Critical Care Update 2022 [4 ed.] 9354656528, 9789354656521

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Critical Care Update 2022

TM

TM

Critical Care Update 2022 Fourth Edition

Editors

Deepak Govil

Rajesh Chandra Mishra

MD EDIC FICCM FCCM

MD (Medicine) FNCCCM EDICM FCCM FCCP FICCM FICP

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

Honorary Consultant, Intensivist, Internist (Sleep Apnea) Khyati Multispeciality Hospital Ahmedabad, Gujarat, India

Dhruva Chaudhry

Subhash Todi

Professor and Head Department of Pulmonary and Critical Care Medicine Postgraduate Institute of Medical Sciences Rohtak, Haryana, India

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

MD (Medicine) DNB DM (Pulmonary and Critical Care Medicine)

MD MRCP

Foreword Deepak Govil

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

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Website: www.jaypeebrothers.com Website: www.jaypeedigital.com © 2022, 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 2022 First Edition: 2019 Second Edition: 2020 Third Edition: 2022 Fourth Edition: March 2022 ISBN: 978-93-5465-652-1

Contributors

Aakanksha Chawla Jain       MD IDCCM IFCCM

Consultant Department of Respiratory Medicine and Critical Care Indraprastha Apollo Hospital New Delhi, India

Abhinav Gupta  MD DNB FNB EDIC Consultant Department of Intensive Care Homerton University Hospital Homerton Row, London, UK

Abhishek Prajapati  MBBS DTCD IDCCM EDIC EDARM FCCU FIECMO PhD (Medicine)

Consultant Department of Critical Care, Pulmonology and Medicine Shree Krishna Hospital, Pramukhswami Medical College Bhaikaka University Anand, Gujarat, India

Abhishek Shrivastava  MBBS MD PDCC FIECMO

Head Department of Anesthesiology, Critical Care and Emergency Medicine Regency Superspeciality Hospital Lucknow, Uttar Pradesh, India

Aditya Nagori  BE PhD Post-Doctoral Fellow Department of Computational Biology Indraprastha Institute of Information Technology New Delhi, India

Aditya Shukla  MD (Anesthesia) Head Department of Critical Care and Emergency Medicine Regency Hospital Ltd Kanpur, Uttar Pradesh, India

Ahsan Ahmed  MBBS DA DNB EDIC IFCCM ICU In-charge and Assistant Professor Department of Anesthesiology KPC Medical College and Hospital Kolkata, West Bengal, India

Ahsina Jahan Lopa  MBBS FICM

Alok Sahoo  MD IDCC

Ajay Prajapati  MBBS MS MCh

Amina Mobashir          

ICU In-charge Department of ICU and Emergency Ashiyan Medical College Hospital Dhaka, Bangladesh Consultant Department of Neurosurgery Maulana Azad Medical College New Delhi, India

Ajit Kumar  DA MD

Additional Professor Department of Anesthesia All India Institute of Medical Sciences Rishikesh, Uttarakhand, India

Ajith Kumar AK  MD DNB EDIC FICCM

Senior Consultant Department of Critical Care Medicine Manipal Hospitals Bengaluru, Karnataka, India

Ajmer Singh MD

Director Department of Cardiac Anesthesia Institute of Critical Care and Anaesthesiology, Medanta—The Medicity Gurugram, Haryana, India

AK Singh  MD (Chest) DNB (Respiratory Medicine) MNAMS FICCM European Diploma (Respiratory Medicine) Consultant Department of Pulmonary and Critical Care Regency Hospital Kanpur, Uttar Pradesh, India

Akhil Taneja  MD IDCCM IFCCM EDIC Fellow-IDSA/SHEA FellowECMO (TSS) Principal Consultant Department of Critical Care Medicine Max Super Specialty Hospital New Delhi, India

Akshay Kumar Chhallani  DNB (General Medicine) FNB (Critical Care Medicine) MNAMS FICP FICP

Consultant Physician and Intensivist Department of Critical Care Medicine Apollo Hospital Navi Mumbai, Maharashtra, India

Associate Professor Department of Anesthesia and Critical Care All India Institute of Medical Sciences Bhubaneswar, Odisha, India DNB (Respiratory Medicine) IDCCM EDRM

Consultant, Institute of Respiratory and Critical Care Medicine and Sleep Disorders Max Hospital New Delhi, India

Amit Gupta  MBBS MD DNB Fellow (Critical Care)

Senior Consultant and Medical Director Department of Pulmonology and Critical Care Medlink Healthcare Patiala, Punjab, India

Amit Kumar Mandal  MBBS DTCD DNB (Respiratory Diseases) Director Department of Pulmonology, Sleep and Critical Care Fortis Hospital Mohali, Punjab, India

Amit Singhal 

BLK-Max Superspeciality Hospital New Delhi, India

Amitkumar Prajapati  MBBS (Anesthesia) IDCCM EDIC FIECMO

Consultant Intensivist Department of Critical Care Shalby Hospital Ahmedabad, Gujarat, India

Amol Kulkarni  MBBS DNB (Medicine) IDCCM Consultant Department of Medicine and Critical Care Seth Nandlal Dhoot Hospital Aurangabad, Maharashtra, India

Amrish Patel  MBBS DTCD Fellow in Critical Care (Indo-Australia) FCCS

Consultant Pulmonologist and Critical Care Specialist Department of Pulmonology and Critical Care Sterling Hospital Ahmedabad, Gujarat, India

vi

Contributors Amrita Prayag  MBBS MSc (Pharmacology)

Research Consultant Department of In-House Research Deenanath Mangeshkar Hospital Pune, Maharashtra, India

Anand Sanghi  MBBS DA DNB FNB EDIC (London) Head Department of Critical Care Medicine Choithram Hospital and Research Centre Indore, Madhya Pradesh, India

Anand Tiwari  MBBS DA DNB IDCCM FNB (Critical Care Medicine) FICCM

Senior Consultant Department of Neurotrauma Intensive Care Unit Ruby Hall Clinic Pune, Maharashtra, India

Anant Pachisia  MBBS MD FNB

Associate Consultant Department of Critical Care Medicine Institute of Critical Care and Anaesthesiology Medanta—The Medicity Gurugram, Haryana, India

Andrew Conway Morris  MB ChB (Hons) BSc (Hons) PhD MRCP FRCA FFICM

Division of Anesthesia Department of Medicine University of Cambridge Cambridge, UK

Anil Jain MD

Director, Cardiac Surgery Epic Hospital Ahmedabad, Gujarat, India

Anirban Bose  MBBS DNB FNB

Associate Consultant Medica Institute of Critical Care Medica Superspeciality Hospital Kolkata, West Bengal, India

Anirban Hom Choudhuri  MD FICCM PGDMLE FIAMLE

Director Professor Department of Anesthesia and Intensive Care GB Pant Hospital New Delhi, India

Anjan Trikha  DA MD FICA MAMS FAMS

Professor, Department of Anesthesiology and Intensive Care All India Institute of Medical Sciences New Delhi, India

Ankur Bhavsar  MBBS DA IFCCM EDIC Head, Critical Care Unit Spandan Multispeciality Hospital Vadodara, Gujarat, India

Ankur Sharma  MD (Anesthesia) PDCC (Transplant Anesthesia)

Associate Professor Department of Trauma and Emergency All India Institute of Medical Sciences Jodhpur, Rajasthan, India

Anuj Clerk  MBBS MD FNB (Critical Care) IDCCM EDIC FIECMO CCIDC

Director, Critical Care Services Department of Critical Care Medicine Sunshine Global Hospital Surat, Gujarat, India

Anushka Mudalige  MBBS MD (Anesthesiology) FRCA FFICM EDIC Consultant Intensivist Department of Medical Intensive Care Unit Colombo North Teaching Hospital Ragama, Gampaha, Sri Lanka

Apurba Kumar Borah  MBBS DA IDCCM Head Department of Critical Care Medicine Narayana Superspeciality Hospital Guwahati, Assam, India

Arjun Alva  MBBS MD (Anesthesia) Administrative Head and Consultant Department of Critical Care Medicine NH, Mazumdar Shaw Multispeciality Hospital Bengaluru, Karnataka, India

Arlene Torres APRN Intensive Care Solutions Department of Critical Care Services Baptist Hospital of Miami Miami, Florida, USA

Arpan Chakraborty          MD FNB (Cardiac Anesthesia)

Senior Consultant Department of Critical Care, ECMO Services and Cardiac Anesthesia Medica Superspecialty Hospital Kolkata, West Bengal, India Past President ECMO Society of India

Arti Singh               MS (Obst and Gyne) DNB (Obst and Gyne) MNAMS

Head and Senior Consultant Department of Obstetrics and Gynecology Regency Hospital Kanpur, Uttar Pradesh, India

Arun Dewan  MBBS MD Principal Director (Critical Care) and Director (Internal Medicine) Department of Internal Medicine and Critical Care Max Smart Super Speciality Hospital New Delhi, India

Arun K Baranwal           MD PG Dip (Critical Care) FCCM FRCPCH FICCM FIAP Department of Pediatrics Advanced Pediatrics Center Postgraduate Institute of Medical Education and Research Chandigarh, India

Arunaloke Chakrabarti        MD DNB FIDSA FECMM FAMS FNASc

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

Arundhati Dileep           AB (Internal Medicine) Fellow (Pulmonary and Critical Care) Fellow Department of Pulmonary Medicine Bronx Health Centre New York City, New York, USA

Arvind Baronia MD

Principal Government Medical College, Uttarakhand Ex-Professor and Head Department of Critical Care Medicine Sanjay Gandhi Postgraduate Institute of Medical Sciences  Lucknow, Uttar Pradesh, India

Ashish Bhalla  MD (Medicine) FRCP (Edinburgh; Glasgow) FICCM

Professor Department of Internal Medicine Postgraduate Institute of Medical Education and Research Chandigarh, India

Ashish K Khanna  MD FCCP FASA FCCM

Associate Professor, Vice Chair for Research Department of Anesthesiology Section on Critical Care Medicine Wake Forest School of Medicine Atrium Health Wake Forest Baptist Medical Center Winston-Salem, North Carolina, USA

Ashit V Hegde  MD MRCP

Consultant Department of Internal Medicine and Intensive Care PD Hinduja Hospital Mumbai, Maharashtra India

Ashootosh Mall  MD (Medicine) Intensivist City Hospital Gorakhpur, Uttar Pradesh, India

Ashutosh Bhardwaj          MD IDCCM EDICM FIECMO

Head and Senior Consultant Dharamshila Narayana Superspeciality Hospital, New Delhi, India

Contributors Asif Ahmed             MBBS DNB (Anesthesiology) (Gold Medal) IDCCM

Barkha Bindu  MBBS MD DNB DM

Senior Consultant and Head Department of Critical Care Medicine Tata Main Hospital Jamshedpur, Jharkhand, India

Consultant Department of Neuroanesthesiology and Neurocritical Care Paras Hospital Gurugram, Haryana, India

Asish Kumar Sahoo  MBBS MD DM

Bhagyesh Shah          

Associate Consultant Department of Critical Care and Emergency Medicine Sir Gangaram Hospital New Delhi, India

Atul Prabhakar Kulkarni        MD (Anesthesiology) FISCCM PGDHHM FICCM

Professor and Head Division of Critical Care Medicine Department of Anesthesiology, Critical Care and Pain Tata Memorial Hospital, Homi Bhabha National Institute Mumbai, Maharashtra, India

Avinash Agrawal  MD IDCCM IFCCM FCCP Professor Department of Critical Care Medicine King George's Medical University Lucknow, Uttar Pradesh, India

Avinash Tank  MS MCh (SGPGIMS) FIAGES

Director Dwarika Super-Speciality Centre for LiverGastro, Obesity and Cancer Surgery Ahmedabad, Gujarat, India

Avneep Agarwal MD

Staff Physician Department of Intensive Care and Resuscitation Department of General Anesthesiology Cleveland Clinic Cleveland, Ohio, USA

Babu Abraham  MD MRCP (UK) FICCM Consultant Department of Critical Care Medicine Apollo Hospitals Chennai, Tamil Nadu, India

Balasubramanian S          MD (General Medicine) DNB (Nephrology)

Senior Consultant Nephrologist Department of Nephrology Apollo Hospitals Chennai, Tamil Nadu, India

Banambar Ray  MD FICCM

Head Department of Critical Care Medicine SUM Ultimate Medicare Bhubaneswar, Odisha, India

Banshi Saboo  MD PhD

Diabetologist Diabetes Care and Hormone Clinic Ahmedabad, Gujarat, India

MBBS DA IDCCM MBA (Healthcare Management)

Consultant Department of Intensive Care Unit CIMS Hospital Ahmedabad, Gujarat, India

Brajendra Lahkar  MD (Internal Medicine) Director Department of Critical Care Medicine and Internal Medicine Health City Hospital Guwahati, Assam, India

Carlos Sanchez MD Head Department of Critical Care Services Hospital General de Quevedo (IESS) Quevedo, Ecuador

Bhalendu Vaishnav  MD (General Medicine)

Chandrakanta Singh 

Bharat Jagiasi  MD FICCM

Chandrashish Chakravarty      MD (AIIMS) MRCP (UK) SCE (Respiratory Medicine) (UK) EDIC MNAMS Fellow in CCM (USA)

Professor and Head Department of Medicine Pramukhswami Medical College and Shree Krishna Hospital Anand, Gujarat, India Head Department of Critical Care Medicine Reliance Hospital Navi Mumbai, Maharashtra, India

Bharat Parikh MD

Consultant Medical Oncologist Department of Medical Oncology Hemato Oncology Clinic Ahmedabad, Gujarat, India

Bhavini Shah 

Director, Microbiology Director, Academics and Research Neuberg Supratech Reference Laboratories Ahmedabad, Gujarat, India

Bhuvna Ahuja             MD (Anesthesiology and Critical Care) FIAPM

Specialist Emergency Medical Officer Department of Emergency Medicine Sanjay Gandhi Postgraduate Institute of Medical Sciences Lucknow, Uttar Pradesh, India

Consultant Department of Critical Care Medicine Apollo Multispecialty Hospital Kolkata, West Bengal, India

Chirag Matravadia  MD (Medicine) Head Department of Critical Care Medicine Wockhardt Hospital Rajkot, Gujarat, India

Chirag Mehta MD Senior Consultant Cardiac Anesthetist EPIC Hospital Ahmedabad, Gujarat, India

Debasis Pradhan  MD IDCCM EDIC EDAIC

Assistant Professor Department of Neurosurgery and Neurocritical Care Lok Nayak Hospital New Delhi, India

Specialty Registrar Department of Anesthesia University Hospital of Derby and Burton Derby, UK

Bikram Kumar Gupta       

Dedeepiya V Devaprasad      

MBBS MD PDCC FACEE EDIC

MD DNB EDIC FICCM

Head Department of Critical Care Medicine Heritage Institute of Medical Sciences Varanasi, Uttar Pradesh, India

