostic techniques. The goals of antibiotic stewardship include avoiding the unnecessary use of broad-spectrum antibiotics and reducing the emergence of antibiotic resistance. However, clinicians are most concerned about providing an appropriate empiric antibiotic regimen to their patients with serious infections. Increasing global rates of antibiotic resistance have made it more difficult to withhold broad-spectrum empiric therapy especially in patients with severe infections.14 As noted above there is an inherent inaccuracy in classification schemes and prediction instruments to include the HCAP classification.21 The limited accuracy of such prediction instruments suggests that local ecology and case mix are likely the predominant drivers for MDR rates in different regions and countries. Therefore, estimating patient risk for infection with MDR pathogens will often result in the overtreatment or undertreatment of significant numbers of patients. An important limitation with using antimicrobial deescalation as an approach for limiting the emergence of resistance is that it focuses the clinician on simply narrowing the antibiotic regimen. A recent systematic review showed that there is no good evidence that antimicrobial deescalation directly results in less emergence of antibiotic resistance.22 The duration of antibiotic therapy may be an even more important determinant for the emergence of antimicrobial resistance and is not intrinsically part of the de-escalation paradigm. A 7-day or 1-week threshold seems to be an important cutoff beyond which the risk of antibiotic resistance emergence increases more dramatically. However, even a few days of antibiotic exposure can promote collateral damage by altering intestinal flora in favor of colonization with MDR bacteria. Short courses of antibiotic therapy have been shown to be effective in a wide spectrum of infections, yet it is also important to recognize that short courses of antibiotics are most likely to be clinically effective when the selected agents are active against the causative pathogen based on susceptibility testing. Short courses of antibiotics can also result in treatment failures when not dosed adequately, especially in the presence of patient factors such as augmented renal clearance. Treatment failures resulting from inadequate antibiotic dosing has emerged as an important problem affecting both the outcomes of critically ill infected patients and helping to promote further antimicrobial resistance.23 Rapid microbiologic diagnostics hold promise for allowing a better balance between the competing goals of providing an

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SECTION 2: Respiratory/Airway/Ventilation  TABLE 2

Molecular pathogen detection in pneumonia.

The FilmArray® lower respiratory tract infection

Unyvero pneumonia panel

Group

Pathogen

Group

Pathogen

Viruses

Adenovirus

Gram-positive bacteria

Staphylococcus aureus Streptococcus pneumoniae

Coronavirus Human metapneumovirus

Qualitative bacteria

Antibiotic resistance markers

Fungi

Citrobacter freundii Escherichia coli

Influenza A

Enterobacter cloacae complex

Influenza B

Enterobacter aerogenes

MERS coronavirus

Proteus spp.

Parainfluenza virus

Klebsiella pneumoniae

Respiratory syncytial virus

Klebsiella oxytoca

Chlamydia pneumoniae

Klebsiella variicola

Cryptococcus pneumophila

Serratia marcescens

Mycoplasma pneumoniae

Morganella morganii

bla CTX-M bla IMP

Nonfermenting bacteria:

Moraxella catarrhalis Pseudomonas aeruginosa

bla KPC

Acinetobacter baumannii complex

bla NDM

Stenotrophomonas maltophilia

bla OXA-48-like

Legionella pneumophila

bla VIM Quantitative bacteria

Enterobacteriaceae

Human rhinovirus/enterovirus

Others/Fungi:

Pneumocystis jirovecii

mecA/mecC and MREJ

Haemophilus influenza

Acinetobacter calcoaceticus-baumannii complex

Mycoplasma pneumoniae

Enterobacter aerogenes/cloacae complex

Chlamydophila pneumoniae

Escherichia coli

Gene

Resistance against

Haemophilus influenzae

ermB

Macrolide/lincosamide

Klebsiella oxytoca

mecA

Oxacillin

Klebsiella pneumoniae group

mecC (LGA251)

Oxacillin

Moraxella catarrhalis

tem

Penicillin

Proteus spp.

shv

Penicillin

Pseudomonas aeruginosa

ctx-M

Third generation cephalosporins

Serratia marcescens

kpc

Carbapenem

Staphylococcus aureus

imp

Carbapenem

Streptococcus agalactiae

ndm

Carbapenem

Streptococcus pneumoniae

oxa-23

Carbapenem

Streptococcus pyogenes

oxa-24/40

Carbapenem

Cryptococcus neoformans/gattii

oxa-48

Carbapenem

oxa-58

Carbapenem

vim

Carbapenem

sul1

Sulfonamide

gyrA83

Fluoroquinolone

gyrA87

Fluoroquinolone

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CHAPTER 27: CAP, HAP, HCAP and VAP: How Should Intensivists Approach this Alphabet Soup? appropriate empiric antibiotic regimen for the treatment of serious infections and the avoidance of unnecessary broadspectrum antibiotics in order to reduce the emergence of resistance. This would appear to be especially important for the empiric utilization of the new antibiotics targeting the most resistant gram-negative bacteria. Rapid diagnostics have the potential for more accurate direction of the use of these new agents in order to achieve an effective balance between efficacy and stewardship. Development of costeffective rapid diagnostics needs to be pursued as an especially important goal for resource-limited countries that have often been at the forefront of the emergence of novel antimicrobial resistance mechanisms due to local patterns of antibiotic use. The use of rapid diagnostics may hold the key for achieving this important balance. There is an urgent need for clinical studies aimed at understanding how to best integrate the use of broad-spectrum antibiotics with these emerging rapid diagnostic technologies in a way that is costeffective and sustainable for the long run. Clinical outcome studies demonstrating the benefit of these new technologies on patient outcomes are needed. Pneumonia, including HCAP, HAP and VAP may be ideal infections to demonstrate the impact of rapid diagnostics as a means of enhancing both antimicrobial treatment and stewardship.24 The most frequent MDR bacteria involved in nosocomial pneumonia are MRSA, P. aeruginosa, the Enterobacteriaceae, and A. baumannii. Conventional microbiology techniques can take >48 hours to provide susceptibility results for respiratory cultures. This may allow the administration of inappropriate antibiotic therapy increasing the likelihood of mortality, morbidity and overall healthcare costs. Moreover, traditional microbiologic diagnostics including Gram stain and semiquantitative conventional culture from direct respiratory samples, followed by bacterial identification using MALDI-TOF (matrix-assisted laser desorption/ionization time-of-flight) mass spectrometry and susceptibility testing of the potential pathogen does not differentiate between colonization and real infection.25 Therefore, simply having a positive culture result can result in treatment with antibiotics when they are not necessary as in the situation of patients colonized with pathogenic bacteria without clinical evidence of infection. The use of rapid diagnostics in pneumonia offers the potential to direct antibiotic selection in order to cover the offending pathogen while avoiding unnecessary use of broad-spectrum agents. However, even these diagnostics will not differentiate between colonization and infection. Two new platforms for molecular pathogen detection in pneumonia are the Curetis Unyvero™ System and the BIOFIRE® FilmArray® Pneumonia Panel both of which allow the rapid detection of various species and antimicrobial resistance markers (Table 2). Given the worldwide scourge of carbapenem-producing organisms,26 having rapid diagnostics available will allow more targeted use of broadspectrum agents and potentially minimize further emergence of resistance to them. A recent meta-analysis found that

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application of rapid microbiologic diagnostic techniques in bloodstream infections was associated with significant decreases in mortality risk in the presence of an established stewardship program, but not in its absence.27 Rapid microbiologic diagnostic techniques also decreased the time to effective antibiotic therapy and the length of hospital stay. The hope is that such techniques will show similar results in patients with pneumonia.

CONCLUSION In summary, increasing antibiotic resistance of pneumonia pathogens, both in the community and healthcare settings, makes accurate classification for purposes of empiric antibiotic prescription problematic. The current pneumonia classification system which encompasses CAP, HCAP, HAP and VAP is a clinical working tool with significant limitations. The application of rapid diagnostic tests to identify drugresistant pathogens and reduce time to appropriate antimicrobial therapy, while avoiding the use of unnecessary broad-spectrum agents when such pathogens are absent, is the way of the future. It is very likely that in the future we will abandon the use of pneumonia classifications in lieu of having more rapid and accurate identification of the causative pathogen(s) and the antibiotics needed to treat them. Note: Dr Kollef’s effort was supported by the Barnes-Jewish Hospital Foundation. There are no other conflicts of interest to report.

REFERENCES 1. Hiramatsu K, Niederman MS. Healthcare-associated pneumonia: a new therapeutic paradigm. Chest. 2005;128:3784-7. 2. Kollef MH, Shorr A, Tabak YP, et al. Epidemiology and outcomes of healthcareassociated pneumonia: results from a large US database of culture-positive pneumonia. Chest. 2005;128:3854-62. 3. Hayes BH, Haberling DL, Kennedy JL, et al. Burden of pneumonia-associated hospitalizations: United States, 2001-2014. Chest. 2018;153:427-37. 4. American Thoracic Society; Infectious Diseases Society. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388416. 5. Craven DE. What is healthcare-associated pneumonia, and how should it be treated? Curr Opin Infect Dis. 2006;19:153-60. 6. Friedman ND, Kaye KS, Stout JE, et al. Healthcare-associated bloodstream infections in adults: a reason to change the accepted definition of communityacquired infections. Ann Intern Med. 2002;137:791-7. 7. Muder RR, Aghababian RV, Loeb MB, et al. Nursing home-acquired pneumonia: an emergency department treatment algorithm. Curr Med Res Opin. 2004;20:1309-20. 8. Kollef MH, Sherman G, Ward VJ. Fraser Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest. 1999;115:462-74. 9. Jones BE, Jones MM, Huttner B, et al. Trends in antibiotic use and nosocomial pathogens in hospitalized veterans with pneumonia at 128 medical centers, 2006-2010. Clin Infect Dis. 2015;61:1403-410. 10. Chalmers JD, Rother C, Salih W, et al. Healthcare-associated pneumonia does not accurately identify potentially resistant pathogens: a systematic review and meta-analysis. Clin Infect Dis. 2014;58:330-39.

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SECTION 2: Respiratory/Airway/Ventilation  11. Kalil AC, Metersky ML, Klompas M, et al. Executive summary: management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63:575-82. 12. Torres A, Niederman MS, Chastre J, et al. International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilatorassociated pneumonia: Guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociación Latinoam Aricana del Tórax (ALAT). Eur Respir J. 2017;50:1700582. 13. Kumar A, Safdar N, Kethireddy S, et al. A survival benefit of combination antibiotic therapy for serious infections associated with sepsis and septic shock is contingent only on the risk of death: a meta-analytic/meta-regression study. Crit Care Med. 2010;38:1651-64. 14. Harris PNA, Tambyah PA, Lye DC, et al. Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance: A Randomized Clinical Trial. JAMA. 2018;320:984-94. 15. Corrado RE, Lee D, Lucero JK, et al. Burden of adult community-acquired, healthcare-associated, hospital-acquired, and ventilator-associated pneumonia: New York City, 2010-2014. Chest. 2017;152:930-42. 16. Kollef KE, Schramm GE, Wills AR, et al. Predictors of 30-day mortality and hospital costs in patients with ventilator-associated pneumonia attributed to potentially antibiotic-resistant gram-negative bacteria. Chest. 2008;134:281-7. 17. Fisher K, Trupka T, Micek ST, et al. A prospective one-year microbiologic survey of combined pneumonia and respiratory failure. Surg Infect (Larchmt). 2017;18:827-33.

18. Burnham JP, Kollef MH. CAP, HCAP, HAP, VAP: The diachronic linguistics of pneumonia. Chest. 2017;152:909-910. 19. Ryan K, Karve S, Peeters P, et al. The impact of initial antibiotic treatment failure: Real-world insights in healthcare-associated or nosocomial pneumonia. J Infect. 2018;77:9-17. 20. Kumar S, Jan RA, Fomda BA, et al. Healthcare-associated pneumonia and hospital-acquired pneumonia: bacterial aetiology, antibiotic resistance and treatment outcomes: a study from North India. Lung. 2018;196:469-79. 21. Sibila O, Rodrigo-Troyano A, Shindo Y, et al. Multidrug-resistant pathogens in patients with pneumonia coming from the community. Curr Opin Pulm Med. 2016;22:219-26. 22. Tabah A, Cotta MO, Garnacho-Montero J, et al. A systematic review of the definitions, determinants, and clinical outcomes of antimicrobial de-escalation in the intensive care unit. Clin Infect Dis. 2016;62:1009-1017. 23. Abdul-Aziz MH, Driver E, Lipman J, et al. New paradigm for rapid achievement of appropriate therapy in special populations: coupling antibiotic dose optimization rapid microbiological methods. Expert Opin Drug Metab Toxicol. 2018; 14:1-16. 24. Kollef MH, Burnham CD. Ventilator-associated pneumonia: the role of emerging diagnostic technologies. Semin Respir Crit Care Med. 2017;38:253-63. 25. Torres A, Lee N, Cilloniz C, et al. Laboratory diagnosis of pneumonia in the molecular age. Eur Respir J. 2016;48:1764-78. 26. Bonomo RA, Burd EM, Conly J, et al. Carbapenem-producing organisms: A global scourge. Clin Infect Dis. 2018;66:1290-97. 27. Timbrook TT, Morton JB, McConeghy KW, et al. The effect of molecular rapid diagnostic testing on clinical outcomes in bloodstream infections: A systematic review and meta-analysis. Clin Infect Dis. 2017;64:15-23.

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28

CHAPTER

Adverse Effects of Oxygen Therapy in ICU Deepak Govil, Mozammil Shafi, Sweta J Patel

INTRODUCTION Oxygen is one of the most commonly used therapeutic agent in hospitalized patients.1 Tissue oxygen delivery is dependent on arterial oxygen saturation and oxygen therapy is cornerstone for increasing oxygen saturation in hypoxemic patients.2 While the use of oxygen therapy in hypoxic patients cannot be overemphasized, its unmonitored administration may be harmful at times. It is a well-known fact that in patients of severe chronic obstructive disease, liberal oxygen therapy may result in carbon dioxide accumulation and worsening of type 2 respiratory failure.3 From the evolutionary point of view humans have experienced and survived hypoxia remarkably well. It is worthwhile to understand that we have neither experienced nor acclimatized to hyperoxia during the process of evolution. A recent meta-analysis of randomized controlled trials (RCTs) by Chu et al. comparing “liberal and conservative oxygen therapy in general hospitalized patients”, in hospital mortality was significantly higher with liberal oxygen therapy group.4 Studies have shown poor outcome with liberal oxygen therapy in certain specific group of patients like myocardial infarction (MI), postcardiac arrest and stroke.

MECHANISM OF HYPEROXIA-INDUCED INJURY Hyperoxia is difficult to define due to varied definitions used in literature. Normal partial pressure of oxygen (pO2) for a person breathing room air, has been defined in the range of 80–100 mm Hg. Exact value above which hyperoxia becomes detrimental is unknown, but studies have shown a linear correlation between hyperoxia and poor outcome. Hyperoxia-induced injury, is primarily caused due to the production of excessive reactive oxygen species (ROS).5 Mitochondria and its enzymatic system like catalase, superoxide dismutase is responsible for scavenging these free radicals and minimizing their effects on cellular level.

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Amount of ROS generation is highly dependent on pO2 and its level increases markedly with increasing pO2. ROS can also be generated due to excessive inflammatory response resulting from microbial infection, trauma and other inflam­ matory conditions. Lung is the most common organ affected by hyperoxia-induced injury. These ROS can cause direct cellular damage through apoptosis and necrosis.6 Besides direct injury, hyperoxia-induced cell damage result in the release of large amount of damage-associated molecular pattern (DAMP).7 DAMPs due to their resemblance with cellular DNA, are recognized by pattern recognition receptors (PRRs), leading to acceleration of inflammation. In addition neutrophils and monocytes migrate at the site resulting in cytokine production and ROS generation and worsening of tissue injury. Besides causing injury to pulmonary epithelium and increasing vascular permeability, cytokines release in circulation may also foster distant organ injury.8

HARMFUL EFFECTS OXYGEN OF IN PATIENTS OF MYOCARDIAL INFARCTION Mismatch between oxygen supply and demand is one of the important reason of myocardial ischemia and infarction. Oxygen therapy has been the cornerstone in management of acute coronary syndrome, to increase oxygen delivery and limit infarct size. On the other hand, hyperoxia-induced coronary vasoconstriction and ROS generation may result in reperfusion injury. Study by Russek et al. in 1950 concluded that 100% oxygen via facemask do not have any impact on onset or duration of angina and also contributed to worsening of electrocardiographic changes of myocardial ischemia.9 A number of researchers later proved the association of high oxygen concentration and poor outcome. Thomas et al. reported a decrease in cardiac output with increasing oxygen concentration.10 Similarly, high oxygen concentration was associated with decrease in cardiac output in a patient of left ventricular failure and baseline oxygen saturation of more than 90%.11 Effect of oxygen therapy on oxygen transport was

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SECTION 2: Respiratory/Airway/Ventilation  demonstrated in a study by Sukumalchantra et al. Their study revealed that oxygen therapy improved oxygen transport and cardiac output in patients who are hypoxemic at baseline, but failed to do so in patient with oxygen saturation more than 90%.12 In a double blinded RCT Rawles and Kenmure compared the effect of oxygen administration via face mask in patients of uncomplicated acute MI. Despite higher pO2 in oxygen therapy group, length of hospital stay remained same. Only side effect seen with oxygen therapy group was relatively higher heart rate compared to control group. The authors concluded that, routine administration of oxygen is not beneficial in nonhypoxic MI.13 Recently two large RCTs evaluated the routine oxygen administration in patients of acute MI. Dion Stub et al. conducted a multicenter RCT of oxygen with facemask at 8 L/min with no oxygen therapy in patients of ST-segment elevation myocardial infarction (STEMI). Out of 441 patients where primary end point was reported, 218 patients were in oxygen and 223 patients in no oxygen group respectively. The result of the study revealed harmful effect of routine oxygen administration in STEMI patients. There was a significant increase in creatine kinase level (primary endpoint) and recurrent MI and upsurge in cardiac arrhythmias in oxygen group compared to no oxygen group. Patient of oxygen group had increased infarct size as measured by cardiac magnetic resonance imaging at 6 months. In a recent multicenter RCT Hofmann et al. compared the effect of oxygen administrations via facemask for 6–12 hours compared with ambient air, in patients suspected of MI. There was no difference between primary outcome of allcause mortality between two groups (5% in oxygen and 5.1% in air group, hazard ratio, 0.97; 95% CI, 0.79–1.21; p = 0.80). There was no difference between two groups in terms of rehospitalization with MI within 1 year.14 Aforementioned evidences, clearly suggest that routine administration of oxygen in a nonhypoxic MI patients is not beneficial and at times detrimental. Routine practice of oxygen administration to nonhypoxic MI patients, should be discouraged.

HARMFUL EFFECTS OXYGEN OF IN POSTCARDIAC ARREST SCENARIO

132

Early aggressive management of successfully resuscitated cardiac arrest patients is crucial due to their severe hemodynamic and respiratory compromise. These patients often develop a multiorgan dysfunction syndrome similar to sepsis, called postcardiac arrest syndrome (PCAS).15 Ischemia reperfusion injury during peri-resuscitation, and underlying disease state are the possible mechanism of PCAS pathogenesis.16 Although hypoxia in postcardiac arrest survivors may exacerbate the neurological injury, excessive oxygen administration can also worsen patient’s outcome. Hyperoxia can worsen the brain injury by

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generation of ROS. Hyperoxia can result in coronary and systemic vasoconstriction resulting in myocardial and brain ischemia.17,18 Secondary brain insult may be caused by hyperoxia-induced seizures. While animal studies have clearly demonstrated the hazards of excessive oxygen administration in early postresu­ scitation period, human trails have shown conflicting results. In a systemic review of animal studies, Pilcher et al. evaluated the outcome of animals ventilated with 100% oxygen with those requiring lesser fraction of expired oxygen.19 Their analysis revealed that, the animals ventilated with 100% oxygen for 60 minutes post-return of spontaneous circulation (ROSC) have worse Neuropathy Disability Score (NDS), compared to other group. Five studies also reported the histological pattern of neuronal injury. Four of the five studies reported injury to deeper brain structures like putamen, hippocampus, caudate nucleus, dorsal respiratory center. It is difficult to extrapolate this data on humans due to inherent risk of bias and methodical drawbacks of studies. Most of the animals were ventilated before cardiac arrest, which is not the case in real life scenario. No neuroprotective strategy like targeted temperature management was used, that has a significant bearing on neurological outcome. Mechanism of cardiac arrest whether electric or hypoxic too could have impacted the results. Human studies have been far more conflicting in this regard. Kilgannon et al., in a retrospective cohort study evaluated the effect of hyperoxia (pO2) >300  mm Hg, normoxia and hypoxia (pO2) 8).24 Of note, the Caprini model is relatively complex as it is comprised of >30 criteria. Hence, healthcare providers may not accurately complete it, which limits its value in VTE risk stratification. Venous thromboembolism risk stratification should also include bleeding risk assessment. Risk factors for bleeding risk in hospitalized medical patients include active gastro­duodenal bleeding, bleeding in the 3 months before admission, thrombocytopenia, 50 × 109/L, age 85 years, INR >1.5 and severe renal failure.25 The IMPROVE bleeding risk score, which uses 11 clinical and laboratory factors, ranges from 0 to 20 points and is calculated at hospital admission, has been externally validated in a study which showed that major bleeding rates increased from 1.5 % in patients with a score of 40 kg/m2), especially during perioperative period of bariatric surgery, enoxaparin, dosed at 40  mg subcutaneously twice daily or based on the patient’s weight, is probably the most appropriate approach.35,36 On the other hand, UFH is preferred over LMWH in patients with severe renal disease (glomerular filtration rate 15% of patients with severe sepsis or septic shock did not meet diagnostic criteria within 3 hours of ED presentation.9 The major trials conducted in sepsis report the following time to antibiotic administration (TTA): • Rivers (2001)—within 6 hours • Kumar (2006)—median of 6 hours • Jones (2010)—median of 115 minutes (~2 h) • ProCESS (2014)—within 3 hours • ARISE (2014)—median of 70 minutes • ProMISe (2015)—median of 2.5 hours. Although, it is prudent to initiate antibiotic therapy for sepsis as soon as possible, the varying degrees of presentation,