Senior Consultant and In-charge Department of Critical Care Medicine Apollo Hospitals Chennai, Tamil Nadu, India

Biren Chauhan           MBBS MHA (Master in Hospital Administration)

Deeksha Singh Tomar 

Group Chief Operating Officer Department of Administration Sunshine Global Hospitals Surat, Gujarat, India

BK Rao  MD (Anesthesia)

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

DA IDCCM IFCCM EDIC

Consultant Department of Critical Care Narayana Superspecialty Hospital Gurugram, Haryana, India

Deepak Govil  MD EDIC FICCM FCCM Director, Critical Care Institute of Critical Care and Anaesthesia Medanta—The Medicity Gurugram, Haryana, India

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viii

Contributors Deepak Malviya  MD (Anesthesiology)

Divya Pal  MD IDCCM FNB

Geethu Joe  MD Microbiology

Consultant Department of Critical Care Medicine Institute of Critical Care and Anaesthesiology Medanta—The Medicity Gurugram, Haryana, India

Consultant Microbiologist Jupiter Hospital Pune, Maharashtra, India

Edward Smith  BSc MB ChB FRCA

Deepika Jain  MD DNB EDAIC IDRA

Department of Critical Care University Hospital Coventry and Warwickshire Coventry, UK

Associate Professor Department of Critical Care Medicine Maharajgunj Medical Campus, Institute of Medicine, Tribhuvan University Kathmandu, Bagmati, Nepal

Assistant Professor Department of Anesthesia and Intensive Care GB Pant Hospital New Delhi, India

Consultant Department of Medicine and Intensive Care Hinduja Hospital Mumbai, Maharashtra, India

Farhad Kapadia  MD FRCP DA (UK) EDIC

Gerald Marín García MD

Professor and Head Department of Anesthesiology and Critical Care Medicine DR RML Institute of Medical Sciences Lucknow, Uttar Pradesh, India

Deepak Vijayan  MD EDIC MBA Head and Consultant KIMS Health Thiruvananthapuram, Kerala, India

Deepu K Peter             MD DNB (Respiratory Medicine)

Assistant Professor Department of Respiratory Medicine Command Hospital (Northern Command) Udhampur, Jammu and Kashmir, India

Deven Juneja  DNB FNB EDIC FCCP IFCCM FCCM

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

Dhiren Shah  MBBS MS MCh Director CVTS and Heart and Lung Transplantation CIMS Hospital Ahmedabad, Gujarat, India

Digvijaysinh Jadeja         MBBS MD (Medicine) EDIC Senior Consultant Intensivist Department of Critical Care Gokul Hospital Rajkot, Gujarat, India

Dilipbhai Patel Dipanjan Chatterjee 

Fredrik Olsen  MD PhD

Department of Anesthesiology and Critical Care Sahlgrenska University Hospital Gothenburg, Sweden Department of Anesthesiology Section on Critical Care Medicine Wake Forest School of Medicine Atrium Health Wake Forest Baptist Medical Center Winston-Salem, North Carolina, USA

Ganshyam Jagathkar  MD FNB FICC

Director Department of Critical Care Medicover Hospital Hyderabad, Telangana, India

Girish V Hiregoudar  DNB (Medicine) IDCCM

Consultant Physician and Intensivist Apple Saraswati Hospital Kolhapur, Maharashtra, India

Gloria Rodríguez-Vega  MD FACP FCCP FNCS MCCM

Chief Department of Critical Care Medicine HIMA San Pablo-Caguas Caguas, Puerto Rico

Gopal Raval  MB DNB (Respiratory Medicine) DTCD MNAMS EDARM FICCM FCCS (Critical Care)

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

Gauri R Gangakhedkar  DA DNB

Gunjan Chanchalani        

Gaurav Pratap Singh  DA IDCCM IFCCM

Assistant Professor Department of Anesthesiology, Critical Care and Pain Tata Memorial Centre, Homi Bhabha National Institute Mumbai, Maharashtra, India

Gautham Raju             MD PDCC (Critical Care Medicine) FNB (Critical Care Medicine) EDICM

Assistant Professor Department of Critical Care Medicine St John’s Medical College and Hospital Bengaluru, Karnataka, India

Diptimala Agarwal        

Gavin D Perkins 

Director and Head Department of Critical Care and Anesthesiology Shantived Institute of Medical Sciences Agra, Uttar Pradesh, India

Attending Physician Department of Pulmonary and Critical Care Medicine, VA Caribbean Healthcare System San Juan, Puerto Rico

Consultant Pulmonologist and Critical Care Specialist Department of Critical Care Medicine Sterling Hospital and Shilp Chest Disease Centre Ahmedabad, Gujarat, India

Senior Consultant Department of Critical Care, ECMO Services and Cardiac Anesthesia Medica Superspecialty Hospital Kolkata, West Bengal, India MBBS DA PGDHA FICCM

Gentle S Shrestha  MD (Anesthesiology) Fellow in Adult Critical Care (University of Toronto) EDIC FCCP FNCS

MD IFCCM FNB FICCM EDICM

Chief Intensivist Department of Critical Care KJ Somaiya Hospital and Research Centre Mumbai, Maharashtra, India

Gurpreet S Wander  MBBS MD (Medicine) DM (Cardiology) Professor and Head Department of Cardiology Dayanand Medical College and Hospital Unit-Hero DMC Heart Institute Ludhiana, Punjab, India

Gyanendra Agrawal 

MD FRCP FFICM FERC F Med Sci

MD (Internal Medicine) DM (Pulmonary and Critical Care Medicine)

Professor Department of Critical Care Medicine Warwick Medical School University of Warwick Coventry, England, UK

Director Department of Respiratory and Critical Care Medicine JAYPEE Hospital Noida, Uttar Pradesh, India

Contributors Haider Abbas  MD FRCP

Professor and Head Department of Emergency Medicine King George’s Medical University Lucknow, Uttar Pradesh, India

Harendra Thakker  MD DNB FCCP (USA) FCCS (Critical Care)

Senior Consultant Department of Pulmonary and Critical Care Medicine Shalby Multispeciality Hospital Ahmedabad, Gujarat, India

Harjit Dumra  MD (Medicine)

Head Department of Critical Care Medicine Sterling Hospital Ahmedabad, Gujarat, India

Harsh Sapra  MBBS DA FRCP Director Medanta—The Medicity Gurugram, Haryana, India

Himanshu Pandya  MD (Medicine)

Dean Professor of Medicine and Medical Education Pramukhswami Medical College, Bhaikaka University Karamsad, Gujarat, India

Hossam Elshekhali  MBChB (Egypt 2002) Master’s degree in Intensive Care Medicine (Egypt 2011) EDIC ESICM 2018

Specialist Critical Care Medicine Department of ICU Mediclinic Parkview hospital Dubai, UAE

HR Rajathadri MD

Senior Resident (DM Critical Care Medicine) Department of Anesthesiology, Pain Medicine and Critical Care All India Institute of Medical Sciences New Delhi, India

Jagannath Jare  DNB FNB EDIC(I)

Associate Consultant Department of Critical Care Medicine PD Hinduja Hospital Mumbai, Maharashtra, India

Janarthanan S  MD (Anesthesiology), Fell. Onco Crit Care IDCCM IFCCM EDIC

Assistant Professor Department of Critical Care Sri Ramachandra Medical Centre and Sri Ramachandra Institute of Higher Education and Research Chennai, Tamil Nadu, India

Jasbir Singh Chhabra  MBBS MD FRCA DICM (UK)

Consultant, Department of Intensive Care Lancashire Teaching Hospitals NHS Trust Preston, Lancashire, UK

Javier Perez-Fernandez  MD FCCM FCCP General Manager, Intensive Care Solutions Department of Critical Care Services Baptist Hospital of Miami Miami, Florida, USA

Jay Kothari  MD FNB

Consultant and Head Department of Critical Care Apollo Hospital International Ltd Gandhinagar, Gujarat, India

Jay Prakash 

Assistant Professor Department of Critical Care Medicine Rajendra Institute of Medical Sciences Ranchi, Jharkhand, India

Jeetendra Sharma           MD IDCCM IFCCM FICCM

Chief, Critical Care Medicine and Chief, Medical Quality, Artemis Hospital Gurugram, Haryana, India

Jerry P Nolan FRCA

Professor School of Clinical Sciences University of Bristol, Bristol, UK Consultant Department of Anesthesia and Intensive Care Medicine Royal United Hospital Bath, UK

Jigar Mehta MD

Director Department of Critical Care Service KD Hospital Ahmedabad, Gujarat, India

Jigeeshu V Divatia  MD FCCM FICCM

Professor and Head Department of Anesthesiology, Critical Care and Pain Tata Memorial Centre, Homi Bhabha National Institute Mumbai, Maharashtra, India

Jignesh Shah  MD DNB IFCCM EDIC

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

Jothydev Kesavade MD

Chairman and Managing Director Jothydev's Diabetes and Research Centre Thiruvananthapuram, Kerala, India

Juhi Chandwani  MD DA DNB FFARCSI EDIC EPGDHA Senior Consultant Department of Anesthesia and Critical Care Royal Hospital Bowsher, Muscat, Oman

Justin A Gopaldas  MBBS DNB (Internal Medicine) MRCP Consultant Intensivist Department of Critical Care Medicine Manipal Hospitals Bengaluru, Karnataka, India

JV Peter  MD DNB FAMS FRACP FJFICM FCICM FICCM FRCP (Edin) MPhil Professor Medical Intensive Care Unit Christian Medical College Vellore, Tamil Nadu, India

K Subba Reddy  MD PDCC IDCCM IFCCM EDIC

Head Department of Critical Care Medicine Apollo Health City Hyderabad, Telangana, India

K Swarna Deepak  MBBS MD (Internal Medicine) MRCP (UK) EDIC (Denmark) IDCCM IFCCM

Consultant Department of Intensive Care Medicine Lead Consultant Infectious Diseases ICU, ApoKOS Associate Professor, Internal Medicine Apollo Health City Apollo Institute of Medical Sciences and Research Hyderabad, Telangana, India

Kalpana Jain MD Senior Consultant Cardiac Anesthesiologist Epic Hospital Ahmedabad, Gujarat, India

Kalpana Krishnareddy  MBBS FRCA EDIC Head and Adjunct Clinical Professor Department of Critical Care Mediclinic Parkview Hospital Al Barsha, Dubai, UAE

Kalpesh Shah  MBBS MD (Anesthesia) Director and Founder Aarogyam Post-ICU Clinic Ahmedabad, Gujarat, India

Kamal Maheshwari  MD MPH Anesthesiologist Department of Outcomes Research Cleveland Clinic Cleveland, Ohio, USA

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Contributors Kanwalpreet Sodhi  DA DNB IDCCM EDIC

Lalit Gupta  MBBS DA DNB MNAMS

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

Associate Professor Department of Anesthesia Maulana Azad Medical College New Delhi, India

Kapil Borawake  DNB (Medicine) IDCCM FICCM

Lalit Mishra  MBBS MD FCCM

Director Department of Intensive Care and General Medicine Vishwaraj Hospital and Research Centre Pune, Maharashtra, India

Kapil Zirpe  MD (Chest) FCCM FICCM

Head Department of Neuro Critical Care Ruby Hall Clinic, Grant Medical Foundation Pune, Maharashtra, India

Khalid Khatib  MD (Medicine) FICCM FICP Professor Department of Medicine SKN Medical College Pune, Maharashtra, India

Khusrav Bajan  MD EDIC

Consultant Physician and Intensivist Department of Medicine and Critical Care PD Hinduja Hospital Mumbai, Maharashtra, India

Consultant Chest Physician Kailash Hospital, Noida, Uttar Pradesh Former Consultant, Apollo Hospital, New Delhi, India

Lalit Singh  MD FICCM

Professor and Head Department of Respiratory and Critical Care Medicine Shri Ram Murti Smark Institute of Medical Sciences Bareilly, Uttar Pradesh, India

Lalit Takia  MD DM (Pediatric Critical Care) Assistant Professor Department of Pediatrics Atal Bihari Vajpayee Institute of Medical Sciences and Ram Manohar Lohia Hospital New Delhi, India

Lalita Gouri Mitra  DA MD DNB MNAMS (Anesthesia)

KR Balakrishnan  MS MCh

Professor and Officer In-charge Department of Anesthesia, Critical Care and Pain Homi Bhabha Cancer Hospital and Research Centre Mullanpur, Chandigarh, India

Krunalkumar Patel 

MBBS MD MRCP (UK) EDIC

Director Institute of Heart and Lung Transplant and Mechanical Circulatory Support Chennai, Tamil Nadu, India MBBS MD IDCCM FIECMO

Consultant Intensivist Department of Critical Care Sunshine Global Hospital Surat, Gujarat, India

Kunal Punamiya  MBBS MHA Chief Executive Officer Department of Administration SL Raheja Hospital Mumbai, Maharashtra, India

Kunal Sahai  MBBS MD FICP FIMACGP

Awarded Honorary Professor IMA Associate Professor Department of Medicine Narayana Medical College Kanpur, Uttar Pradesh, India

Kushal Rajeev Kalvit 

Senior Registrar Division of Critical Care Medicine Department of Anesthesiology, Critical Care and Pain Tata Memorial Hospital, Homi Bhabha National Institute Mumbai, Maharashtra, India

Lilanthi Subasinghe  Consultant Department of Neurotrauma Centre Intensive Care Unit National Hospital of Sri Lanka Colombo, Sri Lanka

Manasi Shahane  DNB (General Medicine) FNB (Critical Care Medicine) Associate Consultant Department of Critical Care and Emergency Medicine Deenanath Mangeshkar Hospital and Research Center Pune, Maharashtra, India

Manish Bharti  EDIC FNB CCM MD DA MBA (HCA) Senior Consultant and Intensivist Department of Critical Care Medicine Sharda School of Medical Sciences and Research, Sharda University Greater Noida, Uttar Pradesh, India

Manish Munjal  MD FICCM FCCM Medical Director Manglam Medicity Hospital Jaipur, Rajasthan, India

Manoj Edirisooriya  MBBS MD MRCP (UK) EDIC Consultant Intensivist Department of Critical Care Lyell McEwin Hospital Elizabeth Vale, SA, Australia

Manoj Goel MD

Director Department of Pulmonology, Critical Care and Sleep Fortis Memorial Research Institute Gurugram, Haryana, India

Manoj Kumar Rai  MD (Medicine)

Senior Consultant and Head Apollo Hospitals Bilaspur, Chhattisgarh, India

Manoj Singh  MD DNB (Chest) FNB EDIC FICCM

Medanta Hospital Lucknow, Uttar Pradesh, India

Consultant Chest and Critical Care Department of Respiratory, Critical Care and Sleep Medicine Apollo Hospital International Ltd Gandhinagar, Gujarat, India

Luis A Vázquez Zubillaga MD

Mansi Dandnaik  MD IDCCM EDICM

Lokendra Gupta  MD FNB (CCM) MRCEM (UK)

Fellow, Critical Care Medicine Department of Pulmonary and Critical Care Medicine VA Caribbean Healthcare System San Juan, Puerto Rico

Maharshi Desai  MD FNB

Consultant Critical Care Department of Critical Care Apollo Hospital International Ltd Gandhinagar, Gujarat, India

Mahfouz Sharapi  MBBS FCAI

Department of Anesthesia Beaumont Hospital, RCSI Dublin, Ireland

Consultant Critical Care Specialist Department of Critical Care Sterling Hospital Ahmedabad, Gujarat, India

Mayank Vats  MD DNB FNB MRCP FRCP FACP FCCP

Pulmonologist, Critical Care Physician Rashid Hospital Rajasthan, India

Meghena Mathew 

Consultant Department of Critical Care Medicine Apollo First Med Hospital Chennai, Tamil Nadu, India

Contributors Minesh Mehta 

Muralidhar Kanchi         

MD (Medicine) FNB (Critical Care Medicine)

MD FIACTA FICA MBA FASE PhD

Senior Physician and Intensivist Department of Intensive Care Unit Shalby Hospital Ahmedabad, Gujarat, India

Director (Academic), Senior Consultant and Professor Department of Cardiac Anesthesia and Critical Care Narayana Institute of Cardiac Sciences, Narayana Health Bengaluru, Karnataka, India

Mohan Maharaj           MD (Anesthesia) PDCC IDCCM MBA

Head Department of Anesthesia and Critical Care CARE Multi-Specialty Hospital and Trauma Centre Visakhapatnam, Andhra Pradesh, India

Monika Gulati             MD (Anesthesia) FCICM (Australia and New Zealand)

Senior Consultant Department of Intensive Care Medicine Ng Teng Fong General Hospital National University Health System (NUHS) Singapore

Nagarajan Ganapathy        MD DA (Anesthesiology)

Director Department of Critical Care Dhanvantri Institute of Medical Education and Research Erode, Tamil Nadu, India

Nagarajan Ramakrishnan       AB (Internal Medicine, Critical Care, Sleep Medicine) MMM FACP FCCM FICCM FISDA Master’s Degree in Medical Management (MMM)

Niraj Tyagi  MBBS EDIC

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

Niren Bhavsar MD

Consultant and Cardiothoracic Transplant Anesthetist Department of Cardiothoracic Anesthesiology CIMS Hospital Ahmedabad, Gujarat, India

Nirmal Jaiswal  MD (Med) FCCS

Chief Intensivist and ICU Director Teacher IDCCM Suretech Hospital and Research Center Wockhardt Multispeciality Hospital Nagpur, Maharashtra, India

Nitin Arora  FRCA FRCP (Edin) DICM FFICM

Senior Consultant and Director Department of Critical Care Services Apollo Hospitals Chennai, Tamil Nadu, India

Consultant Intensivist Heartlands and Good Hope Hospitals University Hospitals Birmingham NHS Foundation Trust, UK

Professor Department of Internal Medicine and Infectious Disease Institute of Liver and Biliary Sciences New Delhi, India

Naman Shastri  MD FASE FTEE

Nitin Rai  MD DM

Mrinal Sircar            

Narendra Rungta  MD FCCM FICCM FISCCM

Mradul Daga             MD MSc (Infectious Disease)

MD DNB DTCD EDIC EDARM

Director Department of Pulmonology and Critical Care Fortis Hospital Noida, Uttar Pradesh, India

Mritunjay Kumar           MD DNB MNAMS FIACTA DHM

Assistant Professor Department of Anesthesiology, Pain Medicine and Critical Care All India Institute of Medical Sciences New Delhi, India

Mukesh Patel  MD (Chest)

Pulmonologist and Critical Care Specialist Sterling Hospital Ahmedabad, Gujarat, India

Mukul Misra  MD DM (Cardiology)

Ex-Professor and Head Department of Cardiology Dr Ram Manohar Lohia Institute of Medical Sciences, Lucknow Director Department of Cardiology Chandan Hospital Limited Lucknow, Uttar Pradesh, India

Chief Consultant Cardiac Anesthesiologist and Intensivist EPIC Hospital Ahmedabad, Gujarat, India Chairman and Managing Trustee Critical Care Foundation Jaipur, Rajasthan, India

Neeraj Yadav  MBBS DNB Consultant Department of Anesthesiology, Critical Care, and Medicine Regency Superspeciality Hospital Lucknow, Uttar Pradesh, India

Neeru Gaur  DA DNB IDCCM Consultant Department of Critical care Rajasthan Hospital Jaipur, Rajasthan, India

Nikhil Kothari  MD (Anesthesia) PhD MAMS Additional Professor Department of Anesthesiology and Critical Care All India Institute of Medical Sciences Jodhpur, Rajasthan, India

Nikhilesh Jain            DNB (Med) MRCPI PDCC (Critical Care) FCCCM FIECMO Director and Operational Head Department of Critical Care Services CHL Hospitals Indore, Madhya Pradesh, India

Assistant Professor Department of Critical Care Medicine King George Medical University Lucknow, Uttar Pradesh, India

Om P Sanjeev 

Assistant Professor Department of Emergency Medicine Sanjay Gandhi Post Graduate Institute of Medical Sciences Lucknow, Uttar Pradesh, India

Pablo Santillan 

Anesthesiologist Francisco Hernandez N35-50 y America

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

Pankaj Anand  MD IDCCM FCCP

Senior Consultant Department of Critical Care Fortis Escorts Hospital Jaipur, Rajasthan, India

Paola Perez  BAChM MD

Department of Medical School University of Virginia Charlottesville, Virginia, USA

Parikshit S Prayag  MBBS MD ABIM ABMS Consultant Department of Infectious Diseases Deenanath Mangeshkar Hospital and Research Center Pune, Maharashtra, India

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Contributors Patrick M Wieruszewski PharmD

Pradeep Rangappa        

Departments of Anesthesiology and Pharmacy Mayo Clinic Rochester, Minnesota, USA

DNB (Int Med) FJFICM EDIC FCICM PGDipECHO MBA (HCS) FICCM PGDMLE (NLSUI)

Payel Bose               MD (Anesthesiology) FNB (Critical Care Medicine) EDIC SCE Acute Medicine (UK) IDCCM IFCCM

Senior Consultant Department of Critical Care Medicine Medica Superspecialty Hospital Kolkata, West Bengal, India

Piyush Mathur  MD FCCM FASA Staff Anesthesiologist and Critical Care Physician Department of General Anesthesiology Anesthesiology Institute Cleveland Clinic, Cleveland, Ohio, USA

Poonam Malhotra Kapoor      MD DNB MNAMS FIACTA FTEE

Professor Department of Cardiac Anesthesia Cardio-Thoracic Center All India Institute of Medical Sciences New Delhi, India

Prachee Makashir           MD (Medicine) DNB (Medicine) IDCCM

Professor Bharati Vidyapeeth (DTU) Medical College Hospital and Research Centre Pune, Maharashtra, India

Prachee Sathe  MD FRCP FCCCM Director Department of Critical Care Medicine Ruby Hall Clinic, Pune Hon Professor Department of Critical Care Medicine DY Patil Medical College Pune, Maharashtra, India

Pradeep Bhatia  MD FICCM FICA Professor and Head Department of Anesthesiology and Critical care All India Institute of Medical Sciences Jodhpur, Rajasthan, India

Pradip Bhattacharya MD Professor and Head Department of Critical Care Medicine Rajendra Institute of Medical Sciences Ranchi, Jharkhand, India

Pradeep M D’Costa          DNB (Gen Med) Certificate in Critical Care (ISCCM)

ICU In-charge KEM Hospital Intensivist, Sahyadri Hospital Pune, Maharashtra, India

Consultant Intensive Care Physician Manipal Hospital Yeshwantpur, Bengaluru, Karnataka, India

Pradeep Reddy Pakanati  MD IDCC Consultant Department of Critical Care Medicover Hospital Hyderabad, Telangana, India

Pragyan Routray           MD (Internal Medicine) IDCCM

Prasanna Kumar Mishra MD

Consultant Department of Anesthesia and Critical Care Ashwini Hospital Cuttack, Odisha, India

Prashant Nasa             MD FNB (Critical Care Medicine) EDICM SCE-Acute Medicine

Head Department of Critical Care Medicine NMC Specialty Hospital Dubai, UAE

Pratibha Dileep  MD (Medicine)

Consultant and Head Department of Critical Care CARE Hospitals Bhubaneswar, Odisha, India

Head Department of Critical Care Medicine Zydus Hospital Ahmedabad, Gujarat, India

Prakash Deb            

Praveen Kumar  MD FNB EDIC

MD DA DNB EDAIC (UK) IDCCM PDF (Critical Care Medicine)

Assistant Professor Department of Anesthesia, Critical Care and Pain North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences (NEIGRIHMS) Shillong, Meghalaya, India

Prakash Jiandani  MD (Medicine)

Chief Intensivist Department of Critical Care Lilavati Hospital and Research Centre Mumbai, Maharashtra, India

Prakash KC              MD (General Medicine) DNB (Nephrology)

Senior Consultant Nephrologist Department of Nephrology Apollo Hospitals Chennai, Tamil Nadu, India

Prakash Shastri  MD FRCA FICCM

Vice Chairman and Senior Consultant Department of Institute of Critical Care Medicine Sir Ganga Ram Hospital New Delhi, India

Pranay Oza BHMS

ECMO Co-Director Department of Cardiology and Critical Care and ECMO Services Riddhi Vinayak Critical Care and Cardiac Center (RVCC) Mumbai, Maharashtra, India

Prasad Rajhans             MD (anesthesia) FICCM FCCM (USA)

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

Associate Staff Physician Department of Critical Care Medicine Critical Care Institute, Cleveland Clinic Abu Dhabi, UAE

Prithwis Bhattacharyya  MD PDCC

Professor and Head Department of Critical Care Medicine Pacific Medical College and Hospital Udaipur, Rajasthan, India

Priyanka H Chhabra         MD DNB (Anesthesia & Critical Care Medicine) Associate Professor VMMC and Safdarjung Hospital and Safdarjung Hospital New Delhi, India

Priyanka Singhani  MD DNB Associate Professor Safdarjung Hospital New Delhi, India

Purushotham Godavarthy      DNB (Anesthesiology) IDCCM

Consultant ICU Department of Anesthesiology and Critical Care Command Hospital Chandigarh, India

Quirino Piacevoli  MD PhD

Professor and Head Department of Anesthesia and Intensive Care San Filippo Neri Hospital Rome, Italy

Rachit Patel             MBBS DA IDCCM EDIC FCCU PhD (Medicine)

Consultant Department of Critical Care, Pulmonology and Medicine Shree Krishna Hospital, Pramukhswami Medical College Bhaikaka University Anand, Gujarat, India

Contributors Raghu RV MD

Raju Shakya  MD IDCCM IFCCM

Senior Resident Department of General Medicine Maulana Azad medical college New Delhi, India

Fellow, Critical Care Medicine Department of Critical Care Indraprastha Apollo Hospitals New Delhi, India

Rahul Jaiswal  MD DM

Rakesh Garg             MD DNB FICCM FICA PGCCHM MNAMS CCEPC FIMSA Fellowship in Palliative Medicine

Director and Senior Surgeon ReSTORA Care Clinic Noida, Uttar Pradesh, India

Rahul Pandit             MD FJFICM FCICM FCCP EDIC IFCCM DA

Director Department of Critical Care Medicine Fortis Hospital Mumbai, Maharashtra, India

Rajeev A Annigeri  MBBS MD DNB CFN Senior Consultant Nephrologist Department of Nephrology Apollo Hospitals Chennai, Tamil Nadu, India

Rajeev Kumar Bansal         MD DNB (Gastroenterology)

Consultant Gastroenterologist and Hepatologist Salus Hospital Rajkot, Gujarat, India

Rajeev Soman  MD FIDSA

Consultant Infectious Diseases Jupiter Hospital Pune, Maharashtra, India

Additional Professor Department of Onco-Anesthesiology and Palliative Medicine Dr BR Ambedkar Institute Rotary Cancer Hospital All India Institute of Medical Sciences New Delhi, India

Rakhee Baruah  MD IDCCM

Senior Consultant Department of Critical Care Medicine Health City Hospital Guwahati, Assam, India

Ram E Rajagopalan          AB (Internal Medicine) AB (Critical Care)

Professor and Head (Clinical Services) Department of Critical Care Medicine Sri Ramachandra Medical Centre and Sri Ramachandra Institute of Higher Education and Research Chennai, Tamil Nadu, India

Ramanathan Kollengode       MD DNB (Anes) DNB (Cardiac Anes) MNAMS FCICM FCCP Dip Echo

MD (Medicine) DM (Nephrology)

Director, ICU fellowship Programme Cardiothoracic Intensive Care Unit National University Heart Centre Singapore

Consulatant Nephrologist Institute of Liver and Biliary Sciences New Delhi, India

Ramesh Venkataraman        AB (Internal Medicine) AB (Critical Care Medicine) FCCM FICCM

Rajendra P Mathur         

Raj Raval  MD IFCCM

ICU and Emergency Services SAL Hospital Ahmedabad, Gujarat, India

Rajesh Chawla  MD FCCM FCCP

Senior Consultant Department of Respiratory Medicine and Critical Care Indraprastha Apollo Hospitals New Delhi, India

Rajesh Kumar Pande         MD PDCC FICCM FCCM

Senior Director and Head Department of Critical Care Medicine BLK-Max Super Specialty Hospital New Delhi, India

Rajesh Maniar  MD DPM

Director GIPS Hospital Ahmedabad, Gujarat, India

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

Ranajit Chatterjee         MBBS MRCPI EDICM DA (Gold Medal) In-charge Intensive Care Swami Dayanand Hospital New Delhi, India

Ranvir Tyagi  MD FICCM FCCM

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

Ratender K Singh           MD (Medicine) PDCC (Critical Care Medicine) FICCM FACEE Head Department of Emergency Medicine Sanjay Gandhi Post Graduate Institute of Medical Sciences Lucknow, Uttar Pradesh, India

Ravi Jain                MD (Anesthesia) FNB (Critical Care Medicine)

Assistant Professor Department of Critical Care Medicine Mahatma Gandhi University of Medical Sciences and Technology Jaipur, Rajasthan, India

Raymond Dominic Savio       MD DM EDIC FICCM

Lead Consultant Department of Critical Care Apollo Proton Cancer Centre Chennai, Tamil Nadu, India

Reena Shah  MBBS MRCP MSc (ID) FRCP Associate Professor Head of Infectious Diseases Aga Khan University Hospital Nairobi, Kenya