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logistical barriers and non-infective masquerades challenge the clinician to administer the same in a time critical manner.10 A study done by Venkatesh et al. in 267 patients demonstrated that 23% of patients that presented to ED, who were ultimately diagnosed with septic shock could not be included in the performance measure of “antibiotics within 3 hour of ED arrival” because of the variation in presentation of sepsis and septic shock. Venkatesh et al. further suggested that measuring time to antibiotic administration according to the clinical severity of sepsis would correlate as a better performance indicator.11 Analyzing the impact of antibiotic timing in sepsis and septic shock in a meta-analysis of 16,178 patients, Sterling et al. demonstrated that there was no increase in mortality with antibiotic delays of up to 5 hours from recognition of shock.12 Similarly, Puskarich et al. demonstrated in a multicenter randomized control trial of 291 patients that there was no difference in mortality with antibiotic delays of up to 6 hours following ED triage, but did record increased mortality in patients in whom antibiotics were delayed after shock state ensued.13 A prospective multicenter trial done by De Groot et al. in three Dutch EDs during 2015, enrolled 1168 patients with mild to severe sepsis who received antibiotics within 6  hours of ED presentation demonstrated that a decrease in time to antibiotic administration was not associated with improved clinical outcomes.14 A recent trial by Alam et al. on prehospital antibiotics in sepsis administered by emergency medical services personnel showed no difference in mortality in patients receiving prehospital antibiotics with a TTA of 28 minutes compared to patients receiving antibiotics after presentation to ED with a TTA of 70 minutes.15 These findings suggest that timing of antibiotic administration and its influence on outcomes depend on severity of sepsis and shock rather than time since presentation. Consolidation of the SSC bundles within 1 hour manifests the need to eliminate obvious delays in sepsis management. The aggressive ideology backed by equivocal clinical data has led to widespread speculation, and disruption of clinical equipoise within the medical fraternity.16 The main arguments involved in this conflict are: • Time zero is an arbitrary set period, following which there is rapid clinical deterioration, if clinical care bundles are not carried out. This time zero is virtually unknown and occurs at a varied point in the clinical course, depending on the severity of pathology. Assumption that ED triage is time zero for every presentation is inappropriate and unjustified • The mechanical implementation of the bundles restricts medical thought process between colleagues/clinicians to arrive at a presumptive diagnosis and predisposes to increased clinician error17 • Mismanagement of sepsis due to inappropriate and overzealous use of antibiotics, without taking into consideration the spectrum, recent antimicrobial use,

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prior hospitalization and prior colonization or infection with multidrug-resistant organisms, dosage, pharma­ cokinetics, pharmacodynamics and source control of infection at the time of initiation18 • Administration of broad-spectrum antibiotics at triage without clinician input and relevant investigation to ascertain cause of pathology increases the possibility of increasing antibiotic resistance • The incorporation of the 1-hour SCC bundle as a functional quality indicator in various health care systems pressurizes the clinician with concomitant penalties, like cessation or decrements in departmental funding if the targets are not achieved • Administration of antibiotics in the absence of docu­ mented infection can lead to potential preventable and unwarranted adverse drug events • Fear of litigation and insistence on completion of imperative tasks within 1 hour of presentation, coerces the clinician to take decisions in haste and contrary to his or her clinical judgment. The strong biological rationale of early antimicrobial therapy is supported by the theory that antibiotics prevent injury caused by microbial activity and toxin production. Furthermore, cessation of microbial activity prevents or ameliorates physiological progression to development of multiorgan dysfunction syndrome (MODS). This has been validated in various settings of organ system infection like pneumonia and meningitis, where early antibiotics have benefited patients.19,20 Should antibiotics be given within 1 hour to everyone? Yes, in patients with clinical suspicion of infection presenting with sepsis or septic shock. Also, patients with risk factors for developing multidrug resistance and acquiring health care pathogens will benefit from early appropriate antibiotic administration. Some examples of patients belonging to these categories are: • Organ transplant recipients on immunosuppression • Hematological malignancies • Chronic kidney disease on hemodialysis • Long-term care facility residence • Indwelling prostheses or catheters • In hospital admission with recent antibiotic exposure • Immunosuppression secondary to chronic disease like COPD/CCF, steroid use, diabetes, HIV etc. Establishing the need for timely and appropriate anti­ biotics in the patient with septic shock does not nece­ssarily translate to completion of the same. Appropriateness of antibiotics has found to influence outcomes in critically ill patients, a retrospective cohort study done by Montero et al. demonstrated that administration of appropriate antibiotics was associated with decreased mortality and inadequate empirical antibiotic administration led to progression of sepsis to septic shock, nosocomial infections and a significant increase in duration of hospitalisation.21 Elements that hinder timely and appropriate antibiotic administration are:22

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CHAPTER 33: Antibiotic within One Hour: Is it for Everyone? • Delay in diagnosis of sepsis or shock secondary to infection • Delaying antibiotic administration for collection of blood cultures • Failure to identify inappropriate antibiotics, leads to a delay in administration of appropriate antibiotics • Failure to identify risk factors for multidrug resistant organism infections (listed above) and initiate appropriate combination antibiotic therapy • Failure to prescribe stat orders to administer antibiotics • Failure to account for appropriate dose, frequency, route, and schedule based on individualized pharmacokinetics, pharmacodynamics, volume of distribution and organ function • Failure to prescribe alternate antibiotics in the presence of documented allergies • Administrative and logistical issues (unavailability or unaffordability of antibiotics, lack of access for admini­ stration, unavailability of nursing staff for administration) • Lack of priority in administering antibiotics, where multiple drug administrations are involved with limited venous access. Clinicians and healthcare personnel have taken efforts to mitigate these shortcomings in patient care to decrease morbidity and mortality. A prospective study done by Vogtlander et al. which enrolled 500 patients divided equally in a preintervention and postintervention study design of 3  months each, demonstrated that with adequate education of nursing and medical staff, mean time of “order to first dose of antibiotic administration” was reduced from 2.7 hours to 1.7 hours (p = 0.003).23 Some of the methods that can be employed to overcome these barriers to timely and appropriate antibiotic administration are: • Education of healthcare personnel involved in pre­ scribing and administering antibiotics and other lifesaving medications • Incorporation of rapid response teams to determine patients at risk of sepsis and hasten appropriate antibiotic administration • Ensure that antibiotics are administered prior to transfer out of ED, or stipulate time limits for administration of the same • Prescription of initial IV antibiotics as stat order and preferably as IV push bolus • Developing symptom-based treatment pathways and sepsis protocols according to antibiograms of organisms at different institutes. • Appropriate antimicrobial targeting as per results of culture reports and antimicrobial sensitivity testing. In addition to these measures, department/unit policy/ protocols should be drafted taking into consideration the elements that hinder timely and appropriate antibiotic administration mentioned above. Deleterious effects secondary to adherence of strict time critical guidelines have been historically negated by prompt

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realization and continued evidence-based medicine. The Infectious Diseases Society of America (IDSA) guidelines on management of Community Acquired Pneumonia (CAP) serve as an example for the same. Retrospective studies done by Meehan et al. and Houck et al. in 1997 and 2004 demonstrated that antibiotic administration and registration as inpatients with CAP within 8 hours and 4 hours, respectively was associated with decreased mortality outcomes.24,25 In light of these studies, the 1998 and 2003 IDSA guidelines for CAP endorsed antibiotic administration within 8 hours and 4 hours of registration as inpatients as performance indicators.26,27 Further, studies refuted the claim of Time to First Antibiotic Dose (TFAD) for CAP as a quality measure and demonstrated that TFAD was not associated with mortality or morbidity benefits. Pines et al. in 2009 evaluated 8 studies that analyzed TFAD and came to the conclusion that TFAD was found to be associated with overzealous administration of antibiotics and promoted antibiotic resistance.28 IDSA and American Thoracic Society (ATS) subsequently withdrew their support for TFAD in the 2007 IDSA/ATS CAP guidelines.29 The American college of emergency physicians (ACEP) CAP 2009 guidelines advise to administer antibiotics as soon as diagnosis of CAP is established, and state that there is insufficient evidence to prove mortality or morbidity benefits in administering antibiotics within a given time frame.30 There exists discordance in views and opinions amongst international societies with regard to the latest surviving sepsis guidelines. The IDSA despite being a working group that drafted the 2016 SSC guidelines, do not endorse them for the following reasons:31 • Inability to distinguish between suspected sepsis and sepsis • Rigid policy of antibiotic administration within 1 hour of ED presentation • Inability to define measurement of start and end points of “time to antibiotic administration” • Incomplete advice regarding blood culture collection and IV catheter/ access management • Unwarranted use of combination therapy for all cases of septic shock leading to antibiotic usage more than indicated • Lacks specifics regarding use of procalcitonin as a biomarker to guide antimicrobial therapy • Lacks specifics in antibiotic adjustment with regard to pharmacokinetics and pharmacodynamics • Discrepancy of views in prolonged antibiotic prophylaxis • Fixed duration of antibiotic therapy of 7–10 days for all cases of sepsis/septic shock, which do not comply with available evidence with regard to different organ systems. Sepsis is one of the leading causes of mortality globally and the surviving sepsis guidelines have provided clinicians around the world with a framework to tackle sepsis for nearly two decades. In order to best serve patients

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SECTION 3: Infection/Antibiotic/Sepsis/Infection Control and health care personnel, it would be prudent to have congruity between the professional societies that deal with the management of sepsis.32

CONCLUSION Multiple factors influence outcome in sepsis, attribution of antibiotic administration within 1 hour of presentation to mortality reduction cannot be extrapolated with ease. As every patient is different and responds differently to pathological insults, guidelines should serve as tools to assist clinical decisions allowing clinicians to individualize treatment. Guidelines should not dictate health care policies as inappropriately administered antibiotics will increase the incidence of antibiotic resistance. Future research on which target population will benefit the most should shed more light on this conundrum.

REFERENCES

1. Rivers E, Nguyen B, Havstad S, et al. Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock. N Engl J Med. 2001;345(19):1368-77. 2. Rowan KM, Angus DC, Bailey M, et al. Early, Goal-Directed Therapy for Septic Shock—a Patient-Level Meta-Analysis. N Engl J Med. 2017;376(23):2223-34. 3. Mouncey PR, Osborn TM, Power GS, et al. Trial of Early, Goal-Directed Resuscitation for Septic Shock. N Engl J Med. 2015;372(14):1301-11. 4. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive care Med. 2017;43(3):304-77. 5. Levy MM, Evans LE, Rhodes A. The Surviving Sepsis Campaign Bundle: 2018 update. Intensive care Med. 2018;44(6):925-8. 6. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589-96. 7. Ferrer R, Martin-Loeches I, Phillips G, et al. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program. Crit Care Med. 2014;42(8):1749-55. 8. Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goaldirected therapy was initiated in the emergency department. Crit Care Med. 2010;38(4):1045-53. 9. Villar J, Clement JP, Stotts J, et al. Many emergency department patients with severe sepsis and septic shock do not meet diagnostic criteria within 3 hours of arrival. Ann Emerg Med. 2014;64(1):48-54. 10. Liu VX, Fielding-Singh V, Greene JD, et al. The timing of early antibiotics and hospital mortality in sepsis. Am J Respir Crit Care Med.  2017;196(7):856-63. 11. Venkatesh AK, Avula U, Bartimus H, et al. Time to antibiotics for septic shock: evaluating a proposed performance measure. Am J Emerg Med. 2013;31(4):680-3. 12. Sterling SA, Miller WR, Pryor J, et al. The impact of timing of antibiotics on outcomes in severe sepsis and septic shock: A systematic review and metaanalysis. Crit Care Med. 2015;43(9):1907-15. 13. Puskarich MA, Trzeciak S, Shapiro NI, et al. Association between timing of antibiotic administration and mortality from septic shock in patients treated with a quantitative resuscitation protocol. Crit Care Med.  2011;39(9):2066-71.

14. de Groot B, Ansems A, Gerling DH, et al. The association between time to antibiotics and relevant clinical outcomes in emergency department patients with various stages of sepsis: a prospective multicenter study. Crit Care. 2015;19:194. 15. Alam N, Oskam E, Stassen PM, et al. Prehospital antibiotics in the ambulance for sepsis: a multicentre, open label, randomized trial. Lancet Respir Med. 2018;6(1):40-50. 16. Singer M. Antibiotics for Sepsis: Does each hour really count, or is it incestuous amplification? Am J Respir Crit Care Med. 2017;196(7):800-2. 17. Welker JA, Huston M, McCue JD. Antibiotic timing and errors in diagnosing pneumonia. Arch Intern Med. 2008;168(4):351-6. 18. Hranjec T, Rosenberger LH, Swenson B, et al. Aggressive versus conservative initiation of antimicrobial treatment in critically ill surgical patients with suspected intensive-care-unit-acquired infection: a quasi-experimental, before and after observational cohort study. Lancet Infect Dis. 2012;12(10):774-80. 19. Aronin SI, Peduzzi P, Quagliarello VJ. Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing. Ann Intern Med.  1998;129(11):862-9. 20. Auburtin M, Wolff M, Charpentier J, et al. Detrimental role of delayed antibiotic administration and penicillin-nonsusceptible strains in adult intensive care unit patients with pneumococcal meningitis: the PNEUMOREA prospective multicenter study. Crit Care Med. 2006;34(11):2758-65. 21. Garnacho-Montero J, Ortiz-Leyba C, Herrera-Melero I, et al. Mortality and morbidity attributable to inadequate empirical antimicrobial therapy in patients admitted to the ICU with sepsis: a matched cohort study. J Antimicrob Chemother.  2008;61(2):436-41. 22. Funk DJ, Kumar A. Antimicrobial therapy for life-threatening infections: speed is life. Crit Care Clin. 2011;27(1):53-76. 23. Vogtländer NP, van Kasteren ME, Natsch S, et al. Improving the process of antibiotic therapy in daily practice: Interventions to optimize timing, dosage adjustment to renal function, and switch therapy. Arch Intern Med. 2004;164(11):1206-12. 24. Meehan TP, Fine MJ, Krumholz HM, et al. Quality of care, process, and outcomes in elderly patients with pneumonia. JAMA. 1997;278(23):2080-4. 25. Houck PM, Bratzler DW, Nsa W, et al. Timing of antibiotic administration and outcomes for Medicare patients hospitalized with community-acquired pneumonia. Arch Intern Med. 2004;164(6):637-44. 26. Mandell LA, Bartlett JG, Dowell SF, et al. Update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults. Clin Infect Dis. 2003;37(11):1405-33. 27. Bartlett JG, Breiman RF, Mandell LA, et al. Community-acquired pneumonia in adults: guidelines for management. The Infectious Diseases Society of America. Clin Infect Dis. 1998;26(4):811-38. 28. Pines JM, Isserman JA, Hinfey PB. The measurement of time to first antibiotic dose for pneumonia in the emergency department: a white paper and position statement prepared for the American Academy of Emergency Medicine. J Emerg Med. 2009;37(3):335-40. 29. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44 (Suppl 2): S27-72. 30. Nazarian DJ, Eddy OL, Lukens TW, et al. Clinical policy: critical issues in the management of adult patients presenting to the emergency department with community-acquired pneumonia. Ann Emerg Med.  2009;54(5):704-31. 31. IDSA Sepsis Task Force. Infectious Diseases Society of America (IDSA) POSITION STATEMENT: Why IDSA Did Not Endorse the Surviving Sepsis Campaign Guidelines. Clin Infect Dis.  2018;66(10):1631-5. 32. Spiegel R, Farkas JD, Rola P, et al. The 2018 Surviving Sepsis Campaign’s Treatment Bundle: When Guidelines Outpace the Evidence Supporting Their Use. Ann Emerg Med. 2018 S0196-0644(18)30607-3.

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CHAPTER

Dysbiosis and Probiotics in ICU Anshu Joshi

INTRODUCTION The gastrointestinal (GI) tract is inhabited by complex microbial populations, which are often referred to as the gut microbiota. The relationship of gut microbiota with the host has a symbiotic relationship. Gut microbiota contributes to the development and differentiation of the host immune system. Disturbance in normal gut flora is linked to infections and other pathologies. Antibiotic administration perturbs the normal intestinal microbiota. This adversely affects immune defense against various pathogens. Dysbiosis also affects the respiratory system, especially when the patient is unconscious, ventilated or intubated.

DYSBIOSIS Critical illness results in loss of normal, healthy commensal bacteria, allowing overgrowth of disease-promoting patho­ genic bacteria. This phenomenon is known as dysbiosis. The patients become more susceptible to nosocomial infections, sepsis and multiorgan dysfunction syndrome (MODS). The increased incidence of hospital-acquired infection result in increased morbidity and cost of hospital care.1

Equilibrium of Gut Microflora Various metabolic and protective functions are performed by the commensal microbiota. Under normal conditions, there exists equilibrium amongst various species of normally resident bacteria of gut. Normally, feces are rich in total obligate anaerobes such as Bacteroidaceae and Bifidobacterium. There exists equilibrium between obligate anaerobes and total facultative anaerobes. Disturbance of this equilibrium is very important in consequent septic complications. Higher number of obligate anaerobes results in increased expression of genes involved in nutrient absorption, angiogenesis, mucosal barrier fortification, intestinal maturation and xenobiotic metabolism. Reduction in obligate anaerobes and

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increase in facultative anaerobes weakens intestinal mucosal barrier. Thus, intestinal resistance to pathogens becomes weak. This disturbance may be due to severe systemic inflammation or usage of antibiotics. Maintenance of this balance is very important for healthy functioning of immune system.2

Aging and Gut Microbiota Aging influences the composition of the resident microbiota, with higher counts of facultative anaerobes and reduced commensals, such as Lactobacillus and Bifidobacterium. Thus, the gut microbial balance becomes more fragile in elderly, making them more prone to dysbiosis. Along with this, the gut mucosal barrier also weakens in elderly. Increasing gut permeability along with dysbiosis weakens overall immunity in such patients. Hence, critically ill elderly are more prone to develop enteritis even with normal counts of obligate anaerobes.3 Gene pool of gut microbiota is immense and may be at least 100 times as many genes as the human genome. Intestinal dendritic cells carry these commensals to mesen­ teric lymph nodes. A [immunoglobulin A (IgA)] production is induced by dendritic cells, thus protecting against mucosal penetration by commensal bacteria. Toll-like receptors of colonic epithelium recognize these microflora, which results in proliferation of colonic epithelial cells and also protect against epithelial injury. Thus, homeostasis and protection from mucosal injury are important functions of normal commensal gut flora. These become compromised when dysbiotic changes happen.3

Alterations in Growth Conditions Severity of critical illness not only induces dysbiosis, but also influences the changes in microbiota by altering the environmental conditions and community structure of resident commensals. During critical illness, gram-negative

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aerobes displace healthy oral microbial flora. Reduced immigration of food-associated bacteria, subsequently reducing the nutritional supply for commensal microbes is seen in starvation phase of critical illness. Primary means of microbial elimination in healthy individuals from the gut microbiome is rapid transit through the GI tract. Healthy adult expels around 1014 bacterial cells per day via defecation. However, various factors substantially slow this transit time in critically ill patients. Such factors may be pathophysiological (e.g. glucose and electrolyte disturbances and endogenous opioid production) and therapeutic (sedatives, opiates and systemic catecholamine production). Transit time slows in stomach and acidic pH gets neutralized by the use of antacids or other medications administered to the patient. Apart from these, bile salt production drops, IgA production is impaired and the dense gut mucosal barrier becomes fragile. All these factors result in decreased elimination of pathogenic bacteria, especially in the upper GI tract. The result is upper GI tract is overgrown by gram-negative bacteria.4 Critical illness modifies the environmental growth conditions in gut and adversely affects the reproductive rates of commensal bacteria. Alteration in perfusion of intestinal wall results in intense mucosal inflammation, leading to a cascade of environmental changes. High nitrate concentration along with disturbed mucosal oxygen gradient favors dysbiosis. The growth of Proteobacteria phylum bacteria (like Pseudomonas aeruginosa and Escherichia coli) and some members of the Firmicutes phylum (such as Staphylococcus aureus and Enterococcus species) increases. Disruption and thinning of dense mucus layer in intestinal wall happens during critical illness phase. The mucus layer harbors protective commensals and is protective in nature. Even the medical management during intensive care stay (e.g. proton-pump inhibitors, systemic catechol amines and systemic antibiotics) has propensity to change growth conditions for healthy gut flora. Such alterations in ecology result in unstable microbiota with low diversity.4 The stomach and proximal small intestine, which are usually sparsely populated, become overgrown by a small number of species, such as E. coli, P. aeruginosa, and Enterococcus spp. and become stagnant reservoir of potential pathogens like E. coli, P. aeruginosa and Enterococcus. These changes may progress to extra-abdominal infections and multiorgan failure. On the other hand, lower GI tract, loses microbial diversity, and the community is overrun by few (e.g. S. aureus, Enterococcus, E. coli and P. aeruginosa) bacterial species. These species are low in healthy adults, but become prominent in critical illness. In addition to them, rare fungi such as Candida also increases during dysbiosis. Growth of Candida predicts poor outcome. Gut microbial flora resembles an infection rather than a healthy diverse microbial community.

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Respiratory Tract Critical illness-induced dysbiosis is also seen in respiratory tract. Depressed consciousness and endotracheal intubation results in accelerated immigration of oropharyngeal microbes via microaspiration. The dynamics of the aerodigestive tract gets reversed in critically ill patients. In healthy condition, the primary source of microbial community for lungs and stomach remains oropharynx. However, in critically ill patients, the dysbiotic overgrown stomach and small intestine become source of microbiota for mouth and lungs. In healthy cases, oropharynx is usually populated by benign Prevotella and Veillonella species. In critical illness, it becomes populated by pathogenic bacteria like Proteobacteria, such as P. aeruginosa and Klebsiella pneumoniae.4 Cough reflex becomes blunted by depressed consciou­ sness and sedation and mucociliary clearance is reduced by acute illness and intubation. Both the microbial immigration and elimination are decreased due to elevation of the head of the bed, especially when cough reflex and mucociliary clearance are impaired. Also the alveolar surfactant inactivation happens, which decreases the elimination of surfactant-sensitive bacteria.4 The GI tract acts as the “motor” of systemic inflammatory response syndrome (SIRS) and of organ failure irrespective of the location of the initial infection. Gut microbiota and gut barrier homeostasis disturbances are transmitted to and further propagated by downstream organs. Organs like lung and spleen harbor large populations of immune cells. Hence, transmission of such disturbances to these organs lead to inflammation induced organ failure, which is quite common in intensive care settings.5

ANTIBIOTICS-INDUCED DYSBIOSIS Diarrhea in tube-fed patients should not be always attributed to feed intolerance and malabsorption. Antibiotic-induced diarrhea or dysbiosis is now getting increasingly recognized as one of the leading cause of diarrhea in critically ill patients. Suppression of fermentation, thereby inhibiting the production of short-chain fatty acids (SCFA), especially butyrate and supporting overgrowth of certain pathogens are two recognized mechanisms of antibiotic-associated dysbiosis. Clostridium difficile growth is one prominent example of the later mechanism of antibiotic associated dysbiosis. Other reasons of C. difficile proliferation are usage of broad-spectrum antibiotics, proton pump inhibitors and elemental tube feeds.6

PROBIOTICS Probiotics are defined by the World Health Organization as “viable microorganisms that, when ingested in adequate amounts, can be beneficial for health”. Prebiotics are non­

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CHAPTER 34: Dysbiosis and Probiotics in ICU digestible food ingredients (oligofructose) that are beneficial to the host through their selective stimulation of specific bacteria within the colon. Synbiotic is combination of preand probiotic. Probiotics are thought to restore commensal gut flora by suppressing dysbiosis by inducing host cell antimicrobial peptides and release of antimicrobial factors. In addition, probiotics favorably modulate immune cell proliferation, stimulate local mucus and IgA production and inhibits inflammatory nuclear factor kappa B activation. Repletion of healthy commensal microbiota via pro­ biotics, prebiotics, stool transplantation or combination therapies may help to prevent dysbiosis in gut and other sites and to maintain gut mucosal integrity. In addition to above mentioned benefits, probiotics also promote antioxidant activity at gut mucosal levels and prevents gut apoptosis.1 New trials have been done to evaluate the benefits of probiotic therapy in critically ill patients. It was found that probiotics usage has resulted in reduced incidence of confirmed ventilator-associated pneumonia (VAP), as well as lower mean time to develop VAP.7 Lactobacillus GG has been found safer and of some benefit in even in reducing incidence of overall infectious complications and VAP in critically ill patients.8 Recent meta-analysis in Journal of the American Medical Association (JAMA) has showed that probiotics could reduce antibiotic associated diarrhea by 40%.9 Finally, a recent Cochrane meta-analysis of probiotic use in C. difficile colitis and diarrhea demonstrated that probiotics could reduce C. difficile-associated diarrhea by 64% in patients taking antibiotics (23 studies, n  =  4,213).10 Probiotics also reduced the risk of side effects associated with antibiotic use in this analysis. Other strains of probiotics such as Pediococcus pentosaceus, Lactobacillus paracasei subspecies paracasei, and Lactobacillus plantarum have been found safer and helped reducing the infectious complications in Whipple’s procedure.8 In a Cochrane review, none of the probiotics studied had an effect on intensive care unit (ICU) mortality or incidence of diarrhea.8 In addition to probiotic use, fecal transplantation has shown> 90% effectiveness in inducing a cure against C. difficile colitis11 and “stool pills” also may soon show promise for treating this increasingly aggressive infection.