Reena Sharma            MD (Medicine) Fellow in Rheumatology Consultant Rheumatologist Swastik Rheumatology Clinic Ahmedabad, Gujarat, India

Rekha Das  MD FCCS Trainer

Professor and Head Department of Anesthesia, Critical Care and Pain Acharya Harihar Post Graduate Institute of Cancer Cuttack, Odisha, India

Reshu Gupta Khanikar  MBBS DA IDCCM Senior Consultant and Head Department of Critical Care Medicine Health City Hospital Guwahati, Assam, India

Revathi Aiyer             MD DNB (Medicine) IFCCM EDIC Director Department of Medical and Surgical ICU Sterling Hospitals Vadodara, Gujarat, India

Ridam Pal  B Tech

PHD student Department of Computational Biology Indraprastha Institute of Information Technology New Delhi, India

Ripal Patel Shah  MBBS DA IDCCM FCCS

Consultant Intensivist Critical Care Unit Zydeus Hospital, Orchid ICU and Hospital Ahmedabad, Gujarat, India

Ripon Choudhary  DA MD

Assistant Professor Department of Anesthesia and Intensive Care GB Pant Hospital New Delhi, India

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Contributors Ritesh Aggarwal          MBBS DNB IDCC EDIC (Europe)

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

Ritesh Shah  MD IDCCM FICCM FIECMO Director Department of Critical Care Unit Sterling Hospitals Vadodara, Gujarat, India

Ritika Sharma  MD FNB EDIC

Associate Consultant Department of Critical Care Medicine PD Hinduja Hospital Mumbai, Maharashtra, India

Riyan Sukumar Shetty MD

Head of ECLS and Consultant Pediatric ITU Narayana Institute of Cardiac Sciences, Narayana Health Bengaluru, Karnataka, India

Rohit Aravindakshan Kooloth   MBBS MD(Anesthesiology) EDIC(London) IDCCM, Fellowship in Advanced Intensive Care Medicine (University Hospitals Birmingham, UK)

Consultant Department of Critical Care Apollo Specialty Hospital Chennai, Tamil Nadu, India

Roop Kishen  MD FRCA

(Retd) Consultant Anesthesia and Intensive Care Medicine Salford Royal NHS Foundation Trust, Salford Hon Lecturer (Retired) Translational Medicine and Neurosciences University of Manchester Manchester, UK

Rozil Gandhi            DMRD DNB Fellow in Interventional Radiology

Sabina Regmi             MD (Anesthesiology) DM (Neuroanesthesia) Consultant Department of Neurosurgery/ Neuroanesthesia Lok Nayak Hospital New Delhi, India

Sachin Gupta             MD IDCCM IFCCM EDIC FCCM FICCM Director Department of Critical Care Narayana Superspeciality Hospital Gurugram, Haryana, India

Sadik Mohammed  MD (Anesthesiology)

Associate Professor Department of Anesthesiology and Critical Care All India Institute of Medical Sciences Jodhpur, Rajasthan, India

Sai Praveen Haranath        MBBS MPH FCCP AB (Int Med) AB (Pulmonary Med) AB (Crit Care)

Senior Consultant Department of Pulmonary and Critical Care Apollo Hospitals, Apollo Health city Hyderabad, Telangana, India

Sai Saran  MD IDCCM DM EDIC

Assistant Professor Department of Critical Care Medicine King George’s Medical University Lucknow, Uttar Pradesh, India

Sambit Sahu MD

Clinical Director Department of Critical Care KIMS Hospitals Hyderabad, Telangana, India

Sameer Jog              MD (Internal Medicine) IDCCM EDIC

Consultant Intensivist Department of Critical Care and Emergency Medicine Deenanath Mangeshkar Hospital and Research Center Pune, Maharashtra, India

Sandeep Kantor  MD FCCM FICCM

Consultant Critical Care Department of Critical Care Medicine Royal Hospital Muscat, Oman

Sanjay Dhanuka  MBBS MHA EDIC

Intensivist, Physician and CEO Eminent Hospitals Indore, Madhya Pradesh, India

Sanjay N Pandya  MD DNB (Nephrology) Consultant Nephrologist Department of Nephrology Samarpan Hospital Rajkot, Gujarat, India

Sanjay Nihalani           MBBS MD (Anesthesia) IDCCM EDIC

Specialist ICU Department of ICU Mediclinic Parkview Hospital Dubai, UAE

Sanjay Shah              MS (Gen Surgery) DNB (Gen surgery) FNB (Trauma Care)

Head (Emergency Department) Senior Consultant Trauma Surgeon Apollo Hospitals Ahmedabad, Gujarat, India

Sanket Shah  MD DM PDF

Consultant Hemato Oncologist and Bone Marrow Transplant Physician HOC Vedanta Ahmedabad, Gujarat, India

Santhosh Vilvanathan         MD DM (Cardiac Anesthesia)

Consultant Institute of Heart and Lung Transplant and Mechanical Circulatory Support MGM Healthcare Chennai, Tamil Nadu, India

Saswati Sinha  MD (Medicine) IDCCM EDIC

Consultant Department of Interventional Radiology Sushrut Hospital Ahmedabad, Gujarat, India

ICU In-charge Unique Hospital Surat, Gujarat, India

Samir Gami MD

Critical Care Specialist Department of Critical Care AMRI Hospitals Kolkata, West Bengal, India

Ruchira Khasne          

Samir Patel               MD (Internal Medicine) EDIC MRCP2 (UK)

Satish Deopujari  MD DCH MNANS

MBBS DA DNB IDCCM EDAIC and EDIC

Head Department of Critical Care Medicine SMBT Institute of Medical Sciences and Research Center Nashik, Maharashtra, India

Saad Mahdy  MBBS MSce FCAI

Department of Anesthesia Limerick University Hospital Ireland

Administrative Head and Senior Consultant Intensivist Shree Krishna Hospital, Bhaikaka University Karamsad, Gujarat, India

Samir Sahu  MD FICCM

Director Department of Critical Care, Pulmonology, Quality and Academics AMRI Hospitals Bhubaneswar, Odisha, India

Director, Shree Clinics Professor Emeritus Indira Gandhi Government Medical College and Hospital, Nagpur Adjunct Professor of Practice (Mechanical Engineering), VNIT, Nagpur Chairman Academics Nelson Mother and Child Hospital Nagpur, Maharashtra, India Former Chairman National (Pediatric Intensive chapter 1998–2000 India)

Contributors Saurabh Debnath          MBBS DNB (Anesthesiology) FNB (Critical Care Medicine) IDCCM FCCM Senior Consultant Department of Critical Care Medicine Peerless Hospitex Hospital Kolkata, West Bengal, India

Saurabh Pradhan           MD (Anesthesiology & Critical Care) DM (Critical Care Medicine) Senior Consultant Department of Critical Care Unit, Anesthesiology and Critical Care Nepal Medical College and Teaching Hospital Kathmandu, Nepal

Saurabh Taneja            MD FNB EDICM Exec MBA (HCA)

Consultant Department of Critical Care Medicine Sir Ganga Ram Hospital New Delhi, India

Sauren Panja  MD FNBE EDIC FICCM FICP Head and Senior Consultant Department of Critical Care Medicine RN Tagore Hospital Kolkata, West Bengal, India

Shailender Kumar           DA DNB DM (Neuroanesthesia)

Associate Professor Department of Anesthesiology Pain Medicine and Critical Care All India Institute of Medical Sciences New Delhi, India

Shakya Mohanty DrNB

Trainee Department of Critical Care Medicine Artemis Hospital Gurugram, Haryana, India

Shankha S Sen            MD (Gen Medicine) FACP FICP FIACM FISH FIAMS Consultant Physician Chairman, ISCCM, SILIGURI Branch

Sharanya Kumar MD

Anesthetist Institute of Heart and Lung Transplant Krishna Institute of Medical Sciences Ltd Secunderabad, Telangana, India

Sharmili Sinha  MD DNB EDIC FICCM PGDHM

Senior Consultant Department of Critical Care Medicine Apollo Hospitals Bhubaneswar, Odisha, India

Sheila Nainan Myatra  MD FCCM FICCM

Professor Department of Anesthesiology, Critical Care and Pain Tata Memorial Hospital, Homi Bhabha National Institute Mumbai, Maharashtra, India

Shikha Sachan  MD (Anesthesia) IDCCM EDIC

Consultant Critical Care Medicine Regency Hospital Kanpur, Uttar Pradesh, India

Shilpa Goyal  MD MNAMS

Additional Professor Department of Anesthesiology and Critical Care All India Institute of Medical Sciences Jodhpur, Rajasthan, India

Shivangi Khanna           MD (Anaesthesia), FNB (Critical Care Medicine)

Attending Consultant Critical Care Medicine EHCC Hospital Jaipur, Rajasthan, India

Shivaprakash M Rudramurthy    MD PhD ECMM

Professor and In-charge Department of Medical Microbiology Postgraduate Institute of Medical Education and Research Chandigarh, India

Shrikant Sahasrabudhe       MD (Chest)/IDCCM/TDD

Director and Head Senior Consultant Pulmonologist and Critical Care Specialist Department of Pulmonology and Critical Care Medicine Medicover Hospitals Aurangabad, Maharashtra, India Examiner and Teacher for IDCCM /CTCCM

Shrikanth Srinivasan         MD DNB FNB EDIC FICCM

Consultant and Head Department of Critical Care Medicine Manipal Hospitals New Delhi, India

Shweta Chandankhede       MBBS MD IDCCM IFCCM

Consultant Department of Critical Care Medicine Care Hospitals Hyderabad, Telangana, India

Shyamsunder Tipparaju  MD PDCC FICCM Chairman Galen Health Group Hyderabad, Telangana, India

Siddharth Chand MD

Sidhaant Nangia  Clinical Fellow Sidhaashray Health Services New Delhi, India

Simant Kumar Jha           DA DNB (Anesthesiology) PGDHM FIPM (Pain Fellowship) PDCR Certificate Course in Medical Law and Ethics Senior Consultant Department of Critical Care Medicine PSRI Hospital New Delhi, India ATLS Instructor, FCCS Consultant, FCCS OBS Instructor

Simran J Singh             MD FRCP (London) EDIC FICCM Consultant Intensivist and Physician PD Hinduja Hospital and Medical Research Centre Mumbai, Maharashtra, India

Sivakumar MN  DA DNB IDCCM EDIC FICCM Head Department of Critical Care Medicine Royal Care Super Speciality Hospital Limited Coimbatore, Tamil Nadu, India

Smita Sharma  MD IDCCM Senior Consultant Department of Respiratory and Critical Care Medicine Jaypee Hospital Noida, Uttar Pradesh, India

Sree Bhushan Raju           MD DM DNB MNAMS MBA FISN FASN FACP FISOT FIACM Professor and Unit Head Department of Nephrology Nizam’s Institute of Medical Sciences Hyderabad, Telangana, India

Srinath Marreddy  MD EDIC Dr NB Resident Department of Critical Care and Emergency Medicine Deenanath Mangeshkar Hospital and Research Center Pune, Maharashtra, India

Srinivas Samavedam         MD DNB FRCP FNB EDIC DMLE FICCM MBA

Senior Resident Department of Medicine Maulana Azad Medical College New Delhi, India

Head and Medical Director Department of Critical Care Virinchi Hospitals Hyderabad, Telangana, India

Siddharth Verma  MBBS DA IDCCM

Subhajyoti Ghosh  MD PhD

Department of Critical Care Unit Care N Cure Multispeciality Hospital Bilaspur, Chhattisgarh, India

Consultant Diabetologist Apollo Clinic Dibrugarh, Assam, India

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Contributors Subhal Dixit             

Sunil T Pandya            

MD (Med) IDCCM FCCM FICCM FICP

MD PDCC (Cardiac & Neuro Anesthesia), Post Doctorate Fellow— Obstetric Anesthesia

Director Department of Critical Care Sanjeevan Hospital Pune, Maharashtra, India DrNB Resident Department of Critical Care Medicine BLK-Max Super Specialty Hospital New Delhi, India

Chief Department of Anesthesia, Perioperative Medicine and Critical Care Anesthesia and Obstetric Critical Care AIG Hospitals, Gachibowli, Hyderabad Fernandez Hospitals, Hyderabad Founder Director PACCS Health Care Pvt Ltd Hyderabad, Telangana, India

Subhash Todi  MD MRCP

Suresh Kumar Sundaramurthy  

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

MBBS MD (Anesthesia), DNB (Anesthesia) EDAIC FIPM MNAMS

Subhankar Paul  MBBS MD MRCEM

Sudhir Khunteta  MD FCCM FICCM Director and Chief Intensivist Department of Critical Care Shubh Hospital Jaipur, Rajasthan, India

Sujata Rege             MBBS DNB Fellowship in Infectious Diseases

Consultant Infectious Diseases Department of Infectious Diseases Bharati Vidyapeeth University and Medical College Bharati Hospital and Research Centre Pune, Maharashtra, India

Sulagna Bhattacharjee        MD (Anesthesiology) DNB DM (Critical Care)

Consultant Department of Critical Care Apollo Proton Cancer Centre Chennai, Tamil Nadu, India

Suresh Rao KG MD

Co-Director Institute of Heart and Lung Transplant MGM Healthcare Chennai, Tamil Nadu, India

Susruta Bandyopadhyay       MD Dip (Cardiology)

Director Department of Critical Care AMRI Hospitals Kolkata, West Bengal, India

Swagata Tripathy  MD DNB IDCC EDIC

Assistant Professor Department of Anesthesiology, Pain Medicine and Critical Care All India Institute of Medical Sciences New Delhi, India

Additional Professor and I/C ICU Department of Anesthesia and Critical Care All India Institute of Medical Sciences Bhubaneswar, Odisha, India Fellow Neuro-anesthesia, Walton Centre, Liverpool

Suneel Kumar Garg         

Swati Deepak Parmar       

MD FNB IFCCM EDIC FICCM FCCP FCCM

MBBS DNB (Anesthesiology)

Senior Critical Care Physician Founder and MD Saiman Healthcare Pvt Ltd New Delhi, India

Sunil Garg              

Clinical Fellow Department of Cardiothoracic Intensive Care National University Hospital Singapore

MD (Medicine) FNB (Critical Care Medicine) EDIC SCE-Acute Medicine

Syed Moied Ahmed        

Specialist Physician and Critical Care Specialist NMC Royal Hospital Dubai Investments Park, Dubai

Professor Department of Anesthesiology and Critical Care Jawaharlal Nehru Medical College Aligarh Muslim University Aligarh, Uttar Pradesh, India

Sunil Karanth             MD (Internal Med) FNB (Critical Care Medicine) EDIC FCICM (Aus/NZ) Chairman of Critical Care Services Manipal Health Enterprises (P) Ltd Adjuvant Professor in Critical Care Medicine Manipal University Manipal, Karnataka, India