ASPEN/SCCM Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient; 2016 This guideline suggests that, “while the use of studied probiotics species and strains appear safe in general ICU patients, they should be used only for select medical and surgical patient populations for which randomized controlled trials (RCTs) have documented safety and outcome benefit.

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No recommendation can be made this time for the routine use of probiotics across the general population of ICU patients”.8 Probiotics may be considered for use in selective patient populations (e.g. liver transplantation, trauma and pancreatectomy) in which RCTs have documented safety and outcome benefits (prevention of VAP, pseudomembranous colitis and antibiotic-associated diarrhea).8

ROLE OF PREBIOTICS Short-chain fatty acid, especially butyrate is essential for the maintenance of cellular homeostasis and a normal colono­ cyte phenotype. SCFA have anti-inflammatory effects, either directly by regulating the release of prostaglandin E2, cytokines and chemokines from human immune cells or supporting the growth of bifidobacteria and lactobacilli. Normal resolution of inflammation in colonocytes is stimulated by SCFA.6 Hence, SCFA are anti-inflammatory and immune modulatory in action. SCFA production also enhances colonic blood flow as well as fluid and electrolyte uptake.12 Short-chain fatty acids are produced by normal commensal bacteria of the gut. However, in critical illnessinduced dysbiosis, the SCFA production is impaired. Dietary prebiotic fibers taken help to make up for this deficit. Dietary prebiotic fibers also have an impact on the gut microbiota and the gut barrier function. Fructo­oligo­ saccharides (FOS) are indigestible carbohydrates fermented in the colon into SCFAs. SCFAs (especially butyrate) provide nutrition for the colonocyte, increase colonic blood flow and stimulate pancreatic secretions. Prebiotics (e.g. FOS and inulin) stimulate the growth of bifidobacteria and lactobacillus, often referred to as the “healthy” bacteria.

ASPEN/SCCM Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient; 2016 This guideline suggests that “a fermentable soluble fiber additive (e.g. FOSs and inulin) be considered for routine use in all hemodynamically stable medical or surgical intensive care placed on a standard enteral formulation. The guidelines suggest 10–20 g of a fermentable soluble fiber supplement can be given in divided doses over 24 hours as adjunctive therapy if there is evidence of diarrhea”.

CONCLUSION Various factors contribute to dysbiosis in critically ill patients. Critical illness modifies the environmental growth conditions in gut and adversely affects the reproductive rates of commensal bacteria. Equilibrium between obligate anaerobes and total facultative anaerobes gets disturbed. Respiratory tract also gets involved. This further weakens the immune system of the patient. Repletion of commensal

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SECTION 3: Infection/Antibiotic/Sepsis/Infection Control microbiota via probiotics, prebiotics, stool transplantation or combination therapies may help to prevent dysbiosis in gut and other sites. General recommendations for probiotic usage across all ICU patient population are not there. However, in cases where the safety and outcome benefits are established, probiotics can be used. On the other hand, prebiotics can be routinely considered in stable intensive care patients, who are on standard enteral nutrition.

REFERENCES 1. McDonald D, Ackermann G, Khailova L, et al. Extreme Dysbiosis of the Microbiome in Critical Illness. mSphere. 2016;1(4):e00199-16. 2. Shimizu K, Ogura H, Hamasaki T, et al. Altered gut flora are associated with septic complications and death in critically ill patients with systemic inflammatory response syndrome. Dig Dis Sci. 2011;56(4):1171-7. 3. Ubeda C, Pamer E. Antibiotics, microbiota, and immune defense. Trends Immunol. 2012;33(9):459-66. 4. Dickson R. The microbiome and critical illness. Lancet Respir Med. 2016; 4(1):59-72.











5. Wischmeyer P, McDonald D, Knight R. Role of the microbiome, probiotics, and ‘dysbiosis therapy’ in critical illness. Curr Opin Crit Care. 2016;22(4):34753. 6. O’Keefy S, Ou J, Delany J, et al. Effect of fiber supplementation on the microbiota in critically ill patients. World J Gastrointest Pathophysiol. 2011;2(6):138-45. 7. Mittal R, Coopersmith CM. Redefining the gut as the motor of critical illness. Trends Mol Med. 2014;20:214-23. 8. McClave SA, Taylor BE, Martindale RG, et al. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2016;40(2):159211. 9. Li Q, Wang C, Tang C, et al. Successful treatment of severe sepsis and diarrhea after vagotomy utilizing fecal microbiota transplantation: a case report. Crit Care. 2015;19:37. 10. Gilbert JA, Jansson JK, Knight R. The Earth Microbiome project: successes and aspirations. BMC Biol. 2014;12:69. 11. Caporaso JG, Lauber CL, Walters WA, et al. Ultra-high-throughput microbial community analysis on the Illumina HiSeq and MiSeq platforms. ISME J. 2012;6:1621-4. 12. Greer JB, O’Keefe SJ. Microbial induction of immunity, inflammation, and cancer. Front Physiol. 2011;1:168.

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CHAPTER

MALDI-TOF: Utility in ICU Anand Shah, Camilla Rodrigues

INTRODUCTION Intensive care units (ICUs) have fewer than ten percent of the total number of beds in most hospitals, more than 20% of all nosocomial infections are acquired in ICUs and carry substantial morbidity, mortality, and expense.1-4 In addition, multidrug-resistant (MDR) pathogens are much more frequently isolated in ICUs.5-6 This hinders the initiation of appropriate, effective antibiotic therapy, which correlates with excess mortality.7-9 Sepsis is a global healthcare issue leading to a large number of diseases with significant morbidity and mortality in the community. It is one of the important causes of admission in the ICUs because of more severe illnesses of hospitalized patients and to the persistently high incidence of nosocomial infections. Overall mortality of septic patients estimates to 30% and increasing to 50% when associated with shock.10 Bloodstream infections, Septic shock and endocarditis represent severe disease with significant mortality and morbidity. Blood cultures (BCs) are an important part of the diagnostic process,11 yet the number of blood culture positive tends to be low and a majority are contaminated with  skin flora12. After blood collection, using conventional methods for identification (ID) and susceptibility testing of positive BCs may require up to 72 hours.13 In addition, initial Gram staining does not differentiate between contamination and a clinically significant bloodstream infection (BSI). Consequently, broad-spectrum empiric treatment is usually continued until the final ID of organism and/or antibiotic susceptibility report are available. However, up to 38% of initially prescribed antibiotics for bloodstream infections are inappropriate which leads to increased antibiotic resistance, unnecessary cost and poor outcome.14,15 The availability of rapid and reliable infectious disease diagnostics that can provide results directly from patient specimens represents a major unmet need in managing critically ill patients. Recent molecular methods for microbial

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ID have found some application but these methods do not provide complete solution. There is still an urgent need for rapid and simple technique for microbial ID.

MALDI-TOF MS FOR ORGANISM IDENTIFICATION The principle of this measurement is based on the ability of an electric and/or magnetic field to deflect a flow of ions, each with a mass and a charge proportional to their trajectories.16 Matrix-assisted Laser Desorption/Ionization Time-ofFlight Mass Spectrometry (MALDI-TOF MS) has revolutio­ nized the ID of microbial species in clinical microbiology laboratories and has become the new gold-standard method owing to its key advantages of simplicity and robustness.17 At present, MALDI-TOF MS is considered the holy grail of rapid microbial ID despite only being introduced for use in routine laboratories less than 10 years ago. The diagnostic applications covers ID of common gram-positive, gramnegative, aerobic, and anaerobic bacteria, as well as mycobacteria, yeasts, and molds (Fig. 1).18 Traditional bacterial ID from cultures is complex, requiring observation of colony growth, classification by staining, and biochemical testing by manual or semi­ automated methods. Less than 10% of bacteria causing infections are identified by conventional methods by 24 hours after growth is observed. Less than 90% of bacteria can be identified correctly to species level by conventional methods. The accuracy of MALDI-TOF ID is 98.3% and can be performed from a single bacterial colony, the same day culture growth is observed. Compared to conventional methods, MALDI-TOF MS decreases the time to organism ID by approximately 1.2–1.5 days.19-21 During the past decade, the clinical impact of severe fungal infections has increased especially in immunocompromised patients or those who are on ventilation in ICU settings. Rapid and reliable species ID is essential for antifungal treatment for which conventional biochemical methods

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MALDI-TOF MS FOR BLOODSTREAM INFECTIONS DIRECTLY FROM BLOOD CULTURE Given the accuracy of MALDI-TOF MS for bacterial and fungal ID, protocols for direct ID of pathogens from positive blood culture broths have been developed. This technology might also be directly applied to some clinical samples other than blood such as urine, cerebrospinal fluid (CSF), pleural fluid, peritoneal fluid and synovial fluid. The major limitation is the amount of bacteria present in the samples and the limit of detection of current MALDI-TOF protocols.24,25 A recent publication from Methodist Hospital in Houston, Texas reported that the use of MALDI-TOF decreased the mean hospital length of stay for gram-negative sepsis from 11.9 to 9.3 days and decreased the mean hospital inpatient cost by $19,547.26 Another study from the University of Michigan showed that MALDI-TOF decreased the time to bacterial ID from 84 to 55.9 hours and the time to optimal therapy from 90.3 to 47.3 hours. This improvement in laboratory turnaround time significantly impacted patient care and patient safety by decreasing mortality from 20.3 to 14.5% and length of ICU stay from 14.9 to 8.3 days.27

MALDI-TOF MS FOR ANTIMICROBIAL SUSCEPTIBILITY TESTING

(MALDI-TOF MS: Matrix-assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry)

FIG. 1: Matrix-assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry operating principle for identification.

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are too time consuming. Additionally high resolution DNA based molecular techniques, such as 16s or 18srRNA or internal transcribed spacer (ITS) DNA sequencing and realtime polymerase chain reaction (PCR) assays are expensive and time consuming. MALDI-TOF MS is a rapid and reliable tool for ID of yeasts and moulds with low expenditure of consumables, easy interpretation of results and a faster turnaround time.22,23 Conventional ID methods for anaerobic bacteria are cumbersome, time consuming and require special anaerobic chamber. With advent of MALDI-TOF MS, anaerobic species ID has certainly increased since ID can be done directly from the colonies on the primary culture plates. The MALDI-TOF MS is also emerging within the evolving field of ID of Nocardia as well as nontuberculous mycobacteria as an ID method that is rapid but perhaps less discriminatory than the widely used sequencing methods.

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The detection of resistance against carbapenems using MALDI-TOF is one the most studied topics right now. Hrabák  et al.  described an innovative method that detects degradation products of carbapenems from the activity of carbapenem resistant pathogens.28 The MALDI-TOF seems to have a cutting edge in detecting the antibiotic resistance by closing the gap between the availability of species ID on the one, and the resistance status on the other hand. MALDI-TOF, similar to species-specific ID, significantly cut short the time duration for the detection of resistance compared to the commonly used antimicrobial susceptibility test (AST) methods using up to now four different methodologies:29,30 1. Resistance peak pattern: Using the classical strain typing methodology, this procedure helps to identify characteristic differences in the MALDI-TOF mass spectra of susceptible and resistant isolates of a given microorganism 2. The MBT-STAR-BL Assay (MALDI Biotyper-Selective Testing of Antibiotic Resistance-b-Lactamase Assay): Bacteria induced hydrolysis of b-lactam antibiotic is detected by the observation of specific mass shifts after a 30–180-minute incubation period of the pathogen with the tested β-lactam antibiotic28,31,32 3. The MBT-RESIST Assay (MALDI Biotyper-Resistance Test with Stable Isotopes Assay): Detection of the amount of

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CHAPTER 35: MALDI-TOF: Utility in ICU incor­porated isotopically labeled amino acids into newly synthesized proteins in the presence of antibiotic is used to determine if a strain is susceptible or resistant;33 Sparbier et al. used this assay for the detection of MRSA using oxacillin and cefoxitin as antibiotics34 4. The MBT-ASTRA (MALDI Biotyper-Antibiotic Suscepti­ bility Test Rapid Assay): Analysis of bacterial growth in the presence and in the absence of antibiotics using an internal standard.34 In 2017 this method was performed in strains of S.  aureus  and ciprofloxacin, oxacillin, cefepime and vanco­ mycin with an overall accuracy rate of 95%35 while very recently it was used for the detection of resistance of two reference B. fragilis strains in clindamycin, meropenem and metronidazole with promising results.36 The main disadvantage of the MBT-ASTRA assay is optimization of the concentration of antibiotic used as well as the incubation time for each species and antibiotic combination. The first of the above methodologies is characterized as “MALDI-TOF equivalent to genotypic analyses.” The rest, most recent ones [i.e. number (II), (III), (IV)] are defined as “MALDI-TOF equivalent to conventional, biochemical resistance tests.”

CONCLUSION The MALDI-TOF allows reporting of accurate, inexpensive micro­biology results to the treating physician the same day a bacterial culture turns positive, which is at least 2 days sooner than traditional methods. This rapid turnaround time facilitates correct, targeted antibiotic therapy and significantly improved patient outcomes. In conclusion, MALDI-TOF MS dominates the field of microbial ID at this stage. New developments, both technological and practical (with respect to the clinical databases), are foreseen that will further broaden the acceptance and integration of the MS technology in clinical microbiology.

REFERENCES

1. Burgmann H, Hiesmayr JM, Savey A, et al. Impact of nosocomial infections on clinical outcome and resource consumption in critically ill patients. Intensive Care Medicine. 2010;36(9):1597-1601. 2. Cohen ER, Feinglass J, Barsuk JH, et al. Cost Savings From Reduced CatheterRelated Bloodstream Infection After Simulation-Based Education for Residents in a Medical Intensive Care Unit. Simul Healthc. 2010;(2):98-102. 3. Zarb P, Coignard B, Griskeviciene J, et al. The European Centre for Disease Prevention and Control (ECDC) pilot point prevalence survey of healthcareassociated infections and antimicrobial use. Euro Surveill. 2012;17(46). 4. Olaechea PM, Palomar M, Álvarez-Lerma F, et al. Morbidity and mortality associated with primary and catheter-related bloodstream infections in critically ill patients. Rev Esp Quimioter. 2013;26:21-9. 5. Hidron AI, Edwards JR, Patel J, et al. NHSN annual update: antimicrobialresistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006-2007. Infect Control Hosp Epidemiol. 2008;29:996-1011.

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6. Brusselaers N, Vogelaers D, and Blot S.The rising problem of antimicrobial resistance in the intensive care unit. Annals of Intensive Care. 2011;1(1):47. 7. Ibrahim EH, Sherman G, Ward S, et al. Antimicrobial Treatment of Bloodstream Infections on Patient Outcomes in the ICU Setting. Chest. 2000;118(1):146-55. 8. Muscedere JG, Shorr AF, Jiang X, et al. The adequacy of timely empiric antibiotic therapy for ventilator-associated pneumonia: An important determinant of outcome. J Crit Care. 2012;27(3):322. 9. Palmer HR, Palavecino EL, Johnson JW et al. Clinical and microbiological implications of time-to-positivity of blood cultures in patients with Gram-negative bacilli bacteremia. Eur J Clin Microbiol Infect Dis. 2013;32(7):955-959. 10. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864–74. 11. Daniels R. Surviving the first hours in sepsis: getting the basics right (an intensivist’s perspective). J Antimicrob Chemother. 2011;66(2):11-23. 12. Dawson S. Blood culture contaminants. J Hosp Infect. 2014;87(1):1-10. 13. Opota O, Croxatto A, Prod’hom G, et al. Blood culture-based diagnosis of bacteraemia: state of the art. Clin Microbiol Infect. 2015;21(4):313-22. 14. Garnacho-Montero J, Gutiérrez-Pizarraya A, Escoresca-Ortega A, et al. Deescalation of empirical therapy is associated with lower mortality in patients with severe sepsis and septic shock. Intensive Care Med 2014;40(1):32-40. 15. Geissler A, Gerbeaux P, Granier I, et al. Rational use of antibiotics in the intensive care unit: impact on microbial resistance and costs. Intensive Care Med. 2003;29(1):49-54. 16. Emonet S, Shah HN, Cherkaoui A, et al. Application and use of various mass spectrometry methods in clinical microbiology. Clin Microbiol Infec. 2010;16(11):1604-13. 17. Van Belkum A, Welker M, Pincus D, et al. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry in clinical microbiology: what are the current issues? Ann Lab Med. 2017;37:475-83. 18. Van Belkum A, Welker M, Dunne WM, et al. The infallible microbial identification test: does it exist? J Clin Microbiol 2015;53:1786. 19. Vlek AL, Bonten MJ, Boel CH. Direct matrix-assisted laser desorption ionization time-of-flight mass spectrometry improves appropriateness of antibiotic treatment of bacteremia. PLoS One. 2012;7(3):e32589. 20. Perez KK, Olsen RJ, Musick WL, et al. Integrating rapid pathogen identification and antimicrobial stewardship significantly decreases hospital costs. Arch Pathol Lab Med. 2013;137:1247-54. 21. Huang AM, Newton D, Kunapuli A, et al. Impact of rapid organism identification via matrix-assisted laser desorption/ionization time-of-flight combined with antimicrobial stewardship team intervention in adult patients with bacteremia and candidemia. Clin Infect Dis. 2013;57:1237-45. 22. Marklein G, Josten M, Klanke U, et al. Matrix-assisted laser desorption ionization-time of flight mass spectrometry for fast and reliable identification of clinical yeast isolates. J Clin Microbiol. 2009;47(9):2912-7. 23. Montero CI, Shea YR, Jones PA, et al. Evaluation of Pyrosequencing technology for the identification of clinically relevant non-dematiaceous yeasts and related species. Eur J Clin Microbiol Infect Dis. 2008;27(9):821-30. 24. Moussaoui W, Jaulhac B, Hoffmann AM, et al. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry identifies 90% of bacteria directly from blood culture vials. Clin Microbiol Infect. 2010;16(11):1631-8. 25. Munson EL, Diekema DJ, Beekmann SE, et al. Detection and treatment of bloodstream infection: laboratory reporting and antimicrobial management. J Clin Microbiol. 2003;41(1):495-7. 26. Perez KK, Olsen RJ, Musick WL, et al. Integrating rapid pathogen identification and antimicrobial stewardship significantly decreases hospital costs. Arch Pathol Lab Med. 2013;137:1247-54. 27. Huang AM, Newton D, Kunapuli A, et al. Impact of rapid organism identification via matrix-assisted laser desorption/ionization time-of-flight combined with antimicrobial stewardship team intervention in adult patients with bacteremia and candidemia. Clin Infect Dis. 2013;57:1237-45. 28. Hrabák J, Walkova R, Studentova V, et al. Carbapenemase activity detection by matrix-assisted laser desorption ionization-time of flight mass spectrometry.  J Clin Microbiol 2011;49:3222-7.

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SECTION 3: Infection/Antibiotic/Sepsis/Infection Control 29. Kostrzewa M, Sparbier K, Maier T, et al. MALDI-TOF MS: an upcoming tool for rapid detection of antibiotic resistance in microorganisms. Proteomics Clin Appl. 2013;7:767-78. 30. Sparbier K, Schubert S, Kostrzewa M. MBT-ASTRA: A suitable tool for fast antibiotic susceptibility testing? Methods. 2016;104:48-54. 31. Burckhardt I, Zimmermann S. Using matrix-assisted laser desorption ionizationtime of flight mass spectrometry to detect carbapenem resistance within 1 to 2.5 hours. J Clin Microbiol. 2011;49:3321-4. 32. Sparbier K, Schubert S, Weller U, et al. Matrix-assisted laser desorption ionizationtime of flight mass spectrometry-based functional assay for rapid detection of resistance against b-lactam antibiotics. J Clin Microbiol. 2012:50;927-37.

33. Sparbier K, Lange C, Jung J, et al. MALDI biotyper-based rapid resistance detection by stable-isotope labeling. J ClinMicrobiol. 2013;51:3741-8. 34. Lange C, Schubert S, Jung J, et al. Quantitative matrix assisted laser desorption ionization-time of flight mass spectrometry for rapid resistance detection. J Clin Microbiol. 2014;52:4155-62. 35. Maxson T, Taylor-Howell C, Minogue T. Semi-quantitative MALDI-TOF for antimicrobial susceptibility testing in Staphylococcus aureus. PLoS One. 2017;12(8):e0183899. 36. Justesen US, Acar Z, Sydenham TV, et al. Antimicrobial susceptibility testing of Bacteroides fragilis using the MALDI Biotyper antibiotic susceptibility test rapid assay (MBT-ASTRA). Anaerobe. 2018;54:236-9.