MBBS MD PhD FICCM FCCP FICM

Tamanna Bajracharya        MD (Anesthesiology) Fellowship in Intensive Care

Associate Professor Department of Anesthesia and Critical Care KIST Medical College and Hospital Lalitpur, Nepal

Tanima Baronia  MD IDCCM ICU In-charge Ruby Hall Clinic Pune, Maharashtra, India

Tanmay Jain  MD DNB EDRM IDCCM

Associate Consultant Department of Critical Care Medicine Reliance Hospital Navi Mumbai, Maharashtra, India

Tapas Kumar Sahoo          MD FNB FICCM FCCP EDIC MBA Senior Consultant and Head Department of Critical Care Medicine Medanta Hospital Ranchi, Jharkhand, India

Tavpritesh Sethi  MBBS PhD

Associate Professor Department of Computational Biology Indraprastha Institute of Information Technology New Delhi, India

Tejas Karmata  MD (Medicine)

Director and Senior Consultant Intensivist Department of Critical Care Gokul Hospital Rajkot, Gujarat, India Accredited Teacher ISCCM

Tejash Parikh IDCCM

Intensivist Zydus Hospital Ahmedabad, Gujarat, India

Tushar Patel MD

Intensivist and Pulmonologist Jivandeep Critical Care Unit Vatsalya Hospital Rajkot, Gujarat, India

Ujwala Mhatre             DA DNB (Anesthesiology) IFCCM IDCCM

Senior Consultant Department of Critical Care Ramkrishna Care Hospital Raipur, Chhattisgarh, India

Unmil Shah  MD DNB

Transplant Pulmonologist Krishna Institute of Medical Sciences Malkapur, Maharashtra, India

Vaishali Solao             MD (Medicine) FNB (Critical Care) Director Department of Liver and Transplant ICU Sir HN Reliance Foundation Hospital Mumbai, Maharashtra, India

Vajrapu Rajendra  MBBS MD FNB EDIC Head Department of Critical Care Medicine Aware Gleneagles Global Hospitals Hyderabad, Telangana, India

Contributors Vandana Sinha MD

Director and Head Department of Critical Care Medicine and Internal Medicine Ayursundra Superspecialty Hospital Guwahati, Assam, India

Varun Byrappa  MBBS MD DNB FNB EDIC

Associate Professor Department of Emergency Medicine Kempegowda Institute of Medical Sciences Bengaluru, Karnataka, India

Vasant Nagvekar           MD (Medicine) Fellowship in Infectious Diseases

Certificate ASTMH Consultant Department of Infectious Diseases Lilavati and Global Hospital Mumbai, Maharashtra, India

Venkat Kola  MD DNB IDCCM EDIC

Clinical Director Department of Critical Care Medicine Yashoda Hospital Hyderabad, Telangana, India

Venkat S Goyal  MD DM (Cardiology)

Consultant Cardiologist Department of Cardiology Riddhivinayak Multispeciality Hospital Mumbai, Maharashtra, India

Vetriselvan P  MD (Anes) DM (Critical Care) Assistant Professor Department of Critical Care Sri Ramachandra Medical Centre and Sri Ramachandra Institute of Higher Education and Research Chennai, Tamil Nadu, India

Vijay Mishra  MD FRCA FICCM

Director Department of Critical Care Bhagwan Mahavir MEDICA Hospital Ranchi, Jharkhand, India

Vijay Narain Tyagi          MBBS MD (TB & Respiratory Disease) FCCS FCCP EDARM Head and Consultant Department of Pulmonary and Critical Care Metro Hospitals and Heart Institute Meerut, Uttar Pradesh, India

Vijil Rahulan              MD FCCP (USA) ABIM (Pulmonary & Critical Care)

Chief of Transplant Pulmonology Department of Heart and Lung Transplant Krishna Institute of Medical Sciences Hyderabad, Telangana, India

Vikas Gulia              MBBS MD EDIC EDAIC MBA (Health)

Vivek Kakar  MD DNB FRCA MA MSc

Consultant Department of Anesthesia and Critical Care George Eliot Hospital NHS Trust Nuneaton, West Midlands, UK

Staff Physician and Section Head, Cardiothoracic Critical Care Department of Critical Care Institute Critical Care Institute Cleveland Clinic, Abu Dhabi, UAE

Vikas Kesarwani  MD FICM DCH

Vivek Nangia MD

Senior CMO Hospital and Adjunct Senior Lecturer Auburn Hospital, Western Sydney Local Health District & University of Notre Dame NSW, Australia

Principal Director and Head Institute of Respiratory, Critical Care and Sleep Medicine Max Hospital New Delhi, India

Vikas Marwah            

Director and Consultant Department of Pediatrics Colours Children Hospital Nagpur, Maharashtra, India

MD (Resp Med) SCE (Resp Med, UK)

Professor Department of Pulmonary, Critical Care and Sleep Medicine Army Institute of Cardio-Thoracic Sciences Pune, Maharashtra, India

Vikas Sikri  DNB IDCCM

HOD Critical Care Senior Consultant Pulmonary and Sleep Medicine Department of Pulmonary and Critical Care Medicine Mohandai Oswal Hospital Ludhiana, Punjab, India

Vimal Bhardwaj  MD FNB EDIC

Consultant Intensivist Department of Critical Care Narayana Hrudayalaya Bengaluru, Karnataka, India

Vinay Singhal  MD (Anesthesiology) IDCCM

Additional Director and Head Department of Critical Care Medicine Fortis Hospitals Ludhiana, Punjab, India

Vipul Pranlal Thakkar  MD IDCCM

Consultant and Head Department of Critical Care Medicine CIMS Hospital Ahmedabad, Gujarat, India

Vishwesh Mehta  MBBS FCCCM Internal Medicine Specialist Vishesh Jupiter Hospital Indore, Madhya Pradesh, India

Vivek Gupta  DA DNB (Anesth) FIACTA FICCM Consultant Department of Cardiac Anesthesia and Intensive Care Dayanand Medical College and Hospital Hero DMC Heart Institute Ludhiana, Punjab, India

Vivekkumar K Shivhare  MD (Pediatrics)

VVSSD Prasanthi  MD IDCCM

Consultant Department of Critical Care Medicine Continental Hospital Hyderabad, Telangana, India

William Rodríguez-Cintrón      MD MACP FCCP FCCM

Chief Department of Pulmonary and Critical Care Medicine VA Caribbean Healthcare System San Juan, Puerto Rico

Yash Javeri  MBBS IDCCM FICCM

Head Department of Anesthesiology, Critical Care and Emergency Medicine Regency Superspecialty Hospital Lucknow, Uttar Pradesh, India

Yatin Mehta              MD MNAMS FRCA FAMS FICCM FIACTA FTEE Chairman Medanta Institute of Critical Care and Anesthesiology Adjunct Professor, NBE President, Sepsis Forum of India, The Simulation Society (TSS) Past President, ISCCM, IACTA, RSACP, SWAC ELSO Medanta—The Medicity Gurugram, Haryana, India

Yatindra Dube MD

Intensivist Department of Medicine and Critical Care Suyash Hospital Nashik, Maharashtra, India

YP Singh MD

Senior Director and Head Max Super Specialty Patparganj, New Delhi, India

xvii

Foreword

Dear Friends, As President of the ISCCM (2021–2022), it is my proud privilege to present to you the Critical Care Update 2022, on the occasion of the 28th Annual Conference, CRITICARE–2022 at Ahmedabad. The COVID-19 pandemic has proven to be the ultimate acid-test for critical care professionals in terms of skill, knowledge, practice and above all improvizations in the face of limitations in resources and staff. Notwithstanding, our doctors rose to the challenge and did a fine job worth commending. The objective and endeavor of the manual remain to enhance knowledge and strengthen clinical practice in critical care. The manual broadly covers depths of scientific topics over all major organ systems and global current critical care practices. It is styled to serve as a ready bedside reference guide to all practitioners of critical care medicine. The chapters which are authored on wide evidence-based literature and knowledge, have been meticulously sifted, selected, and edited by experts in the discipline. The manual covers the full spectrum of critical care management and practice with contributions from experts in leading institutes across the country and abroad. The emphasis as always has been both on evidence and experience to make the manual more relevant and impactful to our young and upcoming critical care professionals. I would like to extend my heartiest regards to the authors and section editors of the manual for their dedication and hard work in bringing together this invaluable reference text. A warm thanks to all members of staff of the ISCCM and M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, who have worked silently. I hope that this manual benefits intensivists, postgraduate trainees, critical care residents, and all allied critical care professionals in strengthening their concept of critical care medicine, and they, in turn, are able to extend that benefit to the patients for whom they care—the ultimate goal and purpose of the manual. Deepak Govil President ISCCM (2021–2022)

Preface to the Fourth Edition

Critical Care Update 2022 will be the 6th consecutive publication of this series which will be released during the Ahmedabad Annual Congress of Indian Society of Critical Care Medicine in April 2022. This congress will be convened in person after a hiatus of two years. It is indeed commendable that the Society has continued to pursue its traditional academic activities and could bring about this edition of the update book during the pandemic with authors’ contributing even when hard pressed with clinical work. The digitization of the editorial process has been the highlight of this edition with manuscript submission, review by section editors and corrections by authors all happening seamlessly on a single platform. This process will certainly improve the content and quality of the journal as will be judged by the readers. The digitization process has also enabled timely publication and increase in number of chapters with new sections such as Applied Physiology, Machine Learning and Artificial Intelligence, Medicolegal and COVID-related issues. Increasing the scope of the update book gives opportunities to induct more contributors increasing the scientific base of the society. Review of chapters by section editors who are experts in the field also maintains quality of the manuscripts submitted. The editorial board has been instrumental in selecting the chapters which are relevant to current clinical practice and will be of help to clinicians and trainees in critical care. We hope you enjoy the congress and happy reading. Editorial Board Critical Care Update 2022

Preface to the First Edition

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

Contents

SECTION 1: Applied Physiology

1. Physiology of Cerebral Blood Flow Autoregulation

3

Bhuvna Ahuja, Sabina Regmi, Ajay Prajapati



2. Hardcore Mathematics in Intensive Care: Alveolar Gas and Shunt Equation

8

Satish Deopujari, Vivekkumar K Shivhare, Jignesh Shah



3. Dynamic Airway Collapse and its Clinical Effects

14

Javier Perez-Fernandez, Arlene Torres, Paola Perez



4. Physiology and Pharmacology of Vasopressor Selection in Septic Shock

18

Fredrik Olsen, Patrick M Wieruszewski, Ashish K Khanna



5. Cardiac Output, Arterial Elastance, and Transmural Pressure

23

Swati Deepak Parmar, Ramanathan Kollengode



6. Immune Dysregulation in Sepsis

35

Andrew Conway Morris

SECTION 2: Infections/Sepsis/Infection Control

7. Approach to Sepsis in Immunocompromised Patients

43

Khalid Khatib, Mritunjay Kumar



8. Newer Biomarkers in Sepsis: What after Procalcitonin?

48

Ashit V Hegde



9. Infection Prevention: Why Still a Nightmare?

51

Prasanna Kumar Mishra, Samir Sahu

10. Acinetobacter Sepsis: What do We have?

55

Reshu Gupta Khanikar, Reena Shah, Rakhee Baruah

11. Higher Dose of Antibiotics: When and Where?

61

Pratibha Dileep, Arundhati Dileep

12. Immunoglobulins in Sepsis: Where to Use?

64

Payel Bose, Saurabh Debnath

13. Therapeutic Drug Monitoring

69

Chandrashish Chakravarty

14. Syndromic Polymerase Chain Reaction-based Diagnostics in Sepsis

73

Bhavini Shah

SECTION 3: Pulmonology/Ventilation 15. Role of High‑flow Nasal Cannula: Has It Change the Outcome?

83

Ahsan Ahmed, Ahsina Jahan Lopa, Anirban Bose

16. Awake Proning Shrikant Sahasrabudhe, Sauren Panja, Saswati Sinha

86

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Contents

17. Utility of ROX Score in Predicting HFNC Failure

90

Harjit Dumra, Tushar Patel, Mukesh Patel

18. Selecting the Right Noninvasive Ventilation Interface

94

Ranajit Chatterjee, Sivakumar MN, Rekha Das

19. How to Predict the SILI in Noninvasive Ventilation and High-flow Nasal Cannula?

99

Manoj Singh, Jay Kothari, Maharshi Desai

20. Peri-intubation Complications and Management

102

Vandana Sinha, Brajendra Lahkar

21. Impact of Obesity on Difficult Weaning

106

Anand Tiwari, Kapil Zirpe

22. Selecting Appropriate Humidification (Active and Passive)

110

Sharmili Sinha, Ranajit Chatterjee, Bhuvna Ahuja

23. Identifying Pulmonary Embolism in Bedside Where Computed Tomography Pulmonary Angiography is not Possible

114

Deepak Govil, Anant Pachisia, Divya Pal

24. Relevance of Berlin Definition

120

Rajesh Chawla, Raju Shakya, Aakanksha Chawla Jain

25. Hemodynamics in Severe Acute Respiratory Distress Syndrome

124

Edward Smith, Nitin Arora

26. Lung Transplant: Lessons for the Intensivist

128

Suresh Rao KG, Santhosh Vilvanathan, KR Balakrishnan

SECTION 4: Nephrology/Acid Base/Fluid Electrolyte 27. Fluid Administration in Emergency Department: Do’s and Don’ts

135

Debasis Pradhan, Prakash Deb, Prithwis Bhattacharyya

28. Changing Strategy of Fluid Management in Four Phases of Septic Shock: Principles and Practice

141

Carlos Sanchez, Ahsina Jahan Lopa, Pablo Santillan

29. Hyperchloremia Side Effects

148

Mahfouz Sharapi, Ahsina Jahan Lopa, Saad Mahdy

30. Albumin Misuse in Intensive Care Unit

152

Deepak Vijayan, Sree Bhushan Raju

31. Precision Mathematics in Fluid Electrolytes in Intensive Care Unit

156

Sanjay N Pandya, Rajendra P Mathur

32. Delaying Renal Replacement Therapy in Acute Kidney Injury: How Long?

161

Rajeev A Annigeri, Dedeepiya V Devaprasad

33. Continuous Urine Output Monitoring

165

Ramesh Venkataraman, Meghena Mathew

SECTION 5: Neurocritical Care 34. Analgosedation in Neurosurgical Intensive Care Unit

171

Quirino Piacevoli, Ahsina Jahan Lopa

35. Delirium in the Intensive Care Unit

174

Luis A Vázquez Zubillaga, Gerald Marín García, William Rodríguez-Cintrón, Gloria Rodríguez-Vega

36. Point-of-care Electroencephalography

177

Barkha Bindu, Harsh Sapra

37. Curing Coma Yash Javeri, Abhishek Shrivastava, Neeraj Yadav

184

Contents

38. Status Epilepticus Relook

188

Sivakumar MN, Shankha S Sen, Bhuvna Ahuja

39. Postintensive Care Syndrome—An Indian Perspective

195

Vikas Marwah, Deepu K Peter, Shailender Kumar

SECTION 6: Gastroenterology and Nutrition 40. Enteral Feeding in Patients on Noninvasive Ventilation and Prone Position

203

Ganshyam Jagathkar, Pradeep Reddy Pakanati

41. Optimizing Calorie and Protein Goals in Acute Hypoxemic Respiratory Failure

209

Anushka Mudalige, Lilanthi Subasinghe, Manoj Edirisooriya

42. Individualized Nutritional Strategies in Intensive Care Unit

214

Kanwalpreet Sodhi, Ruchira Khasne, Ujwala Mhatre

43. Recent Trials in Stress Ulcer Prophylaxis

219

Srinivas Samavedam

SECTION 7: Cardiac Critical Care 44. Intraoperative and Postoperative Transfusion Threshold in Cardiac Surgery

225

Naman Shastri, Chirag Mehta, Kalpana Jain, Anil Jain

45. Cardiogenic Shock: Role of Mechanical Support Devices

229

Ajmer Singh, Yatin Mehta

46. B-type Natriuretic Peptide Interpretation in Intensive Care Unit

234

BK Rao, Niraj Tyagi, Asish Kumar Sahoo

47. Acute Cor Pulmonale Management

239

Girish V Hiregoudar, Manoj Singh, Varun Byrappa

48. Intra-aortic Balloon Pump in Cardiogenic Shock: Are We Done and Dusted?

242

Justin A Gopaldas, Pradeep Rangappa

49. Sinus Tachycardia in Intensive Care Unit: Should it be Treated?

247

Mukul Misra, Ashootosh Mall, Lokendra Gupta

SECTION 8: Endocrine and Metabolism 50. Are Steroids Interchangeable?