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CHAPTER

Therapeutic Drug Monitoring for Beta-lactams and Colistin: Is it Ready for Prime Time? Ayesha Sunavala, Umang Agrawal, Parmee V Gala

INTRODUCTION In the year 2018, the management of sepsis in India faces several significant hurdles, of which extreme drug resistance (XDR) among gram-negative (GN) pathogens is undoubtedly the gravest. In addition, a growing proportion of patients with diverse host factors such as extremes of age, profound immunosuppression, and obesity survive prolonged states of critical illness due to sophisticated hemodynamic and ventilatory support systems and extracorporeal therapies like continuous renal replacement therapy (CRRT). These patients have dynamic physiological fluctuations owing to organ dysfunction, variable volumes of distribution, hypoalbuminemia, and augmented renal clearance which can lead to unpredictable pharmacokinetic (PK) alterations. Finally, the increasing dependence on mechanical ventilation and long-standing catheters and devices create an ideal

environment for biofilm production further compounding the issues of antimicrobial penetration and emergence of resistance.1 A combination of diverse factors that contribute to altered PK in critically ill patients is shown in Flowchart 1. Given the above, individualized antimicrobial therapy with a pivotal focus on applying PK knowledge at the bedside may be considered an obligation for clinicians managing these challenging infections. Therapeutic drug monitoring (TDM) appears to be a promising means of PK optimization. It is based on the premise that drug concentrations at the intended site of action cannot be routinely measured, but their desired or adverse effects may correlate better with plasma or blood concentrations than they do with standard dosing.2 Traditionally, TDM was indicated predominantly to reduce the risk of toxicity of drugs with a narrow therapeutic

(VD: volume of distribution; Cl: clearance; MIC: minimum inhibitory concentration; ECMO: extracorporeal membrane oxygenation; RRT: renal replacement therapy; PK/PD: pharmacokinetic/pharmacodynamic)

FLOWCHART 1:  Factors contributing to variable pharmacokinetic in sepsis.

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SECTION 3: Infection/Antibiotic/Sepsis/Infection Control index, e.g. phenytoin, digoxin, aminoglycosides, etc. However, in the current landscape, TDM of antimicrobials may prove to be a useful tool for various important indications: • To ensure sufficient drug concentrations in plasma in patients with altered/variable PK, e.g. critical illness, neutropenic sepsis • To optimize doses based on the pharmacokinetic/ pharmacodynamic (PK/PD) index for drugs which have an unpredictable relationship between dose and clinical outcome, i.e. drugs with nonlinear PK • To determine concentrations at physiologically protected sites, e.g CSF drug concentration in CNS infections • To check fluctuations in antimicrobial levels in patients on other agents with potential drug interactions • To ensure the rapid achievement of steady-state plasma concentration (Css,avg) of the salvage drug to prevent the development of heteroresistant populations especially in XDR organisms • To minimize toxicity in drugs with a narrow therapeutic range wherein serum concentration, efficacy and toxicity are correlated.

(PKPD: pharmacokinetic/pharmacodynamic; MIC: minimum inhibitory concen­ tration)

FIG. 1:  Desired PK/PD parameters for β-lactams in critically ill patients.

THERAPEUTIC DRUG MONITORING FOR BETA-LACTAMS—CURRENT DATA

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Utility of TDM for Beta-Lactams (BL) in an ICU setting has been studied extensively.3-6 The main aim of TDM for these antibiotics is to achieve appropriate PK/PD targets to ensure maximal efficacy rather than to monitor drug toxicity.2 Udy et al.7 observed that up to 82% of ICU patients with augmented renal clearance failed to achieve therapeutic concentrations of BLs with standard doses. On the other hand, potential drug accumulation and toxicity in case of reduced renal clearance is likely. Hence, standard BL dosing recommended for noncritically ill patients may be subtherapeutic or toxic for a septic patient. The PK/PD parameter that best guides the dosing of BLs is time above minimum inhibitory concentration (MIC) (T >MIC). This is the percentage of time of the dosage interval in which the serum level exceeds the MIC. With use of in vitro killing-curve studies, maximum killing is usually achieved at 3–4 times the MIC.8 Maintaining free BL concentration above the MIC (fT >MIC) for 40–70% of the dosing interval generally yields a good therapeutic response.9 It has been suggested however that to obtain a similar therapeutic response in a critically ill patient, higher exposures (100% fT >MIC) may be needed in view of immunological impairment and/or high inoculum effect10 as demonstrated in Figures 1 and 2. Roberts et al.10 attempted to determine whether BL antibiotic dosing in critically ill patients achieves concen­ trations associated with maximal activity and whether antibiotic concentrations affect patient outcome. Multiple BLs were studied (amoxicillin-clavulanate, ampicillin, cefazolin, cefepime, ceftriaxone, doripenem, meropenem and piperacillin-tazobactam). They measured free antibiotic

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(MIC: minimum inhibitory concentration)

FIG. 2:  Relation of positive clinical outcome with fT >MIC of β-lactams in critically ill patients.

concentrations at 50% (50% fT>MIC) and 100% (100% fT>MIC) of dosing interval and calculated PK/PD ratios (defined as ratio of measured antibiotic drug concentration to the MIC). In situations where MIC was not available, breakpoint values as determined by EUCAST guidelines were used in calculation of PK/PD ratio. Liquid chromatography method was used to measure drug levels for most of the BLs. For highly protein bound drugs (like cefazolin and ceftriaxone), free drug concentration was measured directly using ultrafiltration technique. They defined positive clinical outcome as completion of treatment course without change or addition of antibiotic therapy, and with no additional antibiotics commenced within 48 hours of cessation. They found that off the 248 patients treated for infection, 16% did not achieve 50% fT >MIC and these patients were 32% less likely to have a positive clinical outcome [odds ratio (OR), 0.68; p = 0.009). This reiterates the fact that PK changes in

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CHAPTER 36: Therapeutic Drug Monitoring for Beta-lactams and Colistin: Is it Ready for Prime Time? critically ill patient results in unpredictable drug levels which may consequently lead to treatment failure. In addition, they found that for the 50% fT >MIC and 100% fT >MIC data, higher PK/PD ratios were associated with higher likelihood of a positive clinical outcome. Mckinnon et al.11 studied the relationship between AUC/ MIC and T >MIC with clinical and microbiological outcomes in septic patients treated with cefepime and ceftazidime. They found that a PK/PD target of 100% fT >MIC as against fT >MIC lower than 100% and AUC/MIC >250 as against AUC/ MIC MIC for critically ill

Mckinnon et al.11

Cefepime, ceftazidime

Bacteremia and sepsis

AUC/MIC >250 and 100% fT >MIC in critically ill

Tam et al.4

Cefepime

Gram negative infections

Optimum bactericidal activity at 4 × MIC

Li et al.12

Meropenem

Lower respiratory tract infection

100% T >MIC

Roberts et al.16

Multiple

Critically ill

50–100%/4–5 × MIC

(PKPD: pharmacokinetic/pharmacodynamic; MIC: minimum concentration; AUC: area under the curve; ICU: intensive care unit)

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inhibitory

However, the absence of a prospective randomized controlled trial demonstrating either a clinical or an economic benefit of TDM for BLs is lacking. Among centers performing TDM for these drugs, there seems to be significant heterogeneity in the type of BL measured, drug assay methods and the patients selected. A chromatography-based method is required for analyzing BL concentrations. The pitfalls of this method are a relatively long turnaround time (6–24  hours), [compared to immunoassays for aminoglycosides and glycopeptides (30 min)], high cost and the need for skilled operators.17

THERAPEUTIC DRUG MONITORING OF COLISTIN—CURRENT DATA The polymyxins are concentration-dependent antibiotics with a narrow therapeutic window and dose-limiting nephrotoxicity. The free (unbound) area under the concentration-time curve (fAUC)/MIC is the PK/PD index that best predicts the activity of polymyxins against gramnegative bacilli. In other words, the higher the fAUC/MIC, the stronger the bactericidal effect. On the other hand, the higher the MIC of infecting bacteria (Fig. 3), higher is the fAUC required to attain the target relation. In vitro studies on polymyxins reveal rapid concentrationdependent killing against Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa, with a minimal postantibiotic effect at clinically achievable concentrations.18 However, despite the rapid initial killing, regrowth occurs quickly (as early as within 2 h of the initial exposure) leading to hetero-resistant strains. Amplification of these polymyxin-resistant subpopulations has been shown to play an important role in the rapid emergence of resistance. Additionally, inoculum effect has also been reported in vitro.19

(PKPD: pharmacokinetic/pharmacodynamic; MIC: minimum inhibitory concen­ tration; AUC: area under the curve; fAUC: area under the concentration–time curve)

FIG. 3:  The PK/PD index of polymyxins depicting reduced fAUC with rising MIC.

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FIG. 4:  Role of loading dose in achievement of colistin steady state concentrations.

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Polymyxins are available in two formulations. The prodrug colistimethate sodium (CMS)/polymyxin E has been found to take more than 36 hours to reach an adequate colistin Css,avg with standard dosing in patients with good renal function. In critically ill patients, significant interpatient variation in the Css,avg has been observed even among patients with similar CLCr and those receiving the same daily dose of CMS.18 This lag period can be partially overcome by using a loading dose as shown in Figure 4. In addition, little is currently understood about the PK of CMS and formed colistin in extravascular sites like the central nervous system. The distribution of colistin into the cerebral spinal fluid (CSF) has been found to be only 7% of the total serum colistin concentrations in patients without CNS infection and 11% in patients with external ventricular drain-associated ventriculitis (EVDV).20 Loading followed by higher than standard doses have been recommended in critically ill patients as well as immunosuppressed hosts in whom increased reliance on antimicrobial therapy to drive bacterial clearance is expected. However, higher doses carry a higher risk of toxicity. Polymyxin B (PMB) on the other hand is formulated as a sulfate salt, i.e. its active antibacterial form. The PK profile of PMB is thought to be relatively uncomplicated. However, compared with CMS, fewer studies have examined the pharmacokinetics of PMB following IV administration. Based on the above, TDM has been explored as a practical means to overcome these challenges. The case for TDM is even stronger for CMS than for PMB because of the greater interindividual variability. Although a number of microbiological assays have been developed (e.g. high-performance liquid chromatography, liquid chromatography–tandem mass spectrometry), these are difficult to interpret, more so for colistin because they are not able to differentiate between the colistin present in a plasma sample at the time of its collection and that formed in vitro by ongoing hydrolysis of CMS during the assay. Stringent procedures must be implemented to

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prevent ongoing conversion of CMS to colistin during the sample collection, storage and transportation to the TDM laboratory. These difficulties do not occur with PMB, as it is not administered as a prodrug.21 Despite these issues, as far back as 2007, the British National Formulary (BNF) had recommended serum colistin concentration monitoring especially in renal impairment, cystic fibrosis and neonates; with the target “peak” plasma concentration (~30 min after IV injection or infusion) of 10–15 mg/L (125–200 U/mL).22 Studies reveal that colistin concentration fluctuations are limited within a dosing interval, especially when administered three times daily. Hence, peak and trough concentrations are of less significance and a plasma concentration determined at any time would probably provide an appropriate estimate of Css,avg for the purposes of drug monitoring. However, sampling immediately before CMS dosing has been advised because CMS concentrations would then be minimal and the risk of colistin concentration overestimation resulting from postsampling CMS hydrolysis would, therefore, be considerably reduced.23 Small series and case reports have explored TDM as an optimization tool for colistin with variable results. Yamada et al.24 used liquid chromatography-tandem mass spectrometry for determination of colistin levels in a 56-year-old woman with multidrug resistant (MDR) Pseudomonas aeruginosa bloodstream infection. She responded to standard doses of colistin with negative blood cultures on day 8. However, her renal function progressively declined. Trough plasma levels of colistin were higher than expected, doses were reduced and renal function of the patient improved. Muders et al.25 studied five patients with MDR Acinetobacter baumannii sepsis. TDM was established to guide dosing with a target of constant colistin plasma troughlevels above 2 mg/L. Individual courses of CMS and colistin plasma levels showed a heterogeneous pattern and were not predictable even though individual dosing was adjusted to body weight and renal function respectively. Tafelski et al.26 described a case of MDR Acinetobacter brain abscess where TDM of serum and CSF was used to adjust doses of systemic and intraventricular colistin. Based on serially raised CSF concentrations, the intraventricular application interval was increased paralleled with adjustments in IV colistin which eventually lead to a good clinical and microbiological outcome. TDM in this case also helped in reducing manipulations of the EVD thus decreasing the risk of potential contamination during repeated application of the intraventricular antibiotic. Additionally, TDM may ensure that sufficient colistin peak levels combat developing heteroresistance and facilitate drug diffusion into the tissues.  Despite the above evidence, few studies have failed to show the benefit of TDM for colistin on clinical outcome.

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CHAPTER 36: Therapeutic Drug Monitoring for Beta-lactams and Colistin: Is it Ready for Prime Time? A prospective observational cohort study by Sorli et al.27 was performed on 91 patients infected by XDR P. aeruginosa sepsis treated with IV CMS. Colistin plasma levels at steady-state (Css) were recorded. The primary and secondary end points were clinical cure and 30-day all-cause mortality. Colistin plasma levels were not observed to be related to clinical cure or early mortality. The patients who developed clinical failure had higher APACHE II indices. Additionally, they had achieved higher Css values and were more likely to have developed AKI than patients with clinical cure thus making a case for TDM to reduce toxicity. The PK variables of PMB have not been as extensively scrutinized as colistin. Accurate means of measurements of PMB concentration with high performance liquid chroma­ tography-mass spectrometry (LC-MS) assays have been developed. However, little is known about the application of TDM to PMB.

CONCLUSION While we clutch at straws in eager anticipation of novel antibiotics against the gram-negative “superbugs”, every effort must be made to optimize the clinical use of the salvage agents available, thus maximizing their efficacy while minimizing the emergence of resistance and toxicity. Although, much data does exist on the benefits of TDM as an effective tool in this regard, no large randomized trials exist to support its true impact on clinical outcome and mortality till date. TDM is relatively uncharted territory in our country. Given the current climate of progressive and unrelenting “antimicrobial drought”, TDM unequivocally merits our urgent attention and deeper understanding with clinical studies on its real-time application. We believe it is prime time.

REFERENCES

1. Wong G, Sime FB, Lipman J, et al. How do we use therapeutic drug monitoring to improve outcomes from severe infections in critically ill patients? BMC Infect Dis. 2014;14:288. 2. Ghiculesco R. Abnormal laboratory results: Therapeutic drug monitoring: which drugs, why, when and how to do it. Aust Prescr. 2008;31(2):42-4. 3. Sime FB, Roberts MS, Peake SL, et al. Does beta-lactam pharmacokinetic variability in critically ill patients justify therapeutic drug monitoring? A systematic review. Ann Intensive Care. 2012;2(1):35. 4. Tam VH, McKinnon PS, Akins RL, et al. Pharmacodynamics of cefepime in patients with Gram-negative infections. J Antimicrob Chemother. 2002;50(3):425-8. 5. Roberts JA, Ulldemolins M, Roberts MS, et al. Therapeutic drug monitoring of beta-lactams in critically ill patients: proof of concept. Int J Antimicrob Agents. 2010;36(4):332-9. 6. Pea F, Viale P, Cojutti P, et al. Dosing nomograms for attaining optimum concentrations of meropenem by continuous infusion in critically ill patients with severe gram-negative infections: a pharmacokinetics/pharmacodynamicsbased approach. Antimicrob Agents Chemother. 2012;56(12):6343-8.

7. Udy AA, Varghese JM, Altukroni M, et al. Subtherapeutic initial b-lactam concentrations in selected critically ill patients: association between augmented renal clearance and low trough drug concentrations. Chest. 2012;142(1):30-39. 8. Craig WA, Ebert S. Killing and regrowth of bacteria in vitro: a review. Scand J Infect Dis Suppl. 1990;74:63-70. 9. Craig WA. Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporins. Diagn Microbiol Infect Dis. 1995;22(1-2):89-96. 10. Roberts JA, Paul SK, Akova M, et al. DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014;58(8):1072-83. 11. McKinnon PS, Paladino JA, Schentag JJ. Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T >MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections. Int J Antimicrob Agents. 2008;31(4):345-51. 12. Li C, Du X, Kuti JL, et al. Clinical pharmacodynamics of meropenem in patients with lower respiratory tract infections. Antimicrob Agents Chemother. 2007;51(5):1725-30. 13. Pea F, Viale P, Damiani D, et al. Ceftazidime in Acute Myeloid Leukemia Patients with Febrile Neutropenia: Helpfulness of Continuous Intravenous Infusion in Maximizing Pharmacodynamic Exposure. Antimicrob Agents Chemother. 2005;49(8):3550-53. 14. Nyhlén A, Ljungberg B, Nilsson-Ehle I. Pharmacokinetics of meropenem in febrile neutropenic patients. Swedish Study Group. Eur J Clin Microbiol Infect Dis. 1997;16(11):797-802. 15. Sime F, Roberts MS, Warner MS, et al. Altered Pharmacokinetics of piperacillin in febrile neutropenic patients with hematological malignancy. Antimicrob Agents Chemother. 2014;58(6):3533-7. 16. Roberts JA, Norris R, Paterson DL, et al. Therapeutic drug monitoring of antimicrobials. Br J Clin Pharmacol. 2012;73(1):27-36. 17. Huttner A, Harbarth S, Hope WW, et al. Therapeutic drug monitoring of the β-lactam antibiotics: what is the evidence and which patients should we using it for? J Antimicrob Chemother. 2015;70(12):3178-83. 18. Zavascki A. Polymyxins for the treatment of extensively-drug-resistant Gramnegative bacteria: from pharmacokinetics to bedside. Expert Rev Anti Infect Ther. 2014;12(5):531-3. 19. Tran TB,Velkov T, Nation RL, et al. Pharmacokinetics/pharmacodynamics of colistin and polymyxin B: are we there yet? Int J Antimicrob Agents. 2016;48(6):592-7. 20. Ziaka M, Markantonis SL, Fousteri M, et al. Combined intravenous and intraventricular administration of colistin methane sulfonate in critically ill patients with central nervous system infection. Antimicrob Agents Chemother. 2013;57(4):1938-40. 21. Nation R, Velkov T, Li J. Colistin and Polymyxin B: Peas in a Pod, or Chalk and Cheese? Clin Infect Dis. 2014;59(1):88-94. 22. BNF 53. London: BMJ and RPS Pub.; 2006. 23. Couet W, Grégoire N, Marchand S, et al. Colistin pharmacokinetics: the fog is lifting. Clin Microbiol Infect. 2012;18(1):30-39. 24. Yamada T, Ishiguro N, Oku K, et al. Successful colistin treatment of multidrugresistant Pseudomonas aeruginosa infection using a rapid method for determination of colistin in plasma: usefulness of therapeutic drug monitoring. Biol Pharm Bull. 2015;38(9):1430-33. 25. Muders T, Dahmen F, Weibrich C, et al. Therapeutic drug monitoring of colistin in multidrug-resistant Acinetobacter Baumannii-related sepsis. Am J Respir Crit Care Med. 2014;189:A3107. 26. Tafelski S, Wagner L, Angermair S, et al. Therapeutic drug monitoring for colistin therapy in severe multiresistant Acinetobacter intracerebral abscess: A single case study with high-dose colistin and review of literature. SAGE Open Med Case Rep. 2017;5:2050313X17711630. 27. Sorlí L, Luque S, Segura C, et al. Impact of colistin plasma levels on the clinical outcome of patients with infections caused by extremely drug-resistant Pseudomonas aeruginosa. BMC Infect Dis. 2017;17(1):11.

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CHAPTER

Steroids in Septic Shock: What do the Recent Studies Tell Us? Narendra Rungta

INTRODUCTION Steroids have been the most discussed group of medicines in any intensive care unit (ICU). Role of steroids in septic shock has been one of the hottest issues for almost 100 years. It is general understanding that steroid use in septic shock is associated with improvement in hemodynamics, organ function and reduced ICU and hospital stay because of their anti-inflammatory effects. However, despite significant research work during last 25 years, use of steroids in septic shock remains a dilemma. The data accumulated so far and the various guidelines have not answered the question clearly. Therefore, it is important to review the recent data and discuss the role of steroids in septic shock. We will be mostly confined to discussing data since beginning of the current century

STEROID PHYSIOLOGY IN SEPSIS Sepsis influences body systems and metabolism in many ways which may have adverse impact on adrenal system. Some of these may be direct myocardial depression leading to reduced left ventricular ejection fraction (LVEF) almost in 50% cases. Other mechanisms like autonomic dysregulation, mitochondrial dysfunction and microvascular dysfunction may also be adding to it. Membrane expression of betareceptors is also reduced in sepsis leading to disturbed heart rate versus vagal action (catecholamine seems to be favoring bacterial growth and their virulence in sepsis and exogenous catecholamines may make things worse. Adrenal stimulation increases insulin resistance and hyperglycemia. Cortisol effects may be directly or indirectly responsible for many physiological functions in body which may be: • Maintenance of effective blood volume through activation of mineralocorticoid receptor activity and sodium reten­ tion at renal level • Retention of sodium and water in the interstitium of the smaller blood vessels leading to maintenance of peripheral vascular resistance

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• Maintain microcirculation • Maintain and enhance contractility of blood vessels and thus blood pressure in response to Alpha agonists as modulation of alpha-agonist receptor second messenger and adenosine triphosphate sensitive K+ channels • They inhibit nitric oxide expression at renal cortex level thus ensure good oxygen supply to kidneys • Attenuate brain dysfunction in sepsis by maintaining the blood brain barrier. A large number of studies have been published during last 100 years. Diljani Annane has been one of the largest contributors to the data on this subject. We take you through the journey of this data during last 20 years

Clinical Trials Annane et al. (2002) published a very well received study published in JAMA using low-dose hydrocortisone and fludrocortisone.1 They studied 229 patients with the hypothesis that there is over all suppression of adrenal activity in patients with sepsis and they respond much poorly than nonseptic patients to corticotrophin. They reported survival benefit to the tune of 10% (63% deaths in non-hydrocortisone group to 53% in patients receiving hydrocortisone). This study made a change in practice of physicians across the globe and also formed the basis of the SSC guidelines published in 2004,2 which recommended low-dose hydrocortisone 50 mg 6 hourly and fludrocortisone in patients of septic shock. They also recommended corticotrophin stimulation test in such patients. They sighted two studies by two groups Cronine et al. (1995, CCM) and Wheeler et al. (1999, NEJM) who had reported that highdose hydrocortisone did not help in septic shock and in fact could do more harm. Annane et al. (2004) authored Cochrane systemic review on corticosteroids for treating severe sepsis and septic shock.3 They identified 25 studies with a long course of low dose corticosteroids significantly reduced 28‐day mortality, increased the proportion of shock reversal by day 7 , reduced

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CHAPTER 37: Steroids in Septic Shock: What do the Recent Studies Tell Us? Sepsis‐related Organ Failure Assessment (SOFA) score by day 7 and survivors’ length of stay in the intensive care unit without inducing gastro-duodenal bleeding, superinfection or neuromuscular weakness. Corticosteroid increased the risk of hyperglycemia. They concluded that overall, corticosteroids did not change mortality in severe sepsis and septic shock. A long course of low dose corticosteroids reduced 28‐day mortality without inducing major complications; metabolic disorders were increased. Sprung et al. the Corticus Group published their data on the topic of hydrocortisone therapy for patients with septic shock.4 They performed corticotrophin test in a cohort of patient of which 233 were non-responders. The non-responders did not show any mortality difference at 28 days. The corticotrophin responders also had a similar outcome (28.8% in the hydrocortisone group and 28.7% in the placebo group, p = 1.00). At 28 days, 86 of 251 patients in the hydrocortisone group (34.3%) and 78 of 248 patients in the placebo group (31.5%) had died (p = 0.51). The shock reversal was quicker in the hydrocortisone group but they had more episodes of superinfection, including new sepsis and septic shock. The conclusion was that in patients with septic shock hydrocortisone did not improve survival or reversal of shock in the overall patient population or nonresponders to corticotrophin. In patients with septic shock, either overall or in patients who did not have a response to corticotrophin, although hydrocortisone hastened reversal of shock in patients in whom shock was reversed. The Cochrane review on this topic was published in 2010. It included data from 15 trials of 2022 subjects performed between 1955 and 2002, a variety of treatment protocols in terms of dosage and duration. Corticosteroids yielded no patient-oriented benefit. There was no statistically significant difference in mortality between the control group and those who received corticosteroids. This was true regardless of the dosing regimen or duration of treatment. Likewise, corticosteroids were not associated with harm. The Cochrane Review (2010) also had a subgroup analysis of five studies involving 465 subjects that tested “low-dose” corticosteroids (5 days). In this subgroup there were statistically significant improvements in 28-day all cause mortality (ICU mortality and hospital mortality) with corticosteroids. On the basis of this analysis the Cochrane Review concluded that sufficient evidence to recommend low dose, long course corticosteroid therapy for septic shock. The trials were questioned in terms of being underpowered and less than adequate subjects in 4 out of 5 studies.5, 6

PROGRESS Registry7 The PROGRESS (Promoting Global Research Excellence in Severe Sepsis) cohort study of severe sepsis was analyzed to study the baseline characteristics and outcome of patients

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treated with low-dose corticosteroids (LDC : equivalent or lesser potency to hydrocortisone 50 mg six-hourly plus 50 μg 9-alpha-fludrocortisone) and use of vasopressors. 79.8% (7,160/8,968) of patients received vasopressors, and 34.0% (3,051/8,968) of patients received LDC. Regional use of LDC was highest in Europe (51.1%) and lowest in Asia (21.6%). 14.2% of patients on LDC were not receiving any vasopressor therapy. LDC patients were older, had more co-morbidities and higher disease severity scores, and a greater hospital mortality rate than in the non-LDC group (58.0% versus 43.0%; p 5 days ) • There are no contraindications to steroid use.

REFERENCES













1. Annane D, Sébille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288(7):862-71. 2. Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign Management Guidelines Committee. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004;32(3):858-73. 3. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids for treating severe sepsis and septic shock. Cochrane Database. Syst Rev. 2004;(1):CD002243. 4. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358(2):111-24. 5. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA. 2009;301(22):2362-75. 6. Annane D. Corticosteroids for sepsis: registry versus Cochrane systematic review! Crit Care. 2010;14(4):185. 7. Beale R, Janes JM, Brunkhorst FM, et al. Global utilization of low-dose corticosteroids in severe sepsis and septic shock: a report from the PROGRESS registry. Crit Care. 2010;14(3):R102. 8. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids for treating sepsis. Cochrane Database Syst Rev. 2015;(12):CD002243. 9. Dellinger RP, Levy MM, Rhodes A, et. al. Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39(2):165-228. 10. Rhodes A, Evans LE, Alhazzani W, et. al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-77. 11. Gibbison B, López-López JA, Higgins JP, et al. Corticosteroids in septic shock: a systematic review and network meta-analysis. Crit Care. 2017;21(1):78. 12. Venkatesh B, Finfer S, Cohen J, et al. ADRENAL Trial Investigators and the Australian–New Zealand Intensive Care Society Clinical Trials Group. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018;378(9):797-808.

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CHAPTER

Role of Vitamin C in Septic Shock Anirban Hom Choudhuri, Bhuvna Ahuja

INTRODUCTION The term “sepsis” originates from a Greek word “sipsi” meaning “to make rotten” as it was originally believed to be the product of blood putrefaction. The concept prevailed till the 19th century when Leyden propounded that it was not putrefied blood but a toxic substance in the air that actually caused sepsis. Much after this, the infective cause of sepsis was mooted by Ignaz Semmelweis (1818–65) based upon his observation on puerperal sepsis in the Vienna General Hospital. Finally, Hugo Schottmuller formulated the infectivity based definition of sepsis by stating that “sepsis is present if a focus has developed from where pathogenic bacteria, constantly or periodically, invade the bloodstream in such a way that this causes subjective and objective symptom”.1,2 Although, the mechanisms responsible for triggering sepsis and septic shock are a subject of debate and research, TABLE 1

many evidences point toward the role of proinflammatory mediators and cytokines in their causation and subsequent progression to multiorgan failure (MOF). The bigger concern is, however, the death occurring even after an initial improvement following resuscitative therapies. This death may be caused by progressive microvascular dysfunction induced by various cytokines and inflammatory mediators and is always a difficult therapeutic target. The focus of the adjuvant therapies for sepsis has been toward downregulating and modulating the inflammatory responses. Although, no major breakthrough has been achieved as yet, expectations have been kept afloat by experimentation with new drugs and molecules. The Table 1 shows some findings with newer drugs and molecules in sepsis in the recent time.3,4 The recognition of vitamin C as an antioxidant and its key role as a cofactor in numerous biochemical reactions

Studies on new drugs in sepsis and their observations.

Name and year

Molecule

Observations

Reinhart K (2001)

Anti-TNF-α

Only partially effective in patients with sepsis

Lv S (2014)

Anti-TNF-α

• Patients with severe sepsis (before shock) → immunotherapy with anti-TNF-α monoclonal antibodies reduces overall mortality • In patients with shock or high levels of IL-6 (>1,000 pg/mL) → anti-TNF-α therapy may improve survival

Cochrane Database (2002) IVIG

Polyclonal IVIG significantly reduced mortality and is a promising adjuvant in the treatment of sepsis and septic shock

Savva A (2013)

TLR (toll-like receptor) therapy

Anti-TLR4 and anti-TLR2 approaches have a strong potential for prevention and intervention in infectious diseases, notably sepsis

Dhainaut (2009)

Activated protein C (xigris)

Lack of efficacy and an increased incidence of bleeding (drug withdrawn)

Dinarello CM

IL-1

Monotherapy blocking IL-1 activity in a broad spectrum of inflammatory syndromes results in a rapid and sustained reduction in disease severity

Vitamin C

–

IL-10

Recombinant human IL-10 significantly improved survival and lengthened the therapeutic window for rescue surgery in experimental mice

Latifi SQ

(IL: interleukin; IVIG: intravenous immunoglobulin; TNF-α: tumor necrosis factor-alpha)

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SECTION 3: Infection/Antibiotic/Sepsis/Infection Control is not new. But the possibility of its use as an adjuvant therapy for sepsis was explored only when its blood level was detected to be low in septic patients.5 Fowler et al. demonstrated a prompt reduction in the Sequential Organ Failure Assessment (SOFA) score and a concurrent decrease in the values of C-reactive protein (CRP) and procalcitonin (PCT) after using intravenous vitamin C in septic patients.5 Zabet et al. demonstrated a reduction in the norepinephrine dose after administering high dose of intravenous ascorbic acid (25 mg/kg every 6 hourly for 72 h) in a group of surgical critically ill patients.6 More recently, Marik et al. reported a mortality reduction and decreased multiorgan dysfunction syndrome (MODS) with the combined intravenous use of vitamin C, corticosteroids and thiamine in patients with severe sepsis and septic shock.7 The results of the published trials are encouraging and more results from ongoing trials are imminent.8

MITOCHONDRIAL DYSFUNCTION IN SEPSIS Mitochondria are the primary site for production of adenosine triphosphate (ATP) in the cells by oxidative phosphorylation. Mitochondrial damage occurs in response to oxidative and nitrosative stress in sepsis. Although it is not clear whether this damage is actually the cause or effect of stress. The depletion of ATP affects calcium homeostasis leading to early apoptosis and cell death. It has been found that the skeletal muscle antioxidant reserves can diminish sufficiently within 48 hours of ICU admission to cause

cell death.9 To this effect, ascorbic acid appears to have a protective role by limiting mitochondrial injury due to its antioxidant effect. Figure 1 shows the formation of ATP via the flow of electrons in the electron transport chain and Figure 2 shows the generation of mitochondrial reactive oxygen species (ROS).

ANTIOXIDANT EFFECTS OF VITAMIN C In sepsis, the nature and extent of endothelial dysfunction strongly influence the occurrence of MODS and measures to prevent such dysfunction reduce mortality. The cause of this endothelial dysfunction is the unopposed action of the ROS due to oxidative stress. There is also a decrease in the endothelial nitric oxide synthase (eNOS) activity with decreased endothelial nitric oxide (NO) production. The decreased endothelial NO production leads to decreased microcirculatory flow, increased platelet aggregation, and increased platelet leukocyte adhesion. All these can result in the progression from sepsis to septic shock and MOF. The beneficial effects of vitamin C in reducing these effects of ROS are many. The direct ability of vitamin C to scavenge ROS like superoxide and peroxynitrite and activate other ROS scavengers, like glutathione and α-tocopherol is an important in preventing endothelial damage. Vitamin C also helps in the recovery of tetrahydrobiopterin from its oxidized form thereby increasing endothelial NO production and improving microvascular perfusion.

[CoQ: coenzyme Q; Cyt C: cytochrome C; NAD: nicotinamide adenine dinucleotide (NAD+ oxidised form, NADH reduced form); FADH; reduced form of flavin adenine dinucleotide; ADP: adenosine diphosphate; SOD: superoxide dismutase ; ATP: adenosine triphosphate; GSH: glutathione]

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FIG. 1:  Schematic diagram showing generation of adenosine triphosphate (ATP) via flow of electrons along five molecular complexes of electron transport chain. Electron transfer results in reciprocal transfer of protons, generating mitochondrial membrane potential. Reactive oxygen species are generated as by product of the incomplete four electron reduction of molecular oxygen to water, final electron accepted in the process of ATP production.

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CHAPTER 38: Role of Vitamin C in Septic Shock

(Cyt C: cytochrome C; PTP: permeability transition; mtDNA: mitochondrial deoxyribonucleic acid; ROS: reactive oxygen species)

FIG. 2:  Diagram showing mitochondrial reactive oxygen species (ROS) production. Excessive ROS production can lead to oxidative damage to mitochondrial deoxyribonucleic acid proteins and membrane, causing mitochondrial dysfunction. Oxidative damage leads to release of cytochrome C molecule which further leads to apoptosis and necrosis causing disease state and aging. ROS is also helpful in calcium and iron homeostasis and involved in various cell signaling.

VASOPRESSOR SYNTHESIS AND VITAMIN C Vasopressin is a neurohypophyseal hormone which is produced in the hypothalamus and stored in the posterior pituitary gland. It is released in the blood in response to decreased intravascular volume, pressure or increased plasma osmolality. It acts on the vascular smooth muscles and the collecting ducts of the kidneys to cause vasoconstriction and increased water retention. It also induces the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary and helps in the synthesis of corticosteroids in response to stress. In sepsis, vasopressin levels increase dramatically during the early phase but falls in the later phase when the patient progresses to septic shock. Vitamin C acts as a cofactor for the enzyme peptidylglycine α-amidating monooxygenase (PAM) which is necessary for the synthesis of vasopressin. Animal studies confirm that a decrease in the urinary volume and an increase in the sodium excretion along with an increase in the plasma vasopressin and oxytocin levels occur after intravenous ascorbic acid administration.10

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Other than vasopressin, there is also a decline in the synthesis of epinephrine and dopamine in sepsis. Vitamin C is required in the catecholamine biosynthetic pathway in two major steps. In the first step, it acts as a cofactor for the enzyme dopamine β-hydroxylase which converts dopamine into epinephrine. In the second step, it acts as the ratelimiting factor in the synthesis of L-DOPA, the precursor of dopamine.

IMMUNITY AND VITAMIN C The nature and extent of immune response play a key role in sepsis progression. A regulated immune response is beneficial whereas an unregulated immune response is harmful for the progression. Vitamin C has been found to be protective in enhancing certain immune functions like chemotaxis, lymphocytic proliferation and oxidative killing of bacteria. This probably follows the attainment of high concentration of vitamin C in the leucocytes. Although, a few studies have demonstrated the bacteriostatic effects of vitamin C on certain bacteria like Klebsiella, the significance of these effects in human beings is still not clear.

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SECTION 3: Infection/Antibiotic/Sepsis/Infection Control

SEPTIC CARDIOMYOPATHY There is an association between increased cardiomyocyte oxidative stress and the development of septic cardio­ myopathy. This oxidative damage to cardiac myocyte is accompanied with β-adrenoceptor downregulation and altered calcium homeostasis. Vitamin C significantly decreases myocardial oxidant injury, attenuates apoptosis and maintains functional integrity of mitochondria by limiting calcium overload and inhibiting opening of the mitochondrial permeability transition pore (mPTP).

PHARMACOKINETIC AND PHARMACODYNAMICS OF ASCORBIC ACID Unlike other mammals, human beings are unable to synthesize vitamin C in their liver and are dependent on their diet for its supply. The maximal absorption of vitamin C occurs with a daily dose of 500–100 mg through specific sodium-dependent vitamin C transporter 1 (SVCT1) in the intestine which is then circulated in the blood mainly in unbound form to achieve a free concentration of 40– 60  µmol/L. A level of 30% of body surface area), 37 patients were randomized to receive vitamin C at high doses of 4–5 g/h for the first 24 hours after

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admission as compared to patients receiving usual care. The patients randomized to receive vitamin C required less fluid resuscitation and had fewer days on mechanical ventilation.13 In another phase I, double-blind RCT, conducted in 2014 in US, 24 patients admitted to the medical intensive care unit (ICU) with severe sepsis were randomized to receive placebo or IV infusion of vitamin C (low dose group 50 mg/kg/24 h or high dose group 200 mg/kg/24 h) every 6 hours for 4 days. Each group had eight patients. Patients receiving vitamin C

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CHAPTER 39: Vitamin C in Septic Shock: Is it the Holy Grail? had lesser organ dysfunction and lower levels of biomarkers of inflammation and endothelial injury.14 There were no safety issues. In a study (double-blind RCT) conducted in 2016 in Iran, 24 surgical critically ill patients with diagnosis of septic shock on vasopressors were randomized to receive placebo or IV infusions of vitamin C (1.5–2 g every 6 hours). Patients receiving vitamin C had significantly reduced requirement of vasopressors and lower 28-day mortality.12 Recent surge in the use of vitamin C in patients with sepsis and septic shock has peaked with the publication of a trial by Marik et al. in 2017 in US. It was a retrospective beforeafter clinical study. Forty seven consecutive patients of sepsis received vitamin C (1.5 g IV every 6 hours), hydrocortisone (50 mg IV every 6 hours) and thiamine (200 mg IV every 12 hours). These patients were enrolled over a period of 7  months. These patients were compared with 47 patients (with matched baseline characteristics) admitted to their ICU in the previous 7 months. There was a significant reduction of organ dysfunction (as denoted by their SOFA scores), vasopressor requirement, and hospital mortality (8.5% vs. 40.4%) in the treatment group as compared to the historical control group.11 The above trial has faced criticism due to its design (small sample size, presence of historical controls and not concurrent controls, single center). These limitations of the trial make it low quality evidence and the results of the trial should not be used to influence management of patients with sepsis and septic shock.25,26 Another recent (2018) retrospective before-after cohort study from South Korea, compared 53 patients with severe pneumonia who were admitted to medical ICU, and who received thiamine, ascorbic acid, and hydrocortisone combination to patients admitted to that ICU previously with similar illness (historical controls). The patients were matched by propensity scoring. The study group had significant reduction in mortality.27 Again design limitations of the trial (small sample size, single center, nonconsecutive and nonconcurrent historical control patients) prevent broader application of these results.28 A recent systematic review (2018) combined the results of five clinical trials (four RCTs and one retrospective review) conducted in critically ill patients (including some of the above), which had supplemented only vitamin C in these cases. They found no reduction in mortality but vitamin C supplementation in these patients had a vasopressor sparing effects and a reduced need for mechanical ventilation.29

CURRENT STATE OF PRACTICE REGARDING THE USE OF VITAMIN C IN SEPSIS Opinion is divided amongst critical care experts regarding the use of vitamin C in this setting. Many experts and hospitals are already using these combinations of vitamin C, hydrocortisone and thiamine (HAT), while others are calling for more evidence (large RCTs, multicentric, large

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sample size).30-34 There have been no guidelines which have incorporated the results of these trials and made recommendations regarding the use of this combination of drugs. Currently, there are approximately nine prospective RCTs (VICTAS, ACTS, HYVCTTSSS and other trials) going on which will shed further light on the subject.28 Till then the use of vitamin C in patients with sepsis and septic shock is still open to individual interpretation.

CONCLUSION Use of vitamin C in critically ill patients has sound physio­ logical basis and has been adequately demonstrated to be beneficial in animals.35 Its use in humans has been beneficial in small groups of critically ill patients. Critical care experts are divided in their opinion regarding the use of this therapy. Planned future research will lend further evidence.

REFERENCES

















1. Padayatty SJ, Katz A, Wang Y, et al. Vitamin C as an antioxidant: Evaluation of its role in disease prevention. J Am Coll Nutr. 2003;22:18-35. 2. Sorice A, Guerriero E, Capone F, et al. Ascorbic acid: Its role in immune system and chronic inflammation diseases. Mini Rev Med Chem. 2014;14:444-52. 3. Tyml K. Vitamin C and microvascular dysfunction in systemic inflammation. Antioxidants 2017;6:E49. 4. Schorah CJ, Downing C, Piripitsi A, et al. Total vitamin C, ascorbic acid, and dehydroascorbic acid concentrations in plasma of critically ill patients. Am J Clin Nutr. 1996;63:760-5. 5. Long CL, Maull KI, Krishnan RS, et al. Ascorbic acid dynamics in the seriously ill and injured. J Surg Res. 2003;109:144-8. 6. Metnitz PG, Bartens C, Fischer M, et al. Antioxidant status in patients with acute respiratory distress syndrome. Intensive Care Med. 1999;25:180-5. 7. Polidori MC, Mecocci P, Frei B. Plasma vitamin C levels are decreased and correlated with brain damage in patients with intracranial hemorrhage or head trauma. Stroke. 2001;32:898-902. 8. Fain O, Paries J, Jacquart B, et al. Hypovitaminosis C in hospitalized patients. Eur J Intern Med. 2003;14:419-25. 9. Fleischmann C, Scherag A, Adhikari NK, et al. Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am J Respir Crit Care Med. 2016;193(3):259-72. 10. Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45(3):486-552. 11. Marik PE, Khangoora V, Rivera R, et al. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: A retrospective before-after study. Chest. 2017;151:1229-38. 12. Zabet MH, Mohammadi M, Ramezani M, et al. Effect of high dose ascorbic acid on vasopressor’s requirement in septic shock. J Res Pharm Pract. 2016;5:94100. 13. Tanaka H, Matsuda T, Miyagantani Y, et al. Reduction of resuscitation fluid volumes in severely burned patients using ascorbic acid administration: A randomized, prospective study. Arch Surg. 2000;135:326-31. 14. Fowler AA, Syed AA, Knowlson S, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014;12:32. 15. de Grooth HJ, Manubulu-Choo WP, Zandvliet AS, et al. Vitamin C pharma­ cokinetics in critically ill patients: A randomized trial of four IV regimens. Chest. 2018;153:1368-77. 16. Ferrón-Celma I, Mansilla A, Hassan L, et al. Effect of vitamin C administration on neutrophil apoptosis in septic patients after abdominal surgery. J Surg Res. 2009;153:224-30.

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SECTION 3: Infection/Antibiotic/Sepsis/Infection Control 17. Kahn SA, Beers RJ, Lentz CW. Resuscitation after severe burn injury using high-dose ascorbic acid: A retrospective review. J Burn Care Res. 2011;32: 110-7. 18. Nathens AB, Neff MJ, Jurkovich GJ, et al. Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann Surg. 2002;236:814-22. 19. Crimi E, Liguori A, Condorelli M, et al. The beneficial effects of antioxidant supplementation in enteral feeding in critically ill patients: A prospective, randomized, double-blind, placebo-controlled trial. Anesth Analg. 2004;99:857-63. 20. Collier BR, Giladi A, Dossett LA, et al. Impact of high-dose antioxidants on outcomes in acutely injured patients. J Parenter Enteral Nutr. 2008;32: 384-8. 21. Berger MM, Soguel L, Shenkin A, et al. Influence of early antioxidant supplements on clinical evolution and organ function in critically ill cardiac surgery, major trauma, and subarachnoid hemorrhage patients. Crit Care. 2008;12:R101. 22. Moser MA, Chun OK. Vitamin C and heart health: A review based on findings from epidemiologic studies. Int J Mol Sci. 2016;17:E1328. 23. Hercberg S, Galan P, Preziosi P, et al. The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Arch Intern Med. 2004;164:2335-42. 24. Greenberg ER, Baron JA, Tosteson TD, et al. A clinical trial of antioxidant vitamins to prevent colorectal adenoma. Polyp Prevention Study Group. N Engl J Med. 1994;331:141-7. 25. Available from: wikijournalclub.org/wiki/Hydrocortisone,_Vitamin_C,_and_ Thiamine_in_Severe_Sepsis_and_Septic_Shock. Accessed December 30 2018. 26. Blythe R, Cook D, Graves N. Scepticaemia: The impact on the health system and patients of delaying new treatments with uncertain evidence: A case study of the sepsis bundle. F1000Res 2018;7:500.