255

Sunil Karanth, Prashant Nasa, Ajith Kumar AK

51. Interpretation of Cortisol Levels in the Intensive Care Unit

261

Prakash Jiandani, Gunjan Chanchalani

SECTION 9: Trauma Burns 52. Disaster Preparedness

267

Simant Kumar Jha, K Swarna Deepak, Sanjay Shah

53. Severe Head Trauma

273

HR Rajathadri, Sulagna Bhattacharjee, Raymond Dominic Savio

54. Challenges of Managing Polytrauma in Accidental COVID Positive Patient

281

Ritesh Shah, Vikas Sikri, Saswati Sinha

55. Whole Blood in Trauma AK Singh, Nikhil Kothari, Ankur Sharma, Aditya Shukla

286

xxvii

xxviii

Contents

56. Coagulopathies and Reversal Agents

291

Babu Abraham

57. New Chemical Burns

296

K Swarna Deepak, Shyamsunder Tipparaju, Ajit Kumar

58. Infection Control in Burn Patients

300

Simant Kumar Jha, Yash Javeri, Ashutosh Bhardwaj

SECTION 10: Hemodynamic Monitoring 59. Hypotension Prediction Using Artificial Intelligence

307

Avneep Agarwal, Kamal Maheshwari

60. Artificial Intelligence and Management of Hypotension

310

Piyush Mathur, Ashish K Khanna, Tavpritesh Sethi

61. Artificial Intelligence and Algorithmic Approach to Circulatory Shock

314

Bharat Jagiasi, Tanmay Jain, Sheila Nainan Myatra

SECTION 11: Perioperative and Resuscitation 62. Perioperative Risk Prediction

321

Gentle S Shrestha, Saurabh Pradhan, Tamanna Bajracharya

63. Role of High-flow Nasal Cannula in Operating Room

326

Arjun Alva, Mohan Maharaj, Shailender Kumar

64. Postresuscitation Care: Temperature Management after Cardiopulmonary Resuscitation

330

Gavin D Perkins, Jerry P Nolan

SECTION 12: Toxicology 65. New Recreational Designer Drug Overdose Challenges

337

Sai Saran, Lalit Gupta, Haider Abbas

66. Newer Trends in Organophosphorus/Carbamates Revisits

342

Lalit Singh, Narendra Rungta, Diptimala Agarwal

67. Extracorporeal Life Support in Poisoning

347

Vivek Gupta, Vinay Singhal, Gurpreet S Wander

68. What’s New about Antivenom and its Dosing

352

Dilipbhai Patel, Nagarajan Ganapathy, Sanjay Dhanuka

SECTION 13: Hematology Oncology 69. Managing Acute Hemolysis in Intensive Care Unit

359

Subhal Dixit, Khalid Khatib

70. Airway Management Issues in Oncology

362

Rekha Das, Amol Kulkarni, Syed Moied Ahmed

71. Tissue Target Therapy and Associated Complications

368

Asif Ahmed, Bharat Parikh, Rahul Jaiswal

72. Hemophagocytic Lymphohistiocytosis Syndrome: Current Status

372

Arun K Baranwal, Lalit Takia

73. Metabolic Crisis in Oncology Patients

378

Rakesh Garg, Priyanka Singhani, Sulagna Bhattacharjee

74. Intelligent Interpretation of the Hemogram Farhad Kapadia, Ritika Sharma, Jagannath Jare

385

Contents

SECTION 14: Transplant/Organ Donation 75. Liver Transplantation: A Critical Care Perspective

393

Vaishali Solao

76. Heart Transplant: What Intensivist Must Know?

397

Bhagyesh Shah, Dhiren Shah, Niren Bhavsar

77. Lung Complications after Hematopoietic Stem Cell Transplant

402

Mrinal Sircar, Sanket Shah

78. Approach to Donor-derived Infection and Colonization in the Intensive Care Unit

408

Parikshit S Prayag, Vasant Nagvekar

79. Antiviral Drugs in Transplant Recipients

412

Rajeev Soman, Sujata Rege, Geethu Joe

SECTION 15: Autoimmune Diseases 80. Autoimmune Crisis Management: Drugs—Which One and When?

423

Arun Dewan, Bikram Kumar Gupta, Ritesh Aggarwal

81. Identifying Autoimmune Crisis in Intensive Care Unit

428

Kapil Borawake, Reena Sharma

SECTION 16: Medicolegal and Ethics 82. Humanization of Healthcare in the Intensive Care Unit

435

Deven Juneja, Suneel Kumar Garg, Siddharth Verma

83. Public Health Concerns in Pandemic Related to Critical Care Medicine

440

JV Peter

84. Indemnity Insurance for Intensivist

445

Anirban Hom Choudhuri, Sudhir Khunteta, Manish Munjal

85. Ethical Concern in Economically Restricted Package Patients

448

Ashish Bhalla, Bikram Kumar Gupta, Deepak Malviya

SECTION 17: Quality/ICU Organization 86. Effective Communication Skills and Tools in Intensive Care Unit

457

Monika Gulati

87. Critical Care in Discrete Locations

462

Rohit Aravindakshan Kooloth, Suresh Kumar Sundaramurthy, Nagarajan Ramakrishnan

88. Safety Tips for Critical Care Personnel

467

Mohan Maharaj, Shweta Chandankhede, Venkat Kola

89. Step-down Intensive Care Unit: Role in Present Healthcare Scenario

476

Gyanendra Agrawal, Smita Sharma, Ranvir Tyagi

90. Team Building in Intensive Care and Liaising with Administration

479

Kunal Punamiya, Rahul Pandit

91. Interspecialty Communication: Finding the Right Balance

483

Simran J Singh

92. Career Path in Critical Care in India

489

Asish Kumar Sahoo, Prakash Shastri

93. Intensive Care Unit in Night Shakya Mohanty, Shivangi Khanna, Jeetendra Sharma

492

xxix

xxx

Contents

94. How to Mitigate Ill Effects of High Staff Attrition Rates in ICU?

496

Neeru Gaur, Pradeep Bhatia, Revathi Aiyer

95. Purchasing New Devices for Intensive Care: What do I Look for?

499

Vipul Pranlal Thakkar, Lalit Gupta, Vijay Mishra

96. Smart Intelligent Bedside Monitoring and Infusion Pumps

504

Khusrav Bajan

97. Critical Care Trainees Competencies: How to Map and Maintain?

511

Subhash Todi

98. How to Improve Compliance to Protocols in Intensive Care Unit?

515

Arvind Baronia, Gautham Raju, Nitin Rai

99. Trigger Tools in Intensive Care Unit

520

Himanshu Pandya, Pradip Bhattacharya, Samir Patel, Jay Prakash

100. Newer Critical Care Apps

524

Tapas Kumar Sahoo, Lalit Singh, Pankaj Anand

101. Use of Electronic Record and Hybrid Integration of Electronic Intensive Care Unit in Critical Care Practice

529

Sai Praveen Haranath, Priyanka H Chhabra, Pradeep Rangappa

SECTION 18: Radiology 102. Role of Interventional Radiologist in Critical Care Setting

535

Rozil Gandhi, Ankur Bhavsar, Gopal Raval

103. Contrast Nephropathy: What is New?

551

Balasubramanian S, Prakash KC

104. How to Avoid Catastrophe in Radioimaging?

554

Amrish Patel, Digvijaysinh Jadeja, Tejas Karmata

105. Bubble Contrast Imaging

558

Sachin Gupta, Shrikanth Srinivasan, Deeksha Singh Tomar

106. Approach to Undifferentiated Fever in the ICU by POCUS: A New Way?

561

Pradeep M D’Costa

SECTION 19: Present and Future Challenges in ICU Organization and Management 107. Organizational Challenges of Intensive Care Unit in India during the COVID-19 Pandemic: How to Prepare?

571

Ratender K Singh, Om P Sanjeev, Chandrakanta Singh

108. Managing Change in Intensive Care Unit: Why Won’t Doctors Do What They’re Told?

577

Gauri R Gangakhedkar, Jigeeshu V Divatia

109. The Current State of Clinical Information Systems in Critical Care in India

583

Anuj Clerk, Biren Chauhan, Krunalkumar Patel

110. Challenges and Issues in Intensive Care Nursing in India: How to Overcome Them?

589

Susruta Bandyopadhyay, Manoj Kumar Rai, Manish Bharti

111. Gut Dysfunction in Intensive Care Unit: Recent and Future Advances in Diagnosis and Management

592

Avinash Tank, Kalpesh Shah, Rajeev Kumar Bansal

112. Intensive Care Management of Acute Liver Failure: What is New?

596

Lalita Gouri Mitra, Juhi Chandwani, Amit Singhal

113. Caring for the Dying Patient in Indian Intensive Care Unit: Quality of Care, Ethical, and Legal Challenges

602

Abhishek Prajapati, Rachit Patel, Bhalendu Vaishnav

114. Pregnancy-associated Severe Sepsis: Present State and Challenges Anjan Trikha, Prachee Makashir, Sunil T Pandya

607

Contents

SECTION 20: Extracorporeal Membrane Oxygenation and Extracorporeal Cardiopulmonary Support 115. Multimodality Extracorporeal Life Support

613

Poonam Malhotra Kapoor

116. Futility in Extracorporeal Circulation with Mechanical Devices

622

Venkat S Goyal, Pranay Oza, Samir Gami

117. Referral for Extracorporeal Life Support: Right Time

627

Riyan Sukumar Shetty, Vimal Bhardwaj, Muralidhar Kanchi

118. Transport with ECS

634

Deepak Govil, Praveen Kumar, Vivek Kakar

119. Death Declaration in Patients on ECS

638

Sanjay Nihalani, Kalpana Krishnareddy, Hossam Elshekhali

SECTION 21: Data Science and Artificial Intelligence 120. Artificial Intelligence and Data Science in Critical Care

643

Aditya Nagori, Ridam Pal, Tavpritesh Sethi

SECTION 22: Research Methodology 121. How to Critically Appraise a Critical Care Published Paper?

651

Amrita Prayag, Prasad Rajhans, Purushotham Godavarthy

122. Platform Trials

657

Anirban Hom Choudhuri, Deepika Jain, Ripon Choudhary

123. Bayesian Analysis of Trial Results

661

Prashant Nasa, Vikas Sikri

124. Adaptive Clinical Trial Design

666

Kushal Rajeev Kalvit, Atul Prabhakar Kulkarni

125. The Right End-points for Critical Care Trials

670

Ram E Rajagopalan, Janarthanan S, Vetriselvan P

SECTION 23: COVID-19 Related Issues 126. Pathophysiology of Happy Hypoxia in COVID

677

Abhinav Gupta, Vikas Gulia

127. Hypoxemia and Cardiorespiratory Compensation in COVID-19

680

Amit Kumar Mandal, Alok Sahoo, Swagata Tripathy

128. Coronavirus Disease-associated Fungemia

686

Shivaprakash M Rudramurthy, Arunaloke Chakrabarti

129. COVID-19-associated Pulmonary Aspergillosis

692

Avinash Agrawal, Manoj Goel, Vikas Kesarwani

130. Post-COVID Vaccine Complications

699

Sandeep Kantor, Sunil Garg, Mayank Vats

131. Immunomodulators in Coronavirus Disease-2019

704

Subhankar Paul, Rajesh Kumar Pande

132. Decrease in COVID-19-associated Mortality Rates

714

Mradul Daga, Raghu RV, Siddharth Chand

133. Post-COVID Pulmonary Syndrome Jasbir Singh Chhabra, Vijay Narain Tyagi, Lalit Mishra

718

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Contents

134. Right Ventricle Failure in COVID-19

722

Sharmili Sinha, Ravi Jain, Raj Raval

135. Dilemma of D-Dimer in COVID-19

727

Apurba Kumar Borah, Banambar Ray, Pragyan Routray

136. Steroid in Acute and Post-COVID-19 Pulmonary Syndrome

733

Prachee Sathe, Tanima Baronia

137. Fluid Management in COVID-19: Principles and Practice

739

Roop Kishen, Saurabh Taneja

138. Cytokine Removal in COVID-19-related Sepsis/Cytokine Storm

743

Vivek Nangia, Amina Mobashir, Sidhaant Nangia

139. Cough Management in COVID Patients

748

Vinay Singhal, Amit Gupta, Kunal Sahai

140. Post-COVID Neuropsychiatric Complications

752

Anand Sanghi, Chirag Matravadia, Rajesh Maniar

141. Constipation and Diarrhea in COVID Patients: Management

756

Mansi Dandnaik, Ripal Patel Shah, Tejash Parikh

142. Diabetic Ketoacidosis in COVID New Onset Patients

761

Banshi Saboo, Jigar Mehta, Subhajyoti Ghosh, Jothydev Kesavade

143. Unexplained Deterioration in COVID-19 Patients

767

Amitkumar Prajapati, Harendra Thakker, Minesh Mehta

144. Autopsies Findings in SARS-CoV-2 Patients

769

Quirino Piacevoli

145. Perioperative Concerns in COVID

773

Pradeep Bhatia, Sadik Mohammed, Shilpa Goyal

146. Prolong Sedation, Analgesia, and Paralysis in COVID-19—Adverse Outcome

779

Palepu B Gopal, VVSSD Prasanthi

147. Multisystem Inflammatory Syndrome in Adults

785

Yatindra Dube, Akshaykumar Chhallani, Nirmal Jaiswal

148. Lung Transplant Success Stories in COVID

787

Vijil Rahulan, Unmil Shah, Sharanya Kumar

149. Cytomegalovirus Reactivation in COVID Patients

793

Nikhilesh Jain, Vishwesh Mehta

150. Inflammatory Markers in COVID

796

YP Singh, Akhil Taneja, Gaurav Pratap Singh

151. Hyperferritinemia in COVID-19 Patients

800

Vajrapu Rajendra, K Subba Reddy, Sambit Sahu

152. Extracorporeal Membrane Oxygenation in COVID-19: Is it Different?

802

Dipanjan Chatterjee, Arpan Chakraborty

153. Approach to Shock in COVID Patients

806

Manasi Shahane, Sameer Jog, Srinath Marreddy

154. Full-term Pregnancy with COVID-19: An Intensivist’s Perspective

811

Arti Singh, Shikha Sachan

Index815

1 S EC TI ON

Applied Physiology œ Physiology of Cerebral Blood Flow Autoregulation Bhuvna Ahuja, Sabina Regmi, Ajay Prajapati