27. Kim W-Y, Jo E-J, Eom JS, et al. Combined vitamin C, hydrocortisone, and thiamine therapy for patients with severe pneumonia who were admitted to the intensive care unit: Propensity score based analysis of a before-after cohort study. J Crit Care. 2018;47:211-8. 28. Moskowitz A, Andersen LW, Huang DT, et al. Ascorbic acid, corticosteroids, and thiamine in sepsis: A review of the biologic rationale and the present state of clinical evaluation. Critical Care. 2018;22:283. 29. Zhang M, Jativa DF. Vitamin C supplementation in the critically ill: A systematic review and meta-analysis. SAGE Open Med. 2018;6:2050312118807615. 30. Harris R. Doctor turns up possible treatment for deadly sepsis NPR2017. Updated 3/23/2017. Available from: http://www.npr.org/sections/ healthsho ts/2017/03/23/521096488/doctor-turns-up-possible-treatment-fordeadlysepsis. Accessed December 30 2018. 31. Harris R. Did an IV cocktail of vitamins and drugs save this lumberjack from sepsis. National Public Radio; 2018. Podcast. https://www.npr.org/sections/ health-shots/2018/02/21/583845485/did-an-iv-cocktail-of-vitaminsanddrugs- save-this-lumberjack-from-sepsis. Accessed December 30 2018. 32. Farkas J. Metabolic sepsis resuscitation: the evidence behind vitamin C 2017 Available from: https://emcrit.org/pulmcrit/metabolic-sepsis-resuscitation/. Accessed December 30 2018. 33. Mallemat H. The Marik protocol: have we found a “cure” for severe sepsis and septic shock? 2017. Available from: http://rebelem.com/the-marik-protocolhavewe- found-a-cure-for-severe-sepsis-and-septic-shock/. Accessed December 30 2018. 34. Faust J. The skeptics guide to EM; 2017. Podcast. Available from: http:// thesgem.com/2017/04/sgem174-dont-believe-the-hype-vitamin-ccocktailfor-sepsis/. Accessed December 30 2018. 35. Nabzdyk CS, Bittner EA. Vitamin C in the critically ill - indications and controversies. World J Crit Care Med. 2018;7(5):52-61.

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CHAPTER

Candida auris: The Emerging Threat Arunaloke Chakrabarti, Manisha Biswal

INTRODUCTION It is now a global concern that Candida auris, a yeast, is behaving like bacteria, as the organism is—(1) easily developing multiple antifungal resistance, (2) transmitted quickly in hospital environment, (3) causing serious infection and (4) associated with high mortality. The concern is more as the organism cannot be identified easily by usual commercial phenotypic system practiced largely in the clinical laboratories. It requires sophisticated procedures like matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) or DNA sequencing for identification. The presence of the organism first came to light in 2009 while the fungus was isolated from ear infection of a Japanese woman,1 and within a decade, it has been reported causing invasive infection in many countries of five continents.2-5 The peculiar characteristics of the organism have made it a “superbug” and have raised red alert globally to control the infection.6,7

EPIDEMIOLOGY AND RISK FACTORS Due to the sudden appearance of the fungus, scientists revisited the culture collections in their laboratories methodically to identify the earliest appearance of the species and they could find the first appearance of the fungus in 1996 from blood of a hospitalized patient in South Korea.2 The fungus has been reported from over 25 countries on five continents: Africa (South Africa), Asia (China, India, Israel, Japan, Kuwait, Oman, Pakistan, Singapore, South Korea), Europe (Germany, Norway, Spain, UK), North America (Canada and USA), South America (Colombia and Venezuela).8-10 From India the first case was reported in March 2011 from a tertiary care in Kolkata. Subsequently, it spread quickly across the country. In a study on candidemia in Indian intensive care units (ICUs), the fungus had been identified from blood of 19 of 27 ICUs.11 C. auris infection occurs in both sporadic as well as epidemic form. Outbreaks of C. auris infections have been reported in healthcare facilities

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only.6,12 One large outbreak involving 382 cases occurred in a cardiovascular unit of a hospital in UK in 2016.13 Following the outbreak 2,246 patients were screened at admission for C. auris colonization at the same hospital and found only one colonized patient. The observation indicates C. auris harbors in hospital environment and not in the community, though the source of organism in the hospital is not known. Till date, >750 clinical isolates have been reported from all over the world, and majority of the isolates are from India (243) followed by USA (232) and UK (15). But the figure may be grossly underestimated, as diagnostic laboratories in developing countries do not generally speciate Candida isolates. Even when they speciate, commercial phenotypic system is largely being utilized, which cannot identify C. auris. The majority of the laboratories in developed world also use commercial phenotypic system for identification of yeast and possibly under-reporting the agent. The reports on C. auris infection are largely from blood and deep-seated infections compared to urine and superficial sites like the external ear.14 The prevalence of C. auris candidemia cases had been reported as high as 38% of all candidemia cases.9 But it may be exaggeration of the fact, as denominators were small or not known. The multicenter study from India of 1,400 candidemia cases in 27 Indian ICUs, correctly estimated the prevalence of C. auris candidemia at 5.3% of all candidemia cases.11 The duration of ICU stay prior to candidemia diagnosis was significantly longer in patients with C. auris candidemia (median 25, IQR 12–45 days) compared with the non-C. auris candidemia group (median 15, IQR 9–28, p 250 mm of water). {{ Low inflammatory response [CSF white blood cell (WBC) 1:1024 {{ Ability to manage the underlying disease (malignancy has poorer prognosis than AIDS) {{ Low CSF glucose {{ Vision loss.

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A diagnosis of cryptococcosis requires the demonstration of C. neoformans in CSF/sterile tissues or CSF positive for CrAg  tests. Calcofluor stain, India-ink preparation (Fig.  4), Gram stain (Fig. 5), CSF fungal cultures (Fig. 6), blood cultures, latex agglutination (LA) tests (serum and CSF) (Fig.  7) and radiology (Figs. 1–3) are useful diagnostic techniques. Cerebrospinal fluid India ink sensitivity is approximately 80% in patients with AIDS and 50% in non-AIDS patients. With a calcofluor stain, yeast can be identified in a specimen even when numbers are reduced. A few salient points about the (cryptococcal antigen) CrAg LA test are mentioned in Table 2. Higher volume of CSF (5–30 mL) in blood culture bottles should be sent for fungal culture for higher sensitivity. CSF for biofilm array can diagnose cryptococcal meningitis by detecting PCR. Gomori methenamine silver (GMS) fungal stain or periodic acid-Schiff (PAS) stain (Fig. 8) identifies the narrowbased budding yeast in the tissue.

Susceptibility Testing Methods for in vitro susceptibility testing of C. neoformans have been modified and standardized. Voriconazole susceptibility on Vitek is not reliable for Cryptococcus. Most initial isolates have a low minimal inhibitory concentration (MIC) to amphotericin B (AmB), flucytosine (5-FC) and azoles but a high MIC to caspofungin. Cryptococcus neoformans strains that possess known drug-resistance mechanisms like drug target changes or efflux mechanisms have been isolated. When the MIC is

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CHAPTER 41: Cryptococcal Meningitis: Current Treatment Strategy TABLE 1

Difference in clinical presentation and management of cryptococcosis in HIV and non-HIV patients. HIV patients

Non-HIV patients

Onset of symptoms

Subacute or chronic

Acute or subacute

Neck rigidity

May be absent

Usually present

Common strains

C. neoformans

C. gattii often occurs in immunocompetent individuals

Burden of fungi

High

May be low

Treatment

Transplant patients

Induction therapy Induction therapy should be continued until the repeat CSF cultures have sterilized

AmB-d with 5-FC for 2 weeks

L-AmB preferred over AmB-d

Consolidation therapy

Fluconazole (400 mg/day) for 8 weeks

Higher dose of fluconazole (400–800 mg/day)

Maintenance therapy

Fluconazole (200 mg/day)

Fluconazole (200–400 mg/day) Non-HIV, nontransplant patients Duration of induction is longer (>4–6 weeks) and higher dose of fluconazole during consolidation (400–800 mg/day)

Duration of maintenance therapy

Until CD4 >100, low or undetectable VL for >3 months with minimum 1 year of therapy

6–12 months

(AmB-d: amphotericin B deoxycholate; L-AmB: lipid formulations of amphotericin B; 5-FC: 5-fluorocytosine; CSF: cerebrospinal fluid; VL: viral load

FIG. 4:  India-ink preparation showing 5–10 µm budding encapsulated budding yeast (For color version, see Plate 2).

FIG. 5:  Gram-stain showing budding yeast in sputum of a patient with cryptococcal pneumonia with meningitis (For color version, see Plate 2).

initially 16 µg/mL or higher for fluconazole or 128 µg/mL or higher for 5-FC, failure of treatment might possibly be related directly to drug resistance.

pressure should be reduced by 50% if it is extremely high or to a normal pressure of 20 cm of water. If there is persistent pressure elevation of >25 cm water and symptoms, then, lumbar puncture should be repeated daily until the CSF pressure and symptoms have been stabilized for >2 days. Temporary percutaneous lumbar drains or ventriculostomy for persons who require repeated daily lumbar punctures can be considered. Permanent ventriculoperitoneal (VP) shunts should be placed only if the patient is receiving or has received appropriate antifungal therapy and if more conservative measures to control increased intracranial

Management A critical management issue in cryptococcal meningitis is the role of increased intracranial pressure. If the CSF pressure is >25 cm of water and there are symptoms of increased intracranial pressure during induction therapy, CSF drainage by lumbar puncture should be considered. The CSF opening

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FIG. 6:  Cerebrospinal fluid culture growing Cryptococcus (For color version, see Plate 2).

FIG. 7:  Cryptococcal antigen test. Latex agglutination test (For color version, see Plate 2).

TABLE 2

Clinical pearls about cryptococcal antigen test (CrAg).

Specificity 95%

Sensitivity CNS >95%

False-negative CrAg

Prozone phenomenon, chronic indolent meningitis and early infection

False positive CrAg

1% (Trichosporon asahii)

CSF CrAg >1:1024

Indicates high burden of illness, poor host immunity and poorer prognosis

Sr CrAg positivity

Positive Sr CrAg precedes development of cryptococcal meningitis by 22 days

(CNS: central nervous system; CSF: cerebrospinal fluid)

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pressure have failed. If the patient is receiving an appropriate antifungal regimen, VP shunts can be placed during active infection and without complete sterilization of CNS. Immune status of the hosts must be considered in selecting antifungal therapy for cryptococcal meningitis (Table 1). The management of cryptococcal meningitis is classified in three risk groups: (1) HIV-infected individuals, (2) organ transplant recipients, and (3) non–HIV-infected and nontransplant hosts.2 Fungicidal agents should be used for treating the meningeal infections during induction therapy. Induction therapy with AmB-d with 5-FC is the preferred regimen in

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FIG. 8:  Periodic acid-Schiff fungal stain shows Cryptococcus in a lung biopsy specimen (For color version, see Plate 3).

HIV-patients. L-AmB can be chosen as per renal concerns. Duration of induction therapy should be ideally until CSF sterilization. 5-FC results in faster CSF sterilization, allows lower doses of AmB for same therapeutic effect and decreases relapse. However, 5-FC should never be used as monotherapy because of rapid development of resistance. The most important prognostic factor is the ability to control the underlying disease. Highly active antiretroviral therapy (HAART) should be initiated/optimized only after induction treatment is over; generally between 2 and 10 weeks [to avoid immune reconstitution inflammatory syndrome (IRIS)]. Reduction in immunosuppressive therapy should be considered in patients’ with cryptococcal meningitis but a sequential or step-wise reduction in immunosuppression is recommended. Abrupt withdrawal or reversal of immunosuppression can potentially lead to a shift toward a TH1 proinflammatory state posing a risk for IRIS. Disseminated cryptococcosis with no lung or meningeal involvement should be treated as CNS disease. In patient with cryptococcal meningitis with crypto­ coccomas, longer duration of induction therapy AmBd (0.7–1 mg/kg/day IV), liposomal AmB (3–4 mg/kg/day IV) plus 5-FC (100 mg/kg per day orally in four divided doses) of atleast >6 weeks are recommended. Adjunctive therapies include corticosteroids for mass effect and surrounding edema and surgery for large (>3-cm lesion), accessible lesions with mass effect, consider open or stereotactic-guided debulking and/or removal; also, enlarging lesions not explained by IRIS should be submitted for further tissue diagnosis. Pulmonary Cryptococcus infections in immunocompetent hosts can be treated with fluconazole (200–400 mg/day for 3–6 months) alone. During treatment if patient develops new onset symptoms and signs, then, either IRIS or relapse or failure should be considered. The two clearest signs of relapse after

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CHAPTER 41: Cryptococcal Meningitis: Current Treatment Strategy at least 4 weeks of an established antifungal regimen that suggest a change in management are development of new clinical signs and symptoms and repeat positive cultures. In case of suspected failure or relapse, fungal cultures should be kept for prolonged incubation for atleast 2 weeks. Causes of relapse include reinfection with same strain due to high exposure/recurrent exposure, e.g. exposure to pigeons or eucalyptus trees, prostatic reservoir—chronic infection of prostate by Cryptococcus (in males) or discontinuation of maintenance therapy on inadequate immune reconstitution.

Alternatives for Persistence or Relapse • Induction: {{ AmB + 5FC {{ Higher dose AmB, perhaps LF AmB {{ Longer induction phase of 4–10 weeks with AmB (not usually tolerated by the patients) {{ High-dose fluconazole 1,200 mg provides faster clearance but azole alone is not recommended if there is prior azole exposure. • Consolidation phase: {{ Fluconazole 800–1,200 mg, other azoles may have cross resistance and interactions {{ Fluconazole + 5FC for 6 weeks {{ Fluconazole 1200 + 5FC (additive effect)—early fungicidal activity (EFA) approaches that AmB.

Maintenance Therapy However, AmBd once/week has fewer efficacies. It is used in case of if azole intolerance or multiple relapses.

CONCLUSION • When available, all patients should receive a polyene with 5-FC in the induction treatment regimen for cryptococcal meningoencephalitis • Repeat lumbar punctures at 2 weeks to document CSF sterilization should be done before switching to consolidation therapy • Patients with symptomatic increased intracranial pressure should be aggressively identified, treated and monitored • Relapse of symptoms and signs during or after treatment needs to be carefully studied to determine whether this represents failure to control fungal growth (drug resistance or compliance issues) or represents IRIS • Patients with disseminated cryptococcosis or meningo­ encephalitis should be tested for HIV infection.

Acknowledgments Our thanks are due to Dr Camilla Rodrigues, Consultant Micro­ biologists, PD Hinduja, National Hospital, Mumbai, Dr Dheeraj Gautam, Histopathology, Medanta—The Medicity, Dr Jayesh Modi, Dr Jaiprakash, Dr Monica Agarwal, Department of Radiology, Medanta—The Medicity for their contribution.

REFERENCES 1. Perfect JR. Cryptococcus neoformans. In: GL Mandell et al. (Eds). Principles and Practice of Infectious Diseases, 8th edition. Philadelphia: Elsevier Churchill Livingstone; 2015. pp. 2934-48. 2. Perfect JR, Dismukes WE, Dromer F. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010;50:291-322.

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Management of Severe Dengue: Are WHO Guidelines Relevant? Pravin Amin, Vinay Amin

INTRODUCTION Dengue is an arbovirus belonging to the viral family Flaviviridae and has four serologically distinct serotypes (DEN-1, DEN-2, DEN-3, and DEN-4). Dengue is transmitted mainly by the bite of a female species of Aedes aegypti and, to a lesser extent by Aedes albopictus mosquito infected with any one of the four dengue viruses. It occurs in tropical and subtropical areas of the world. Dengue is currently endemic in more than 100 countries in the Africa,the Americas, Eastern Mediterranean, Southeast Asia and the Western Pacific regions. A recent study indicates approximately 390 million dengue infections per year, of which about 96 million manifest clinically with severe disease.1 Annually about 400,000 cases of dengue hemorrhagic fever (DHF) occur, where the case fatality is approximately 5% when untreated, but with appropriate therapy it may reduce to 1280, a comparable IgG enzyme-linked immunosorbent assay (ELISA) titre or a positive IgM antibody test on a late acute or convalescent-phase serum specimen) or • Occurrence at the same location and time as other DF cases Confirmed • A case confirmed by one of the following laboratory criteria: {{Isolation of the dengue virus from serum/autopsy samples {{An at least 4-fold change in reciprocal IgG/IgM titres to one or more dengue virus antigens in paired samples {{Demonstration of dengue virus antigen in autopsy tissue, serum or cerebrospinal fluid samples by immunohistochemistry, immunofluorescence or ELISA {{Detection of dengue virus genomic sequences in autopsy tissue serum or cerebrospinal fluid samples by polymerase chain reaction (PCR) Reportable • Any probable or confirmed case should be reported

DHF

For a diagnosis of DHF, a case must meet all four of the following criteria: • Fever or history of fever lasting 2–7 days, occasionally biphasic • A hemorrhagic tendency shown by at least one of the following: A positive tourniquet test; petechiae, ecchymoses or purpura; bleeding from the mucosa, gastrointestinal tract, injection sites or other locations; or hematemesis or melena • Thrombocytopenia [100,000 cells/mm3 (100 × 109/L)] • Evidence of plasma leakage owing to increased vascular permeability shown by—an increase in hematocrit >20% above average for age, sex and population; a decrease in the hematocrit after intervention >20% of baseline; signs of plasma leakage such as pleural effusion, ascites or hypoproteinemia

DSS

For a case of DSS, all four criteria for DHF must be met, in addition to evidence of circulatory failure manifested by: • Rapid and weak pulse and • Narrow pulse pressure (20 mm Hg or 2.7 kPa) or manifested by • Hypotension for age and • Cold, clammy skin and restlessness

disease. This study established that 22% of patients with shock did not meet with all the criteria for DHF.9 These findings became the source of the revised 2009 WHO classification. A new classification of dengue recommended by WHO Tropical Disease Research (TDR) was published in WHO TDR 2009 Dengue guidelines. This new classification arranges dengue into dengue (D), dengue with warning signs (DW) and severe dengue (SD). It may be challenging to distinguish DHF from DF and other tropical illnesses, e.g. malaria, typhoid fever, leptospirosis, etc. especially in the course of the acute phase of the illness. The 2009 WHO classification (Fig. 1 and Table 2) of dengue group based on the levels of severity:11 • Dengue without warning signs • Dengue with warning signs (abdominal pain, persistent vomiting, mucosal bleeding, lethargy, hepatomegaly, increased hematocrit with thrombocytopenia, fluid accumulation)

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• Severe dengue (dengue with severe plasma leakage, severe bleeding, or organ dysfunction). After defervescence those patients who recover are deemed to have non-SD, however those who get worse usually display warning signs. These set of patients improve following intravenous hydration. But those patients who further worsen are classified as SD, these patients if treated appropriately have a good chance of recovering.11 As opposed to the 1997 guidelines 2009 classification was more sensitive in picking up severe disease which was 39% in the former as opposed to 92% with the later.10,12 A multicentre study among 18 countries with a comparative assessment of dengue clinical guidelines from 1997 and in 2009 to evaluate the variation in use in both Latin America and Asia, revealed that approximately 14% of cases were unable to be grouped using the DF/DHF/DSS classification, compared with only 1.6% with the revised system) (Table 3).13 The study further revealed the usefulness regarding triage and the management

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FIG. 1:  Criteria for dengue with or without warning signs or severe dengue.

TABLE 2

Dengue classification according to the World Health Organization.

Criteria for dengue ± warning signs

Criteria for severe dengue

Probable dengue

Warning signs*

Severe plasma leakage

Live in/travel to dengue endemic area. Fever and two of the following criteria: • Nausea, vomiting • Rash • Aches and pain • Tourniquet test positive • Leukopenia • Any warning signs

• Abdominal pain or tenderness • Persistent vomiting • Clinical fluid accumulation • Mucosal bleed • Lethargy and restlessness • Liver enlargement >2 cm • Laboratory increase in HCT concurrent with rapid decrease in platelet count

Leading to: • Shock (DSS) • Fluid accumulation with respiratory distress • Severe bleeding • As evaluated by clinician • Severe organ involvement • Liver: AST or ALT ≥1000 • CNS: Impaired consciousness • Heart and other organs

Laboratory-confirmed dengue (important when no sign of plasma leakage) *(requiring strict observation and medical intervention) (AST: aspartate aminotransferase; ALT: alanine aminotransferase; CNS: central nervous system; DSS: dengue shock syndrome; HCT: hematocrit)

200

of dengue, reportage during surveillance and endpoints in dengue trials. There are some drawbacks with the revised classification as it needs additional training of healthcare workers. Some of the elements of the prior classification may be appropriate for clinical practice. There needs to be more clarity in the definition of warning signs so as to enhance triaging to select patients who may need hospitalization as compared to those where domiciliary therapy is possible.13 Based on the results of the DENCO study too the revised classification system included two entities, ‘Dengue’ and ‘Severe Dengue’, that has been included into the 2007 WHO

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guidelines.9 The necessity for laboratory confirmation is not clearly stated for SD in the 2009 classification. Without laboratory evidence of confirmed dengue, an unspecified amount of cases that meet the requirements to be labeled as SD may not necessarily be dengue, as the criteria for SD are so broad-based. Whereas, the DHF case definition ignores 99% of non-dengue cases without the necessity for laboratory tests.14 The presence of five or more warning signs seems to be a predictor of SD. Lymphocyte counts 60% of energy and protein requirements by the enteral route alone. With PN we face the problems of hyperglycemia, hyperlipidemia, hypercapnia, trace elements deficiency, over feeding, refeeding syndrome, gastrointestinal (GIT) complications like gastroparesis and mucosal atrophy.

CONCLUSION The metabolic changes occurring during stress in the critically ill patients are a cascade of adaptive response of the body to the said stress which more often turn into maladaptive processes depending on the variables present in the patient physiology. Adaptive changes have implications affecting the overall outcome of the patient admitted in the ICU. The research till date would suggest that glycemic control, supplementary cortisol when indicated and nutrition therapy does affect the outcome in terms of mortality and morbidity. But further research is required to shed light on lot of the metabolic responses of the body and whether any intervention would give tangible benefits, especially in thyroid dysfunction and nutrition supplement.

REFFERENCES 1. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359-67. 2. McCowen KC, Malhotra A, Bistrian BR. Stress-induced hyperglycemia. Crit Care Clin. 2001;17(1):107-24.



3. Bochicchio GV, Sung J, Joshi M, et al. Persistent hyperglycemia is predictive of outcome in critically ill trauma patients. J Trauma. 2005;58(5):921-4. 4. Jeremitsky E, Omert LA, Dunham CM, et al. The impact of hyperglycemia on patients with severe brain injury. J Trauma. 2005;58(1):47-50. 5. Krinsley JS, Grover A. Severe hypoglycemia in critically ill patients: risk factors and outcomes. Crit Care Med. 2007;35(10):2262-7. 6. NICE-SUGAR Study Investigators, Finfer S, Chittock DR, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283-97. 7. Finfer S, Liu B, Chittock DR, et al. Hypoglycemia and risk of death in critically ill patients. N Engl J Med. 2012;367(12):1108-18. 8. Arabi YM, Dabbagh OC, Tamim HM, et al. Intensive versus conventional insulin therapy: a randomized controlled trial in medical and surgical critically ill patients. Crit Care Med. 2008;36(12):3190-7. 9. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354(5):449-61. 10. Wiener RS, Wiener DC, Larson RJ. Benefits and risks of tight glucose control in critically ill adults: a meta-analysis. JAMA. 2008;300(8):933-44. 11. Krinsley JS. Glycemic variability: a strong independent predictor of mortality in critically ill patients. Crit Care Med. 2008;36(11):3008-13. 12. American Diabetes Association. Standards of medical care in diabetes—2016. Diabetes Care. 2016;39(Suppl 1):S1-106. 13. Marik PE, Pastores SM, Annane D, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: Consensus statement from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008;36(6):1937-49. 14. Annane D, Pastores SM, Arit W, et al. Critical illness related corticosteroid insufficiency (CIRCI): a narrative review from a Multispeciality Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). Crit Care Med. 2017:45(12):2089-98. 15. Annane D, Sebille V, Charpenkar C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288(7):862-71. 16. Wiersinga WM, van den Berghe G. Nonthyroidal illness syndrome. In: Braverman LE, Cooper DS (Eds). Werner & Ingbar’s The Thyroid: A Fundamental And Clinical Text, 10th edition. Philadelphia: Lippincott Williams and Wilkins; 2013. pp. 203-17. 17. Arem RT, Deppe SA. Comparison of thyroid hormone and cortisol measurements with APACHE II and TISS scoring systems as predictors of mortality in the medical intensive care unit. J Intensive Care Med. 1997;12:12-7. 18. Van den Berghe G, Baxter RC, Weekers F, et al. The combined administration of GH-releasing peptide-2 (GHRP-2), TRH and GnRH to men with prolonged critical illness evokes superior endocrine and metabolic effects compared to treatment with GHRP-2 alone. Clin Endocrinol (Oxf). 2002;56(5):655-69. 19. McClave SA, Taylor BE, Martindale RG, et al. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient. Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). J Parenter Enteral Nutr. 2016;40(2):159-211.

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Section 11 Transplant/Extracorporeal Support/Imaging

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CHAPTER

Utility of PET-CT in ICU Vishal Agarwal, Yash Javeri, Swati Chandra

INTRODUCTION Critically ill patients often have focus of infection or source point of disease (occult malignancy or inflammatory foci) that are difficult to detect. When conventional imaging techniques fail to demonstrate the focus of infection, positron emission tomography-computed tomography (PETCT)[mainly, but not limited to 18F fluorodeoxyglucose (FDG)] can be of significant help. Patients in intensive care unit (ICU) can be admitted under various suspected causes which require plethora of investigations. Many a times, these batteries of tests are not able to provide either the correct diagnosis or help clearly in outlining the extent of disease. In such cases, molecular imaging can be of immense utility by virtue of its ability to detect hidden foci of infection, inflammation or malignancy with certain degree of confidence. PET-CT is the step forward as it is the cradle of fusion-imaging (providing anatomical and functional imaging, both) and with recent research focusing on various new radiotracers, its area of influence (in decision making) is ever expanding. We are going to discuss in this chapter various conditions (suspected or confirmed) for admission in the ICU and probable role of PET-CT.

ACUTE

STROKE1,2

Patient admitted with the diagnoses of acute ischemic stroke in the ICU needs the conventional supportive management for stabilization. But after the initial management, efforts should be on to find the cause, area and extent of damage; and if possible to delineate the possible salvable tissue thereby optimizing perfusion to ischemic penumbra. Intravenous (IV) recombinant tissue plasminogen activator (tPA) can be used in the time window of upto 4.5 hours to optimize the perfusion. More often the time constraints become a deterred for thrombolysis. Though the initial (and very effective) modalities remain CT and magnetic resonance imaging (MRI); sometimes either due to logistical reasons (e.g. patient

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may not be suitable for MRI with all the ICU paraphernalia attached to him) or limited outcome (sometimes in case of CT), FDG PET-CT can be of tremendous add-on value, especially in identifying the peri-ischemic/penumbra area. As FDG is a glucose analog, it represents the underlying glucose metabolism in the tissue; and thereby hinting at its alive/recoverable state. Hyper uptake of 18F-FDG in the peri-ischemic areas can be explained by different biological theories. However, whether the increased 18FFDG uptake actually depicts an increased glucose metabolism remains a controversy. Despite its potential clinical values, limitations on using 18FFDG PET for acute stroke patients should be acknowledged. Technical factors including optimal timing between 18FFDG injection and PET imaging, relatively long time interval between injection and PET imaging, 24/7 availability of 18F-FDG and presence of hyperglycemia could make it impractical for the management of acute stroke patients. Finally, the inability of acute stroke patients holding still during PET images can also lead to compromised PET image quality.

STATUS EPILEPTICUS3 (FIGS. 1–4) Inter-ictal FDG-PET is more sensitive than inter-ictal singlephoton emission computed tomography (SPECT) and equivalent to ictal SPECT for the lateralization and localization of epileptogenic foci in preoperative patients, refractory to medical therapies with noncontributory EEG and MRI. FDGPET provides vital information on the functional status of the complete brain. Precisely demarcation of the surgical margin based on areas of hypometabolism is not possible.

PARANEOPLASTIC SYNDROME (FIG. 5)4 Diagnosis of paraneoplastic syndrome (PNS) is a difficult task often leading to misdiagnosis and delays. An underlying immune-mediated pathobiology is implicated, and patients should be tested for onconeural antibodies.

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SECTION 11: Transplant/Extracorporeal Support/Imaging

A

C

B

FIG. 1:  False-negative MR findings with left complex partial seizures. Ictal activity was shown in left temporal area on video/EEG. (A) Oblique coronal fast spin-echo T2-weighted MR image shows no abnormalities; (B) Ictal SPECT scan shows hyperperfusion in left temporal lobe (arrows); (C) FDG-PET scan shows hypometabolism in left temporal lobe (arrows). After left anterior temporal lobectomy, pathologic diagnosis was hippocampal sclerosis of a mild degree associated with mild cortical dysplasia.

A

B

C

FIG. 2  (A) FDG-PET image shows extensive hypometabolism throughout right temporal lobe (arrows); (B) FMZ-PET image shows more restricted localization to mesial temporal region in same patient (arrows); (C) Symmetric FMZ distribution in control subject (For color version, see Plate 4).

A

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B

FIG. 3:  11C-WAY-100635 PET in a patient with MRI-negative temporal lobe epilepsy and a right temporal EEG focus; (A) T1-weighted axial MRI reveals no structural abnormality; (B)  11C-WAY-100635 PET imaging shows asymmetric binding with a decrease in both mesial and lateral structures of the right temporal lobe (For color version, see Plate 4).

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CHAPTER 91: Utility of PET-CT in ICU The FDG PET-CT plays a very important role in identifying the occult primary neoplastic pathology in such cases mainly because of FDG being glucose analogue, getting trapped in the sites of high glucose utilization, whole body assessment and better signal to background ratio then CT or MRI.

Outcomes of Patients with a Positive FDG-PET/CT Result Diffuse Lung Infection (Fig. 6) A

The PET accuracy is very high in identifying active granulomatous foci.  FDG revealed more extensive involve­ ment when compared with contrast-enhanced CT scanning. The imaging technique can also quantify response and identify non responders. A molecular change precedes major morphological change.

Parasitic Infection

B FIG. 4: Increased AMT uptake in cortical tubers (arrows); (A) MRI hyperintense right perisylvian tuber; (B) Subtly MRI hyperintense left temporal tuber. 11C-alpha-methyl-L-tryptophan (AMT) is a radiolabeled tryptophan analog (For color version, see Plate 5).

Conventional radiology techniques fails to assess parasitic viability in pulmonary echinococcosis. However, FDG-PET could show the absence of metabolic activity after therapy and helps in identifying responders and relapse of disease.

Acute Respiratory Distress Syndrome5 Intense metabolic activity in the lungs is shown with FDGPET imaging during acute respiratory distress syndrome (ARDS). FDG uptake rate was increased homogenously. The amount of FDG uptake and its distribution varies largely. Rodrigues et  al. investigated eight patients with pulmonary contusion and observed a “diffuse” uptake pattern of FDG within 1–3  days of pulmonary contusion. It could be temporally related to the development of ARDS. 68Ga-citrate can also diagnose ARDS. 68Ga-citrate could explore vascular permeability.

Diffuse Pulmonary Coccidioidomycosis (Fig. 7)6

FIG. 5: Whole body FDG PET-CT detecting the occult small FDG avid soft tissue density lesion in right lung apex; which on HPE was confirmed to be carcinoma lung (For color version, see Plate 5).

A typical example of exemplariness of FDG PET-CT is in a case of initially diagnosed with diffuse pulmonary coccidioidomycosis and started on oral fluconazole. Coccidioidomycosis, or “Valley fever” is a fungal infection caused by inhalation of Coccidioides immitis or Coccidioides posadasii spores. While his symptoms improved, he began to develop tender cutaneous lesions. Biopsies of the cutaneous lesions show  Coccidioides immitis. Subsequent 18F-FDG PET-CT revealed extensive multisystem involvement including the skin/subcutaneous fat, lungs, spleen, lymph nodes and skeleton. Skin involvement is one of the most common mani­ festations of disseminated coccidioidomycosis. Diagnosing

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SECTION 11: Transplant/Extracorporeal Support/Imaging

FIG. 6:  Diffuse lung infection before initiation of antimicrobial therapy. Infectious etiology is depicted by parenchymal alterations as an intense fluorodeoxyglucose uptake (For color version, see Plate 5).

extent of disease is particularly important in this circumstance as osseous coccidioidomycosis predo­ minantly results in osteolytic lesions that increase risk for fractures. Additionally, soft tissue assessment may reveal clinically occult soft tissue abscesses that may require surgical debridement. For this patient, the PET/CT scan results provided information that prompted medication dose escalation and emphasized the need for medication compliance.

Bleomycin-induced Pneumonitis (Fig. 8)

A

B FIG. 7:  (A) Coronal maximum-intensity projection and (B) axial fused PET-CT scan shows FDG-avid disease involving the spleen (blue arrow), osseous structures (green arrows), multiple lymph nodes stations (yellow arrows), and soft tissues, including the skin and subcutaneous tissues (red arrows) (For color version, see Plate 6).

18F-FDG

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Bleomycin is used in several tumor types such as lymphomas, germ cell tumors, Kaposi’s sarcoma, cervical cancer and head and neck malignancies. Pulmonary toxicity is the major side effect of bleomycin. Bleomycin exerts its anti-tumor effect by inducing tumor cell death and inhibition of tumor angiogenesis. Its cytotoxicity occurs by induction of free radicals. Bleomycin forms a part of the ABVD regime for Hodgkin’s lymphoma. The most feared and dose-limiting side effect of bleomycin is its induction of pulmonary toxicity. Lungs and skin lack the bleomycin-inactivating enzyme, bleomycin hydrolase and hence toxicity occurs predominantly in these organs. The central event in the development of BIP is endothelial damage of the lung vasculature due to bleomycin-induced cytokines and free radicals. Ultimately, BIP can progress in lung fibrosis. The diagnosis is established by a combination of clinical symptoms, radiographic alterations, and pulmonary function test results, while other disorders resembling BIP have to be excluded. The mortality associated with BIP is reported in excess of 3% of all patients treated with bleomycin. The PET-CT scan can distinguish between active inflammation and residual lung damage (fibrosis). As BIP is reversible only in the acute inflammatory phase and not in the late fibrotic stage, PET might be useful to for

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CHAPTER 91: Utility of PET-CT in ICU

FIG. 8:  ‘’Lungs on Fire’’ (For color version, see Plate 6).

FIG. 9:  PET-CT images of positive uptake in the right atrial appendage. b TEE image. PET-CT images of FDG positive focus in the right atrial appendage. Second image shows correlative transesophageal echocardiograhic picture (For color version, see Plate 7).

deciding whether to initiate/continue treatment with antiinflammatory agents.

Infarct Imaging Infarct imaging is done to accurately assess the size of infarct.

Occult Source of Infection (Fig. 9) The PET-CT can be performed and a hot spot could indicate an active infection. It was found at the right atrial appendage (RAA).

Heart Failure7 Heart failure (HF) is a complex clinical syndrome that results from any structural or functional impairment of

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SECTION 11: Transplant/Extracorporeal Support/Imaging ventricular filling or ejection of blood. It is the leading cause of hospitalization in elderly people. PET helps non-invasive evaluation of contractility, perfusion, metabolism, and inner­ vation. Functional imaging can help localize and quantify inflammation, angiogenesis, cell death, and even ventricular remodeling.

Infective Causes in Cardiac Diseases (Figs. 10 and 11) Pyrexia of Unknown Origin (Fig. 12) The PUO or FUO is a very common indication for hospital admissions, sometimes even to ICUs. Classical definitions of

A

C

E

B

D

F

G

FIG. 10:  Transaxial CT (A and B), FDG-PET (C and D), and fused PET-CT views (E and F), as well as maximal intensity projection FDG-PET (G) at the level of the pacing box and the intracardiac portions of the lead. There is an increased FDG uptake at the level of the pacing box and in the extravascular and extra-cardiac portion of the lead (arrows in C, E and G) corresponding to pacing box infection with lead infection spreading by contiguity (SUVmax 7.0). An important hotspot (SUVmax 5.3) corresponding to lead endocarditis was also identified in the intracardiac portion of the lead at the right atrial level (arrows in D, F and G) (For color version, see Plate 7).

A

B

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FIG. 11:  (A) Sagittal and (B) transverse 18F-FDG PET-CT images show infected prosthetic mitral valve. Culture was positive for coagulase-negative Staphylococcus (For color version, see Plate 8).

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CHAPTER 91: Utility of PET-CT in ICU

CONCLUSION Functional imaging plays an important role in the diagnosis and management of ICU patients and with the ever expanding armamentarium in terms of newer tracers, this role is only going to increase.

REFERENCES

FIG. 12:  FDG PET-CT in a case of PUO showing a solitary tiny FDG avid left cervical lymph node. HPE confirmed it to be malignant (For color version, see Plate 8).

PUO describe it as fever of >3 weeks, duration without any cause. FDG PET-CT can (and does) play an important role in identifying the occult source point of infection or malignancy and help in management.

1. Howard RS, Kullmann DM, Hirsch NP. Admission to neurological intensive care: who, when, and why? J Neurol Neurosurg Psychiatry. 2003;74. 2. Bunevicius A, Yuan H, Lin W. The Potential Roles of 18F-FDG-PET in Management of Acute Stroke Patients. Biomed Res Int. 2013;2013:634598. 3. Sarikaya I. PET studies in epilepsy. Am J Nucl Med Mol Imaging. 2015;5(5):416-30. 4. Maskery MP, Hill J, Cain JR, et al. The utility of FDG-PET/CT in clinically suspected paraneoplastic neurological syndrome: A literature review and retrospective case series. Front Neurol. 2017;8:238. 5. Capitanio S, Nordin AJ, Noraini AR, et al. PET/CT in nononcological lung diseases: current applications and future perspectives. Eur Respir Rev. 2016;25:247-58. 6. Nia BB, Nia ES, Osondu N, et al. Tip of the iceberg: 18F-FDG PET/CT diagnoses extensively disseminated coccidioidomycosis with cutaneous lesions. Southwest J Pulm Crit Care. 2017; 15(1):28-31. 7. Ko CL, Wu YW. The Clinical Value of Cardiac PET in Heart Failure. 2016. In: Kuge Y., Shiga T., Tamaki N. (eds) Perspectives on Nuclear Medicine for Molecular Diagnosis and Integrated Therapy. Springer, Tokyo.

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92

CHAPTER

Mechanical Ventilation on Extracorporeal Membrane Oxygenation Sandeep Dewan

INTRODUCTION1,2 The classical indications for extracorporeal membrane oxygenation (ECMO) in acute respiratory distress syndrome (ARDS) patients are as follows: • Refractory impairment of gas exchanges despite an optimized ventilatory strategy, i.e. use of protective mechanical ventilation with low tidal volume and high positive end expiratory pressure (PEEP) and no response to rescue therapies • The need to apply unacceptably high tidal volume and/or inspiratory pressures to support oxygenation. An additional indication is represented by interhospital transportation of unstable patients. A large number of patients with ARDS require mechanical ventilation (MV) to avert bad effects of hypoxemia and carbon dioxide retention. However, mechanical ventilation can cause ventilator induced lung injury (VILI). ECMO provides an alternative to rescue patients with severe refractory ARDS in which conventional mechanical ventilation fails to maintain adequate gas exchange. There is a considerable amount of evidence to show that protective ventilation with low tidal volume, high PEEP, and prone positioning can improve overall mortality in this subset of patients. More recently, there is an increasing popularity on the use of awake and spontaneous breathing for patients undergoing ECMO, which is thought to be beneficial for pulmonary rehabilitation and better overall recovery with reduced length of intensive care unit (ICU) stay. However, the optimal setting of the mechanical ventilator during ECMO is still a matter of debate, and no specific studies have been conducted to address this issue.

PROTECTIVE VENTILATION IN EXTRACORPOREAL MEMBRANE OXYGENATION3-6 Conventional ventilation mode can cause VILI. The under­ lying mechanisms of VILI include alveolar over distension

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due to excessive volume (volutrauma), alveolar opening and closing with each breath (atelectrauma), and the release of inflammatory markers causing injury which is known as biotrauma. The effect of ventilation volumes on injury is independent of the peak airway pressure. In clinical practice, ventilation at high airway pressure is observed to cause lung injury manifested as pneumothorax or subcutaneous emphysema. To decrease the incidence of VILI, the concept of protective MV came into practice.

What Happens When the Patient is on Extracorporeal Membrane Oxygenation? Protective ventilation with low tidal volume has long been known as a major component of ventilation strategy for both injured and healthy lung. While the benefit of low tidal volume ventilation is, to reduce lung injury by decreasing the plateau pressure and the tidal volume. It may cause carbon dioxide retention and hypoxemia due to reduced ventilation. Patient population with severe ARDS is actually an extremely heterogeneous group that one size does not fit all, and the relative importance of lung rest versus metabolic demand can be different across the different subset of patients. During veno-venous ECMO (VV-ECMO), mechanical ventilation is still required due to reasons: • ECMO blood flow rate is taking care of only a percentage of the cardiac output and usually it is not enough in hyperdynamic status. A substantial proportion of blood still passes via native lung, not having gone through the artificial lung first • Lung should be mildly ventilated and kept open. Complete collapse of the lung may delay its recovery. To keep the lungs open some PEEP will need to be applied. How much PEEP is good enough to keep the lungs open is still a matter of debate. The major obstacle for performing low tidal volume ventilation is carbon dioxide retention, worsened oxyge­ nation, and intrapulmonary shunt. When tidal volume is

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CHAPTER 92: Mechanical Ventilation on Extracorporeal Membrane Oxygenation decreased to 4 weeks E Presistent failure >3 month

↓ eCCI ≥25% ↓ eCCI ≥50% ↓ eCCI ≥75% or eCCI 25% or to reduce diastolic BP 110–100 mm Hg, whichever is higher, in the first 1–2 hours Further gradual reduction in the BP should be aimed over 24–48 hours5 A too abrupt fall in BP may lead on to a steep decline in the cerebral perfusion as the level falls below the lower limit of autoregulation especially if it is a long-standing hypertension There has to be a tight control on the lowering of BP. The agents used to lower the BP in this scenario should have a short half-life and should be easily titratable

• The agents used as intravenous antihypertensive agents are sodium nitroprusside, esmolol, labetalol, nicardipine, and hydralazine.6 The details about the individual drugs, indications, and dosages are given in Table 4. Apart from specific antihypertensive agents, there are other factors which should be kept in mind which might increase the BP like pain, fever, hypo- or hypervolemia, seizures,7 etc. • The other complications like management of ICP, seizures, anuria, acute myocardial depression should be treated along with the treatment of hypertension • The adverse effects of the frequently used antihyper­ tensives are given in Table 5 • Hypertensive urgency can be treated with oral anti­ hypertensive agents in high dependency unit. However, monitoring of the child according to clinical parameter is important as to detect any acute deterioration either due to disease or medications8 • The usual drugs used in treatment of hypertensive urgency are furosemide, nifedipine, clonidine and minoxidil • The antihypertensives should be used with caution and a knowledge of side effects/adverse effects is impotant.9

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CHAPTER 99: Hypertension Management in Pediatric ICU TABLE 4

Antihypertensive agents.

Medication

Dose and route

Mechanism of action

Duration of action

Sodium nitroprusside

0.5–10 µg/kg/min intravenously

Acts by releasing nitric oxide

1–2 min

Nicardipine

1–3 µg/kg/min intravenously

Calcium channel blocker

15–30 min; may last for up to 3–4 h

Esmolol

125–500 µg/kg/min intravenously

Beta-blocker

10–20 min

Labetalol

0.25–3 mg/kg/h intravenously

Combine alpha- and beta-blocker

Up to 4 h

Hydralazine

0.1–0.6 mg/kg/dose every 4–6 h intravenously

Direct vasodilatation of arterioles

1–4 h

Fenoldopam

0.8–1.2 µg/kg/min intravenously

Dopamine D1 receptor agonist

1h

Phentolamine

0.05–0.1 mg/kg/dose intravenously (maximum of 5 mg/dose)

Alpha-adrenergic blocker

15–30 min

Enalaprilat

5–10 μg/kg/dose every 8–24 h intravenously

Angiotensin-converting enzyme inhibitor

4–6 h

Nifedipine

0.1–0.25 mg/kg/dose every 4–6 h (maximum 10 mg/dose) oral

Calcium channel blocker

4–8 h

Clonidine

0.05–0.1 mg/dose orally

Central alpha-agonist

6–8 h

Minoxidil

0.1–0.2 mg/kg/day (maximum 5 mg/day) orally

Hyperpolarization of in smooth muscle relaxation

Losartan

Dose for 6 years 0.7 mg/kg once daily (maximun dose 100 mg/day) orally

Angiotensin II receptor blocker

24 h

Clevidipine

0.5–3.5 μg/kg/min intravenously

L-type calcium channel blocker

Up to 15 min

TABLE 5

resulting

Up to 24 h

Adverse effects of antihypertensive medications.

Esmolol

Very short acting—may cause profound bradycardia, Raynaud phenomenon

Labetalol

Atrioventricular disturbance, asthma and overt cardiac failure are relative contraindications

Nicardipine

May cause reflex bradycardia, palpitation, peripheral edema

Sodium nitroprusside

Monitor cyanide levels with prolonged (>72 h) use or in renal failure

Fenoldopam

Tachycardia, flushing, headache, hypokalemia

Nifedipine

Flushing, hypotension, tachycardia, syncope, peripheral edema

Hydralazine

Palpitation, flushing, fever, rash, tachycardia, peripheral neuropathy

Losartan

Chest pain, hyperkalemia, elevation in creatinine, diarrhea

KEY LEARNING POINTS • Hypertensive crisis not so rare in children and requires good clinical acumen for early recognition and prompt treatment • Hypertensive emergency should be treated in tertiary level center with invasive arterial pressure monitoring and emergent need to lower the pressure to 25–30% of the value at presentation under strict clinical supervision • Rapid fall in BP can lead on to impairment of end organs especially brain and kidney

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K+ channels

• The advent of potent antihypertensive medications and understanding of pathophysiology has resulted in marked reduction in mortality and morbidity.