œ Hardcore Mathematics in Intensive Care: Alveolar Gas and Shunt Equation Satish Deopujari, Vivekkumar K Shivhare, Jignesh Shah

œ Dynamic Airway Collapse and its Clinical Effects Javier Perez-Fernandez, Arlene Torres, Paola Perez

œ Physiology and Pharmacology of Vasopressor Selection in Septic Shock Fredrik Olsen, Patrick M Wieruszewski, Ashish K Khanna

œ Cardiac Output, Arterial Elastance, and Transmural Pressure Swati Deepak Parmar, Ramanathan Kollengode

œ Immune Dysregulation in Sepsis Andrew Conway Morris

1

Physiology of Cerebral Blood Flow Autoregulation

C H A P T E R Bhuvna Ahuja, Sabina Regmi, Ajay Prajapati

INTRODUCTION The regulation of cerebral blood flow (CBF) is a complex pro­ cess. Various studies recently tried to elucidate the physiology of CBF autoregulation. Mainly four mechanisms have been proposed for cerebral flow autoregulation, that is, myogenic, neurogenic, metabolic, and endothelial responses. However, it is critical to distinguish cerebral autoregulation from flow metabolism coupling as well as carbon dioxide reactivity.1 With deeper understanding of autoregulation, researchers have developed technologies to measure autoregulatory function in real time. An individualized approach to cerebral perfusion pressure (CPP) target based on patients’ distinc­ tive hemodynamics might enhance their outcome in acute brain injury. Autoregulation can be assessed by analyzing the changes in CBF, or it substitutes, because of changes in CPP or mean arterial pressure (MAP).2,3 This chapter deals in depth with the mechanism of auto­ regulation, methods to measure it and its use in various clinical scenarios.

MECHANISM OF AUTOREGULATION Cerebral Blood Flow Regulation and Physiology (Fig. 1)

Another concept to explain CPP is via pressure gradient between MAP and cerebral venous pressure, approximately equivalent to intracranial pressure (ICP). Figure 2 shows the relationship between CBF and MAP. The normal range of MAP is 60–160 mm Hg. CBF = CPP/CVR = (MAP – ICP)/CVR Major contribution to the vascular resistance of the brain is the tone of blood vessels. The smooth muscle tone is moderately influenced by MAP. If CPP increases or decreases, the myogenic reflex will end in vasoconstriction or vasodilation, respectively. This is the classical interpre­ tation of pressure-flow autoregulation. If ICP is stable, CPP and MAP can be used interchangeably. This observation has been exercised to determine changes in brain blood flow for a range of blood pressures (BPs) to determine autoregulation.

Myogenic Response The myogenic response is produced when arterioles and artery smooth muscle cells contract in response to increased pressure and relaxes in response to decreased pressure.

Cerebral blood flow is directly proportional to CPP and inversely proportional to cerebrovascular resistance (CVR).

Fig. 1: Diagrammatic representation of regulation of cerebral circulation.

Fig. 2: The relation between cerebral blood flow and mean arterial pressure.

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Section 1:  Applied Physiology This effect is known as Bayliss effect. The myogenic tone is observed in arterioles and in arteries denuded of endothelium. It mainly involves two phenomena: Myogenic tone, which involves partial constriction at constant pressure and myogenic reactivity, in which alteration in tone due to changes in pressure. Also, a third phenomenon is involved called forced dilatation. It is a protective phenomenon most likely due to activation of K Ca2+ channels in combina­tion with production of reactive oxygen species. Transmural pressure changes activate mechanically sensitive ion channels and proteins in the vessel wall, triggering various downstream cascades. (R) Increase in pressure causes depolarization of smooth muscle cell mem­ brane followed by opening up of voltage-gated calcium channels and influx of calcium ions. Intracellular calcium activates myosin light chain kinase (MLCK), which acti­ vates myosin by phosphorylation. Phosphorylated MLCK increases actin-myosin interaction, causing muscle cell contraction (myogenic tone) and vasoconstriction (myogenic reactivity). With increase in intravascular pres­ sure there may not be significant change in vessel diameter, but further vasoconstriction occurs. The vessel wall stiff­ ens due to enhanced myosin light chain (MLC) phosphor­ ylation and contraction that is further reinforced by actin polymerization. A rare cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, i.e., CADASIL, is an obvious example of smooth muscle cell myogenic regulation. In CADASIL, patients develop smooth muscle cell degeneration in small cerebral arteries. In CADASIL, mutation in the NOTCH3 gene is observed and marked by recurrent ischemic strokes, cognitive impairment, subcortical dementia, mood disturbances such as depression, and apathy, as well as premature death.4

Neurogenic Response Neurogenic cerebral vasoreactivity is seen in small and medium size vessels. Neurotransmitters secreted by neu­ rons and other neural cells play a significant role due to their vasoactive properties. Acetylcholine and nitric oxide (NO) are relatively potent vasodilators, while serotonin and neuropeptide Y stimulate vasoconstriction.5 Infrared videomicroscopy of interneurons and adjacent microvessels in rodents was paramount in displaying that increased depo­ larizing activity of single cortical interneurons gives rise to precise vasomotor responses in adjoining microvessels.6 The transformations in blood flow in response to neuronal activation are discerned as blood oxygen level-dependent (BOLD) signals in functional magnetic resonance imaging (fMRI). The BOLD response has been adapted in many fMRI studies investigating increased cerebral metabolic demand in visual, cognitive, and spatial functioning as well as diseased states of the brain.

There is regional heterogeneity within the brain with anterior circulatory system comprising of denser sympa­ thetic innervation than the posterior circulatory system. The anterior circulation receives sympathetic innervation via the superior cervical ganglion as they run up the carotid artery, whereas the posterior circulation receives its sympa­ thetic innervation via the vertebrobasilar arteries. In conjunction autoregulation has also exhibited superior efficacy within the brainstem. In one of the studies, it was found that in anesthetized cats with severe hypertension, CBF significantly increased in anterior circulation, whereas there was only moderate increase in CBF in the brainstem.7 This points to a possible regional inconsistency in cerebral autoregulation within the brain. Such property may have implications in the development of posterior reversible encephalopathy syndrome (PRES). This syndrome, which incidentally is not always posterior or maybe reversible, is otherwise characterized radiologically by transient bilateral subcortical vasogenic edema within the posterior circulation.8 Several etiologic theories have been proposed including immunologic dysfunction, vasospasm, and barrier breakdown. One such interesting explanation for the edema’s apparent posterior predilection is the relative deficiency of sympathetic tone in the area, resulting in poor autoregulation of blood flow in the setting of abrupt hypertensive episodes.

Metabolic Response The metabolic response plays a role in autoregulation in small size vessels, wherein local environment causes the changes. Carbon dioxide changes effect vasomotor response, with every 1 mm Hg increase in partial pressure of carbon dioxide, there is 4% increase in CBF.9 In situation of hypoperfusion due to hypotension below autoregulatory range, partial pressure of cerebral carbon dioxide increases causing vasodilatation and thus anaerobic respiration. The opposite physiology sets in hyperperfusion situation that is decrease in cerebral partial pressure of carbon dioxide, causing vasoconstriction. One hypothesis states that proton concentration regulation by carbonic anhydrase activity in cerebral vessels smooth muscles plays a role in vasomotor regulation. At severe hypoxemia due to decreased oxygen partial pressures (130 mL/min/1.73 m2 leading to increased clearance of drugs from the system and subtherapeutic drug levels. This is particularly common in young healthy trauma or septic patients. Augmented clearance is difficult to predict and not picked up by standard Cockcroft Gault or MDRD (Modification of Diet in Renal Disease) equations but present in 14–80% of patients. Hence, urinary creatinine clearance must be measured to pick this up from 8 to 24 hours urine collection. On the opposite side, renal dysfunction is very common in ICU and so is toxicity of accumulated drugs from over exposure. The Vd in critical illness can go up from intravenous (IV) fluid bolus and capillary leakage (endothelial dysfunction and loss of glycocalyx). Hydrophilic drugs such as aminoglycosides, beta-lactams, teicoplanin, etc., can change drug concentration from these altered Vd. Similarly very protein bound drugs such as teicoplanin can produce higher free or unbound drug fraction. Obesity is another factor that determines distribution of lipid soluble drugs such as linezolid.

INTERPRETATION OF THERAPEUTIC DRUG MONITORING For accurate analysis of any TDM data, patient’s clinical status has to be taken into account. To do an accurate TDM, the team must be informed in detail about the time of sample, the time of initiation of therapy, and the time of last dose because if a sample is obtained before the drug distribution is complete, the levels will be falsely high. The time of administration and the mode of administra­ tion like bolus versus infusion should be taken into account.

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Section 2:  Infections/Sepsis/Infection Control Any factor which leads to changes in drug absorption should also be kept in mind. Except in few situations, the samples are drawn at the trough or just before the next dose. Peak plasma concentration, Cmax, is helpful for certain antibiotics such as aminoglycosides. For antibiotics whose peak plasma concentration is to be measured, the TDM should be done 30 minutes after the end of infusion and if given by bolus, TDM should be done 60 minutes after the bolus dose. In cases of repeated drug administration, a steady state concentration is reached after about 5 plasma half-lives, so plasma concentration should be measured at this point. However, steady state concentration is reached earlier if a loading dose has been given. For drugs such as amiodarone with long half-lives, the TDM should be done earlier than steady state concentration because there is a risk of toxicity at the initial dose regimen.6,7 In case the drug produces any active metabolite, TDM should encompass both the drug and the metabolite.8

THERAPEUTIC DRUG MONITORING FOR INDIVIDUAL DRUG GROUPS Antimicrobials Antimicrobials generally have different PK/PD indices. These are as follows: ■ The ratio of [Cmax/minimal inhibitory concentration (MIC)] ■ The fraction of time (T) that the unbound drug concentration remains over the MIC during a dosing interval (fT>MIC) ■ The “area under the concentration–time curve during a 24-hour period” to MIC (AUC/MIC) ratio. Now in most laboratories they use limited sampling studies to predict AUC instead of sampling blood every 15 minutes. Use of dosing software have replaced complex nomograms for drugs such as vancomycin. Therapeutic drug monitoring is important for this group of drugs to find out if drug concentrations are reaching above the MIC for the desired period of time. MIC of the drug determines the minimum concentration in blood necessary to kill the microbe growing in culture. It is an important component of PK/PD of the antimicrobial and hence monitoring the drug level is of great significance. Therapeutic drug monitoring is also relevant when we want to ensure minimum drug toxicity like for nephrotoxic drugs. TDM allows dose reduction when unnecessary high concentration is measured. The recent surge of multidrugresistant (MDR) organism along with a lack of upcoming antibiotics has made TDM all the more essential besides antimicrobial stewardship. Measuring therapeutic drug levels are important and cost-effective for antimicrobials which satisfy the following criteria:

■ Significant intra/interindividual PK variability ■ Defined exposure range is associated with drug response. ■ Has defined sampling end points ■ Accurate and timely bioanalytical assays are available.

The A-TEAMICU survey9 was done to understand the use and feasibility of anti-microbial stewardship programs and TDM policies in critical care units from across the globe including USA, Europe, and India. TDM of antimicrobials was practised in 61% of ICUs. Most commonly done are glycopeptides (89%), aminoglycosides (77%), carbapenems (32%), penicillins (30%), azole antifungals (27%), cephalosporins (17%), and linezolid (16%). Continuous infusion of antimicrobials was found in more than 3/4th ICUs. Wherever there was a structured AMS programme, TDM policies also found to be co-existing. In its position paper on TDM for antimicrobials,8 ESICM has given the following guidelines for TDM. It recommends TDM for the following antibiotics: ■ Aminoglycosides: AUC/ MIC has replaced Cmax as the PK/PD index which determines the efficacy of the drug. Cmin (minimum blood concentration) is measured to determine the threshold for oto- and nephrotoxicity. Here, two samples are to be taken. First one should be drawn 30 minutes after infusion is over and the second one should be drawn between 6 and 22 hours postinfusion. To determine Cmax/MIC, another less reliable target, only one sample 30 minutes after infusion needs to be collected. Cmax refers to peak plasma concentration of the drug. Cmin refers to minimum plasma concentration. ■ Beta-lactams, carbapenems: These antimicrobials have concentration-dependent PK and hence fraction of time when blood concentration remains above MIC needs to be measured. Usual target is >50% fT>MIC. Cmin needs to be measured to determine toxicity. Based on this fact, the TDM sample needs to be collected just before or 30 minutes before the next dose. ■ Vancomycin: The AUC/MIC of vancomycin determines its efficacy against the bacteria. Two blood samples need to be collected. First sample should be drawn 60 minutes after end of infusion and the second sample should be drawn 1–2 hours after starting of next infusion. Cmin is measured by collecting blood 30 minutes or just before the next dose. Cmin is used to determine toxic range. AUC/MIC >400 is the target which becomes difficult to achieve for MIC >1. For teicoplanin and linezolid also, it is recommended to measure AUC/MIC for efficacy. Linezolid dosing may need to be increased or dosing intervals changed in critical illness, ARDS, or against microbes with high MIC. Linezolid is lipophilic and dose needs to be changed for obesity. The AUC and Cmin values can predict hematological toxicity of linezolid.