CONCLUSION Hypertensive crisis is a pediatric emergency which should be recognized early and treated appropriately to reduce significant morbidity and mortality. The goal of the treatment should be to lower the BP gradually as to prevent ischemia, minimize and treat end organ damage, and to identify the etiopathology and long-term follow-up.

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REFERENCES

1. Gupta P, Goel D. Blood pressure measurement in critically-ill children: Where do we stand? Indian Pediatr. 2018;55: 289-91. 2. Ehrmann BJ, Selewski DT, Troost JP, et al. Hypertension and health outcomes in the pediatric intensive care unit. Pediatr Crit Care Med. 2014;15(5): 41727. 3. Patel NH, Romero SK, Kaelber DC. Evaluation and management of pediatric hypertensive crises: hypertensive urgency and hypertensive emergencies. Open Access Emerg Med. 2012;4:85-92. 4. Singh D, Akingbola O, Yosypiv I, et al. Emergency management of hypertension in children. Int J Nephrol. 2012:Article ID 420247.



5. Nerenberg KA, Zarnke KB, Leung AA, et al. Hypertension Canada’s 2018 Guidelines for Diagnosis, Risk Assessment, Prevention, and Treatment of Hypertension in Adults and Children. Canadian J Cardiol. 2018:506-25. 6. Hecht J, Mahmood S, Brandt MM. The safety of high dose intravenous labetalol. Cir Car Med. 2018;46(2):434-7. 7. Mallidi J, Penumetsa S, Lotfi A. Management of hypertensive emergencies. J Hypertens. 2013;2:2. 8. Dhadke SV, Dhadke VN, Batra DS. Clinical profile of hypertensive emergencies in an intensive care unit. J Assoc Physicians India. 2017;65(5):18-22. 9. Ipek E, Oktay AA, Krim SR. Hypertensive crisis: an update on clinical approach and management. Curr Opin Cardiol. 2017;32(4):397-406.

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100 CHAPTER

High-flow Nasal Cannula in Children: A Concise Review and Update Anil Sachdev, Abdul Rauf

INTRODUCTION There has been a marked increase in use of noninvasive modes of ventilation in intensive care units (ICUs) over the past few years, owing to the complications associated with invasive mechanical ventilation.1 High-flow nasal cannula (HFNC) is a relatively new noninvasive mode which offers alternative to other modes of oxygen therapy and support. The heating and humidification of air-oxygen mixture allows comfortable delivery at flow rates more than the patient’s inspiratory flow rate, limiting mixing of room air.2 Hence, it is also known as heated humidified high-flow nasal cannula (HHHFNC) therapy (in this chapter, term “HFNC” is used instead of “HHHFNC”). The concept of HFNC therapy originally began in neonatal intensive care units (NICUs) as an alternative to continuous positive airway pressure (CPAP) in premature babies.3 This modality is now used across different age groups, particularly in infants and young children hospitalized with bronchiolitis, despite relative lack of evidence supporting its use. Apart from improving oxygenation, HFNC therapy may improve the efficiency of ventilation, reduce work of breathing and avoid the need for intubation.4 Due to the limited availability of data and lack of consensus to guide its use, HFNC practice varies significantly between different units.5 In this chapter, authors give an evidence-based concise review and update of HFNC therapy in children with focus on clinical application in different settings and implementation in practice.

DEFINITION The minimum flow rate that defines ‘‘high’’ flow is not precisely defined. High-flow may be defined as flow rates ≥2  L/min in neonates, while for older children, flow rates ≥4–6 L/min are considered high.6 A Cochrane review from 2014 defined HHHFNC in children as heated, humidified and

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blended air or oxygen delivered via nasal cannula at different flow rates ≥2 L/min, delivering both high concentrations of oxygen and potentially continuous distending pressure.7

WHY HFNC? THE PRINCIPLE BEHIND HFNC Unlike atmospheric air, oxygen is a dry gas and prolonged administration of it can cause dryness and irritation of mucus membranes. The airway mucosa alone is unable to transfer sufficient heat and humidity at supraphysiologic flow rates.8 The bubble humidifier commonly used with nasal cannula cannot provide adequate humidification for gas flows >3–5 L/min. Hence, it is essential to humidify and heat the air-oxygen mixture prior to delivery for higher flow rates.

INSTRUMENTATION: COMPONENTS OF HFNC SYSTEM The basic components of all HFNC systems remain essentially same and it includes (Fig. 1):9 • Source of pressurized oxygen and air regulated by a flowmeter and blender • Sterile water reservoir attached to a heater humidifier • Insulated and/or heated circuit that maintains tempe­ rature and relative humidity • Nonocclusive cannula interface. An HFNC system can be easily assembled from items regularly used and widely available in most ICUs. The exact composition of HFNC systems may vary between different manufactures. Common commercially available HFNC equipment are Airvo 2 (Fischer and Paykel, New Zealand) and Precision Flow system (Vapotherm Inc, Exeter, United States).

MECHANISM OF ACTION OF HFNC Suggested mechanisms for the reduction in work of breathing and improvement in efficiency of ventilation by HFNC include:10

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SECTION 12: Pediatrics

CLINICAL APPLICATION: ROLE IN CHILDREN IN DIFFERENT SETTINGS Bronchiolitis

FIG. 1:  Basic components of a high-flow nasal cannula (HFNC) system.

• Reduces work of breathing: High flow of gas mixture decreases the work of breathing by reduction in the inspiratory resistance associated with the nasopharynx • Reduction in energy expenditure: Adequate humidification reduces the evaporative losses from the mucosa of the airway and thereby the metabolic work for gas conditioning • Improvement in lung compliance and mucociliary function by supplying adequately warmed and humidified gas. Bronchoconstriction associated with airway cooling is also reduced • Washout of nasopharyngeal dead space leading to improved alveolar ventilation: The nasal passages and oropharynx are continuously flushed and replenished, resulting in better removal of exhaled gas, reduction in rebreathing and increased clearance of carbon dioxide. HFNC needs to remain an “open system” for this mechanism to operate, nasal cannula should not cover more than half the diameter of the nostril and mouth need not be closed • Provides distending pressure: HFNC systems provide some positive airway pressure and the variable and unpredic­ table nature of this pressure is a matter of concern. The amount of pressure delivered may depend on the flow, size of the patient, and the fit of the nasal cannula.11 In a study, HFNC therapy at rates of 2 L/kg/min in infants with viral bronchiolitis, generated mean pharyngeal pressures of more than or equal to 4 cm H2O.12 Pressure increases linearly with the flow and decreases with age and size of the patient.

Most of the evidence supporting the use of high flow in infants and children relates to bronchiolitis. Bronchiolitis is one of the most common reasons in infants for hospitalization worldwide. Current approach to management of hospitalized infants with bronchiolitis is largely supportive. Respiratory support in bronchiolitis was traditionally provided through an escalation of therapy from simple oxygen delivery by nasal cannula, to noninvasive ventilation (NIV) with CPAP and finally to invasive mechanical ventilation.13 HFNC therapy has emerged as a new method of respiratory support for bronchiolitis over last few years. Retrospective studies of HFNC therapy use in infants with bronchiolitis suggested that it is a safe mode of respiratory support which may provide an alternative to nasal CPAP. In a study, 45 infants with moderately severe bronchiolitis who would have traditionally been received nasal CPAP in pediatric intensive care units (PICUs) was given HFNC therapy initially in a general pediatric ward; 11 required escalation of respiratory support, but HFNC therapy reduced the number of infants requiring CPAP.14 Nonrandomized studies have shown reduction in intubation rates in bronchiolitis patients in PICU after HFNC use. An Australian group reported reduction in intubation rate from 37% to 7% in infants admitted with viral bronchiolitis during the 5-year period following introduction of HFNC, while 68% reduction in intubation rate was observed in an American PICU.15,16 However, it was not clear in both studies whether this was due to improved patient care or to a higher admission rate of less sick patients. Prospective data relating to HFNC therapy in bronchiolitis is limited. Two large randomized trials were published recently. The TRAMONTANE study was performed at five French PICU and randomized 142 infants aged 50 mm Hg), lower venous pH (90th  percentile for age) were found to be independently associated with HFNC failure in a study in pediatric ED.21 Responders can usually be differentiated from non­ responders within 60 minutes of initiating HFNC, if not sooner. The nonresponders should be considered for elective escalation of therapy to NIV or invasive ventilation while the responders still warrant further monitoring.

Weaning from HFNC Unfortunately, at present, there is no evidence to suggest any particular approach to weaning. Weaning is initiated once clinical condition has been stabilized for >24 hours. Most authors recommend to initially wean the FiO2 to 0.3–0.4 before reducing flow rates.4 Flow rates may be reduced 1 L/min/h or by 0.5 L/kg every 4 hours under close monitoring. If the child develops respiratory distress at any point, flow rate or FiO2 is increased back to the previous higher level. HFNC therapy is discontinued once the flow rate is below 0.5 L/kg/min and the SpO2 is maintained above 92% with an FiO2 3 L/min.

Further research is warranted to study the efficiency of aerosol therapies via HFNC in pediatric patients before recommendations can be made.45

CONCLUSION Literatures on the use of HFNC therapy suggest good safety profile, less requirement of sedation, improved comfort, and parental satisfaction in contrast to mask-delivered NIV. Due to all these virtues, use of HFNC has already started expanding beyond the confines of PICUs, to pediatric EDs, and wards. There are still gray areas left and questions awaiting authentic answers, like the utility of HFNC beyond bronchiolitis, and correct technique of initiation, titration, and weaning. Results of many quality trials are awaited in near future, which may be able to answer some of these queries.

REFERENCES 1. Patel BK, Kress JP. The changing landscape of noninvasive ventilation in the intensive care unit. JAMA. 2015;314(16):1697-9. 2. Lee JH, Rehder KJ, Williford L, et al. Use of high flow nasal cannula in critically ill infants, children, and adults: a critical review of the literature. Intensive Care Med. 2013;39(2):247-57. 3. Sreenan C, Lemke RP, Hudson-Mason A, et al. High-flow nasal cannula in the management of apnea of prematurity: a comparison with conventional nasal continuous positive airway pressure. Pediatrics. 2001;107(5):1081-3. 4. Hutchings FA, Hilliard TN, Davis PJ. Heated humidified high-flow nasal cannula therapy in children. Arch Dis Child. 2015;100:571-5. 5. Miller AG, Gentle MA, Tyler LM, et al. High-flow nasal cannula in pediatric patients: a survey of clinical practice. Respir Care. 2018;63(7):894-99. 6. Beggs S,Wong ZH, Kaul S, et al. High flow nasal cannula therapy for infants with bronchiolitis. Cochrane Database Syst Rev. 2014:CD009609. 7. Mayfield S, Jauncey-Cooke J, Hough JL, et al. High-flow nasal cannula therapy for respiratory support in children. Cochrane Database Syst Rev. 2014:CD009850. 8. Myers TR, American Association for Respiratory Care. AARC Clinical Practice Guideline: selection of an oxygen delivery device for neonatal and pediatric patients—2002 revision and update. Respir Care. 2002;47(6):707-16. 9. Slain KN, Shein SL, Rotta AT. The use of high-flow nasal cannula in the pediatric emergency department. J Pediatr (Rio J). 2017;93 Suppl 1:36-45. 10. Mikalsen IB, Davis P, Oymar K. High flow nasal cannula in children: a literature review. Scand J Trauma, Resusc Emerg Med. 2016;24:93. 11. Arora B, Mahajan P, Zidan MA, et al. Nasopharyngeal airway pressures in bronchiolitis patients treated with high-flow nasal cannula oxygen therapy. Pediatr Emerg Care. 2012;28(11):1179-84. 12. Milési C, Baleine J, Matecki S, et al. Is treatment with a high flow nasal cannula effective in acute viral bronchiolitis? A physiologic study. Intensive Care Med. 2013;39(6):1088-94. 13. Schroeder AR, Mansbach JM. Recent evidence on the management of bronchiolitis. Curr Opin Pediatr. 2014;26(3):328-33. 14. Kallappa C, Hufton M, Millen G, et al. Use of high flow nasal cannula oxygen in infants with bronchiolitis on a paediatric ward: a 3-year experience. Arch Dis Child. 2014;99(8):790-1. 15. McKiernan C, Chua LC, Visintainer PF, et al. High flow nasal cannula therapy in infants with bronchiolitis. J Pediatr. 2010;156(4):634-8. 16. Schibler A, Pham TM, Dunster KR, et al. Reduced intubation rates for infants after introduction of high-flow nasal prong oxygen delivery. Intensive Care Med. 2011;37(5):847-52.

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CHAPTER 100: High-flow Nasal Cannula in Children: A Concise Review and Update 17. Milési C, Essouri S, PouyauR, et al. High flow nasal cannula versus nasal continuous positive airway pressure for the initial respiratory management of acute viral bronchiolitis in young infants: a multicenter randomized controlled trial (TRAMONTANE study). Intensive Care Med. 2017;43(2):209-16. 18. Kepreotes E, Whitehead B, Attia J, et al. High-flow warm humidified oxygen versus standard low-flow nasal cannula oxygen for moderate bronchiolitis (HFWHO RCT): an open, phase 4, randomised controlled trial. Lancet. 2017;389(10072):930-9. 19. Mayfield S, Bogossian F, O’Malley L, et al. High-flow nasal cannula oxygen therapy for infants with bronchiolitis: Pilot study. J Paediatr Child Health. 2014;50(5):373-8. 20. Franklin D, Dalziel S, Schlapbach LJ, et al. Early high flow nasal cannula therapy in bronchiolitis, a prospective randomised control trial (protocol): A Paediatric Acute Respiratory Intervention Study (PARIS). BMC Pediatr. 2015;15:183. 21. Kelly GS, Simon HK, Sturm JJ. High-flow nasal cannula use in children with respiratory distress in the emergency department: predicting the need for subsequent intubation. Pediatr Emerg Care. 2013;29(8):888-92. 22. Wing R, James C, Maranda LS, et al. Use of high-flow nasal cannula support in the emergency department reduces the need for intubation in pediatric acute respiratory insufficiency. Pediatr Emerg Care. 2012;28(11):1117-23. 23. Hernández G, Vaquero C, Colinas L, et al. Effect of postextubation high-flow nasal cannula vs noninvasive ventilation on reintubation and postextubation respiratory failure in high-risk patients: a randomized clinical trial. JAMA. 2016;316(15):1565-74. 24. Hernández G, Vaquero C, González P, et al. Effect of postextubation high-flow nasal cannula vs conventional oxygen therapy on reintubation in low-risk patients: a randomized clinical trial. JAMA. 2016;315(13):1354-61. 25. Testa G, Iodice F, Ricci Z, et al. Comparative evaluation of high-flow nasal cannula and conventional oxygen therapy in paediatric cardiac surgical patients: a randomized controlled trial. Interact Cardiovasc Thorac Surg. 2014;19(3):456-61. 26. Patel A, Nouraei SA. Transnasal Humidified Rapid-Insufflation Ventilatory Exchange (THRIVE): a physiological method of increasing apnoea time in patients with difficult airways. Anaesthesia. 2015;70(3):323-9. 27. Humphreys S, Lee-Archer P, Reyne G, et al. Transnasal Humidified RapidInsufflation Ventilatory Exchange (THRIVE) in children: a randomized controlled trial. Br J Anaesth. 2017;118(2):232-8. 28. Raineri SM, Cortegiani A, Accurso G, et al. Efficacy and safety of using highflow nasal oxygenation in patients undergoing rapid sequence intubation. Turk J Anaesthesiol Reanim. 2017;45(6):335-9. 29. Schlapbach LJ, Schaefer J, Brady AM, et al. High-flow nasal cannula (HFNC) support in interhospital transport of critically ill children. Intensive Care Med. 2014;40(4):592-9.

30. Coletti KD, Bagdure DN, Walker LK, et al. High-flow nasal cannula utilization in pediatric critical care. Respir Care. 2017;62(8):1023-9. 31. Yoder BA, Stoddard RA, Li M, et al. Heated, humidified high-flow nasal cannula versus nasal CPAP for respiratory support in neonates. Pediatrics. 2013;131(5):e1482-90. 32. Manley BJ, Owen LS, Doyle LW, et al. High flow nasal cannulae in very preterm infants after extubation. N Engl J Med. 2013;369(15):1425-33. 33. Manley BJ, Owen L, Doyle LW, et al. High-flow nasal cannula and nasal continuous positive airway pressure use in nontertiary special care nurseries in Australia and New Zealand. J Paediatr Child Health. 2012;48(1):16-21. 34. Wilkinson D, Andersen C, O’Donnell CP, et al. High flow nasal cannula for respiratory support in preterm infants. Cochrane Database Syst Rev. 2016;2:CD006405. 35. Spentzas T, Minarik M, Patters AB, et al. Children with respiratory distress treated with high-flow nasal cannula. J Intensive Care Med. 2009;24(5):323-8. 36. Weiler TW, Kamerkar A, Hotz J, et al. High-flow nasal cannula offers greater reduction of effort of breathing in children of lower weight. Am J Respir Crit Care Med. 2016;193:A6347. 37. Milési C, Boubal M, Jacquot A, et al. High-flow nasal cannula: recommendations for daily practice in pediatrics. Ann Intensive Care. 2014;4:29. 38. Kawaguchi A, Yasui Y, deCaen A, et al. The clinical impact of heated humidified high-flow nasal cannula on pediatric respiratory distress. Pediatr Crit Care Med. 2017;18(2):112-9. 39. Testa G, Iodice F, Ricci Z, et al. Comparative evaluation of high-flow nasal cannula and conventional oxygen therapy in paediatric cardiac surgical patients: a randomized controlled trial. Interact Cardiovasc Thorac Surg. 2014;19(3):456-61. 40. Hegde S, Prodhan P. Serious air leak syndrome complicating high-flow nasal cannula therapy: a report of 3 cases. Pediatrics. 2013;131(3):e939-44. 41. Slain KN, Martinez-Schlurmann N, Shein SL, et al. Nutrition and high-flow nasal cannula respiratory support in children with bronchiolitis. Hosp Pediatr. 2017;7(5):256-62. 42. Al-Subu AM, Hagen S, Eldridge M, et al. Aerosol therapy through high flow nasal cannula in pediatric patients. Expert Rev Respir Med. 2017;11:945-53. 43. Perry SA, Kesser KC, Geller DE, et al. Influences of cannula size and flow rate on aerosol drug delivery through the Vapotherm humidified high-flow nasal cannula system. Pediatr Crit Care Med. 2013;14(5):e250-6. 44. Ari A, Harwood R, Sheard M, et al. In vitro comparison of heliox and oxygen in aerosol delivery using pediatric high-flow nasal cannula. Pediatr Pulm. 2011;46(8):795-801. 45. Hess DR. Aerosol therapy during noninvasive ventilation or high-flow nasal cannula. Respir Care. 2015;60(6):880-91.

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Section 13 Insights into Sepsis

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101 CHAPTER

Ten Elements that can Improve Outcome in Sepsis Jean-Louis Vincent

INTRODUCTION Sepsis, defined as “life-threatening organ dysfunction caused by a dysregulated host response to infection”,1 remains a leading cause of death in the intensive care unit (ICU). Despite multiple potential candidates and promising preclinical and early clinical studies, there are still no specific sepsis therapies available. Management therefore relies on infection control with antibiotics and source removal and hemodynamic stabilization with adequate fluid administration and vasopressor agents. Here I present ten key elements of sepsis management that should be considered in order to optimise patient outcomes.

IDENTIFY SEPSIS EARLY Rapid diagnosis of sepsis is essential to enable early initiation of appropriate therapy, which has been associated with improved outcomes.2, 3 But sepsis is not always easy to identify or diagnose, especially in critically ill patients. Already the diagnosis of infection is not always easy, as the typical signs and symptoms of infection, e.g. fever, tachycardia, and raised white cell count, may be present in critically ill patients even if they have no infection. Nevertheless, the presence of these signs, especially when supported by raised biomarker levels (e.g. C-reactive protein or procalcitonin)4 and a possible source, should raise suspicion of possible infection, and of sepsis if there is associated organ dysfunction. In some cases, the presence of unexplained organ dysfunction may be recognized first and should also alert physicians to the possibility of sepsis, triggering then the search for an infection. The recently proposed quick sequential organ failure assessment (qSOFA) score1 can be used, particularly on the general ward, as an indicator of early organ dysfunction encouraging relevant investigations to identify a possible source and referral. One of the key factors to ensure sepsis is identified early is to promote awareness of sepsis as a possible diagnosis. All

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healthcare personnel in all hospital departments (not just in the emergency room and ICU) should be trained to know and recognise the key symptoms and signs of sepsis. And a system should be in place such that trained sepsis teams or rapid response systems can be alerted when any patient is suspected to have sepsis, enabling the necessary work up and treatment to be initiated as soon as possible.

GIVE ANTIBIOTICS EARLY Appropriate antibiotics should be initiated as soon as possible,5-6 with initial antibiotic choices aimed at covering all likely pathogens, taking into account the site of infection, local microbiological patterns, and recent anti­ microbial therapy. All relevant cultures should be taken before antibiotics are started if possible but this should not significantly delay treatment. As soon as culture results are available, the antibiotic coverage can be adapted according to the identified microorganisms and antibiotic sensitivities. Doses of antibiotics must also be adequate and adjusted to the individual patient. A 7–8 days course of antibiotics is sufficient in most ICU patients and shorter courses may be appropriate in some patients. Decisions to stop antibiotic therapy should be made on an individual patient basis taking into consideration trends in clinical status and available laboratory data, including biomarker levels.7

CONTROL SOURCE OF INFECTION WITHOUT DELAY Antibiotics alone will not be effective if there is a continuing underlying nadir of infection. Any source of infection must be therefore be identified and removed as soon as possible, for example by surgical drainage of an abscess or by removing infected catheters or other invasive material. If no source is obvious, the patient should be reassessed, using imaging if necessary, and focusing particularly on the “big five” most frequent areas—lungs, abdomen, urinary tract, skin

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SECTION 13: Insights into Sepsis and catheters. If a surgical procedure is needed, it must be performed rapidly.

GIVE FLUIDS AS SOON AS POSSIBLE IF THE PATIENT IS HYPOTENSIVE The use of fluids has always been a mainstay in the treatment of septic shock aimed at restoring an adequate perfusion pressure. However, excess fluid, particularly when it results in a persistent positive fluid balance, is associated with worse outcomes.8 Fluid administration should therefore be guided by the SOSD mnemonic (salvage, optimisation, stabilization, de-escalation)9 and amounts adjusted accor­ ding to the patient’s haemodynamic status and phase. In the Salvage phase, fluids should be given rapidly while monitoring equipment is being positioned and connected. A recent study by Lane et al.10 suggested that patients with sepsis who already received intravenous fluids [median volume 400 mL (interquartile range, 250–500 mL)] in the ambulance prior to hospital admission had reduced hospital mortality rates if their initial systolic blood pressure was low (e.g.