Chapter 13:  Therapeutic Drug Monitoring On the other hand, teicoplanin is largely protein bound and has very variable unbound drug fractions in patients with low plasma proteins. ■ Voriconazole: It is an anti-fungal drug with concentrationdependent PK and hence Cmin needs to be measured. Based on this fact, the TDM sample needs to be collected just before or 30 minutes before the next dose. The blood sampling should be done between day 2 and day 5 of therapy. For certain other toxic antifungals such as flucytosine, Cmax determines toxicity. ■ Antivirals do not fall under society guidelines for measuring TDM. However, there is provision for TDM of ganciclovir/valganciclovir and ribavirin. AUC is the clinical target here. ■ Others: For other antimicrobials, there is no recommendation in favor or against TDM. But for certain drugs such as polymyxins and daptomycin, TDM is useful to determine efficacy and toxicity in special situations and the AUC/MIC should be measured. In the Indian subcontinent, a short mention of polymyxins in regard to TDM seems reasonable. The therapeutic index for colistin is very narrow and hence TDM samples should be collected for Cmin just before the next dose. These samples should also be quickly processed. The data on polymyxin B is scarce. Current evidence suggests that normal dose for loading is 2.5 mg/kg followed by 2.5 mg/kg in divided doses. For MIC >1, the daily dose should be up to 3 mg/kg. These doses are based on total body weight.

■ The ECMO blood flow does not influence the drug levels.

EXTRACORPOREAL MEMBRANE OXYGENATION AND THERAPEUTIC DRUG MONITORING FOR ANTIMICROBIALS

THERAPEUTIC DRUG MONITORING FOR ANTICONVULSANT MEDICATIONS (ANTIEPILEPTIC DRUGS)

Increase in the use of extracorporeal membrane oxygenation (ECMO) in the ICU for the treatment of respiratory and/ or cardiac failure has made TDM in ICU more relevant. Particularly, drug dosing may seem impossible in situations where these patients are on both ECMO and continuous renal replacement therapy (CRRT). However, it is still an uncharted territory whether dose modifications are necessary to improve efficacy of an antimicrobial in septic ECMO patients. In a single centre observational study,10 it was seen that: ■ Serum concentrations of piperacillin and standard-dose meropenem (1 g IV 8 hourly) were significantly lower in ECMO patients than in control population. ■ A large chunk of ECMO patients treated with piperacillin (48%) and linezolid (35%) did not attain the prespecified MIC targets. ■ It is interesting to note that 13–15% patients receiving piperacillin or linezolid also did not achieve adequate drug concentration in the non-ECMO group making a point for monitoring TDM in case of these drug therapies.

Antiepileptic drugs (AEDs) are one of the most frequently used drug in the ICU and here lies the relevance of TDM for AEDs in ICU.15 Therapeutic drug monitoring helps to improve the quality of care, helps to check adherence, and increase safety especially in ICU patients and patients who are on polypharmacy. It has been noted that there is a significant PK variability for individual AED drugs and lot of enzyme inductions in view of multiple drugs patients are on, hence TDM is a safe bet for optimal therapy. There have been various studies on TDM for AED but there is a lack of such studies for critically ill patients. Still we will discuss some of the large studies in order to see what are the observations of TDM for AED. In a tertiary center study in India, we see that a significant percentage (51%) of patients had a plasma concentration of the AEDs below the therapeutic levels. This percentage was even higher, (54%) when two or more AEDs were being used.16



Therapeutic drug monitoring for antimicrobials in patients on renal replacement therapy (RRT) are as follows: Various renal replacement therapies (RRTs) affect drug clearance in different ways. In general, the following conditions lead to higher drug clearance: ■ Higher dialysate and ultrafiltrate rates ■ Longer durations of dialysis ■ Higher permeability hemofilters. If we put together the methods of drug clearance by dialysis along with duration of RRT, as a general rule, we arrive at the following efficiency of drug removal: Continuous venovenous hemodiafiltration (CVVHDF) > continuous venovenous hemodialysis (CVVHD) > continuous venovenous hemofiltration (CVVH) > prolonged intermittent renal replacement therapy (PIRRT) ≥ ischemic heart disease (IHD).11 In patients receiving CRRT, although the standard dose of meropenem is 500 mg IV 8 hourly, the dosing of 1 g every 8 hours infused over 3 hours should be considered for pathogens with higher MICs (2–4 mg/L).12 Piperacillin-tazobactam 4.5 g every 8 hours in ICU patients receiving CVVHDF has been shown to attain target drug levels for organisms with an MIC ≤32 mg/L.13 A prospective study of intensive care unit patients receiving CVVH and vancomycin therapy concluded that 500–750 mg every 12 hours would be adequate to achieve the target trough goals, and serum vancomycin concentrations should be closely monitored.14

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Section 2:  Infections/Sepsis/Infection Control In patients who were referred for TDM, because of suspected toxicity, 59% had a drug concentration above the desired range. In another study on TDM for valproate levels, they chose to study the unbound fraction of valproate. The unbound valproate levels in patients with glomerular filtration rate (GFR) 70 years, and those who were suspected to have toxicity were studied. The study concluded that it was clinically more useful to monitor the free fraction of valproate as compared to total valproate levels. In patients with signs of toxicity, only 5% had a total VAL level above the desired range whereas 37% had an unbound valproate level in the toxic range.17 In a systemic review by Zanab et al., it was concluded that TDM of AEDs had no effect on final seizure outcome. It only led to a better control of seizure frequency.18

CONCLUSION The complex pathophysiology and polypharmacy in ICU makes it difficult to predict drug dosages which shall reach effective drug concentrations at the site of action. The two most common classes of drugs in this category are antimicrobials and anticonvulsants. There is increasing evidence and recommendation that TDM is necessary in ICU population. Also with increasing antimicrobial resistance, TDM will become an important equipment to fight emergence of super bugs in near future.

REFERENCES 1. Touw DJ, Neef C, Thomson AH, Vinks AA. Cost effectiveness of therapeutic drug monitoring: a systemic review. Ther Drug Monit. 2005;27(1):10-7. 2. Birkett DJ. Pharmacokinetics made easy: Therapeutic Drug Monitoring. Aust Prescr. 1997;20:9-11. 3. Ghiculescu RA. Therapeutic drug monitoring: which drugs, why, when and how to do it. Aust Prescr. 2008;31:42-4. 4. Bodenham A, Shelly MP, Park GR. The altered pharmacokinetics and pharmacodynamics of drugs commonly used in critically ill patients. Clin Pharmcokinet. 1998;14(6):347-73. 5. Mahmoud SH, Shen C. Augmented renal clearance in critical ill‐ ness: an important consideration in drug dosing. Pharmaceutics. 2017;9(3):36. 6. Kang JS, Lee MH. Overview of therapeutic drug monitoring. Korean J Intern Med. 2009;24(10):1-10. 7. Tabah A, De Waele J, Lipman J, Zahar JR, Cotta MO, Barton G, et al. The ADMIN-ICU survey: a survey on antimicrobials dosing and monitoring in ICU. J Antimicrob Chemother. 2015;70(9):2671-7.

8. Abdul-Aziz MH, Alffenaar JC, Bassetti M, Bracht H, Dimopoulos G, Marriott D, et al. Antimicrobial therapeutic drug monitoring in critically ill adult patients: A position paper. Intensive Care Med. 2020;46(6):1127-53. 9. Lanckohr C, Boeing C, De Waele JJ,  de Lange DW, Schouten J, Prins M, et al. Antimicrobial stewardship, therapeutic drug monitoring and infection management in the ICU: results from the international A- TEAMICU survey.  Ann Intensive Care. 2021;11(1):131. 10. Kühn D, Metz C, Seiler F, Wehrfritz H, Roth S, Alqudrah M, et al. Antibiotic therapeutic drug monitoring in intensive care patients treated with different modalities of extracorporeal membrane oxygenation (ECMO) and renal replacement therapy: a prospective, observational single-center study. Crit Care. 2020;24:664. 11. Hoff BM, Maker JH, Dager WE, Heintz BH. Antibiotic dosing for critically ill adult patients receiving intermittent hemodialysis, prolonged intermittent renal replacement therapy, and continuous renal replacement therapy: An Update. Ann Pharmacother. 2020;54(1):43-55. 12. Ulldemolins M, Soy D, Llaurado-Serra M,  Vaquer S, Castro P, Rodríguez AH, et al.  Meropenem population pharmacokinetics in critically ill patients with septic shock and continuous renal replacement therapy: influence of residual diuresis on dose requirements. Antimicrob Agents Chemother. 2015;59(9):5520-8.  13. Varghese JM, Jarrett P, Boots RJ, Kirkpatrick CM, Lipman J, Roberts JA. Pharmacokinetics of piperacillin and tazobactam in plasma and subcutaneous interstitial fluid in critically ill patients receiving continuous venovenous haemodiafiltration. Int J Antimicrob Agents. 2014;43(3):343-8.  14. Sin JH, Newman K, Elshaboury RH, Yeh DD, de Moya MA, Lin H.  Prospective evaluation of a continuous infusion vancomycin dosing nomogram in critically ill patients undergoing continuous venovenous haemofiltration. J Antimicrob Chemother. 2018;73:199-203.  15. Landmrak CJ, Johannessen SI, Patsalos PN. Therapeutic drug monitoring of antiepileptic drugs: Current status and future prospects. Expert Opin Drug Metab Toxicol. 2020;16(3): 227-38. 16. Taur SR, Kulkarni NB, Gogtay NJ, Thatte UM. An audit of therapeutic drug monitoring services of anticonvulsants at a tertiary care hospital in India. Ther Drug Monit. 2013;35(2):183-7. 17. Wallenburg E, Klok B, de Jong K, de Maat M, van Erp N, Stalpers-Konijnenburg S, et al. Monitoring protein-unbound valproic acid serum concentrations in clinical practice. Ther Drug Monit. 2017;39(3):269-72. 18. Al-Roubaie Z, Guadagno E, Ramanakumar AV, Khan AQ, Myers KA. Clinical utility of therapeutic drug monitoring of antiepileptic drugs: Systematic review. Neurol Clin Pract. 2020;10(4):344-55.

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Syndromic Polymerase Chain Reaction-based Diagnostics in Sepsis

C H A P T E R Bhavini Shah

INTRODUCTION Sepsis is a life-threatening organ failure induced by a dysregulated host response to infection, and it is the leading cause of mortality in intensive care units (ICUs).1 When the body’s immunological reaction to a viral, fungal, or (more typically) bacterial infection produces damage, malfunction, or even failure of the host’s own tissues and organs, sepsis develops. The cornerstone of sepsis therapy is the prompt use of antimicrobial medicines that are active against the causing bacteria.2 Represents a prime public fitness hassle and is most of the maximum not unusual place motives for admission to the in depth care unit (ICU). Mortality associated with sepsis stays high, regardless of enhancing effects in healthcare, being the second one main motive of loss of life withinside the noncoronary.3 Patients who remain in the critical care unit for >24 hours were examined daily for signs and symptoms of systemic inflammatory response syndrome (SIRS), sepsis, and severe sepsis using American College of Chest Physicians (ACCP)/Society of Critical Care Medicine (SCCM) criteria. If the patient presented two almost all of the following clinical symptoms, SIRS was considered to be present; (1) body temperature >38°C or 90 bpm; (3) hyperventilation indicated by a respiratory rate >20 beats per minute (bpm) or a PaCO2 (partial pressure of carbon dioxide) 1,600 samples, there was a high degree of agreement between the BCGP test results and those obtained with conventional blood culture and analysis methods, regardless of whether the samples were fresh or frozen, and a high degree of concordance in the identification of a mecA-methicillin resistance mediated by S. aureus and S. epidermidis and vancomycin resistance mediated by vanA or vanB in E. faecalis, and E. faecium organisms.32

FilmArray® FilmArray (Biofire Diagnostics, Salt Lake City, UT, USA) is a multiplex PCR tool that analyzes 24 sepsis-causing organisms and four antibiotic resistance genes. The assay is based on the extraction and purification of blood culturepositive nucleic acids and the amplification of target genes by first-stage reverse transcriptase PCR. It is a low complexity system for the clinician that only requires injecting the blood culture sample into a bag and starting the instrument; therefore, laboratory procedures can be performed by personnel without training in molecular techniques. The BioFire FilmArray BCID panel is a two-step nested multiplex PCR assay with the ability to detect 24 target

organisms and 3 antimicrobial resistance genes from positive blood cultures in approximately 1 hour (bioMérieux Diagnostics, 2021). Bacterial targets detected by the BioFire FilmArray BCID panel include Staphylococcus species, S. aureus, Streptococcus species, S. pneumoniae, S. pyogenes, S. agalactiae, Enterococcus arten, Listeria monocytogenes, Enterobacterales, Acinetobacter baumannii, Enterobacter cloacae-complex, E. coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus arten, Pseudomonas aeruginosa, Serratia marcescens, Haemophilus influenzae, and Neisseria meningitidis.3 The panel can also detect five common yeasts, including Candida albicans, Candida glabrata, Candida parapsilosis, C. krusei, and Candida tropicalis. In terms of antimicrobial resistance, the BioFire (RoxanneRule et al., 2021).

Magicplex Magicplex (Seegene, Seoul, South Korea) is a multiplex PCR performed on whole blood that identifies 73 gram-positive and 12 gram-negative bacteria, six fungi (five Candida spp. and Aspergillus fumigatus), and three antibiotic resistance markers can be detected (vanA, vanB, and mecA) with a turnaround time (TAT) of 4–5 hours. Assay evaluations have shown low-to-moderate sensitivity and specificity (0.47 and 0.66, respectively),14 which limits its usefulness as a surrogate for blood cultures, but has the advantage of being able to detect pathogens clinically relevant from negative culture material.15 MagicPlex Sepsis Test is a real-time PCR test that simultaneously analyzes the presence of pathogens and resistance to methicillin (mecA) and vancomycin (vanA and vanB). After creating an amplicon bank using normal PCR, over 90 genus-level pathogens and resistance markers are screened. Results are available in 5 hours (including isolation of pathogen DNA). A subsequent selective identification of pathogens is possible (only 27 pathogens can be detected at the species level) in an additional 30 minutes. P. aeruginosa, A. baumannii, Stenotrophomonas maltophilia, S. marcescens, Bacillus fragilis, Salmonella typhi, Stacolaebsiella, K. pneumoniae, Streptococcus haemolyticus, S. agalactiae, Streptococcus E. faecalis, E. faecium, and Enterococcus gallinarum are among the bacteria that cause food poisoning.

Lightcycler SeptiFast The SF MGrade Test (Roche Diagnostics, Mannheim, Germany) is a CE-IVD (CE-in vitro diagnostic)-approved MultiPlex Realtime PCR that can detect 25 sepsis pathogens directly from whole blood (19 bacteria and 6 fungi). With an analytical sensitivity of 3–30 CFU/mL, the TAT is between 5 and 8 hours. 16 SeptiFast’s utility in the microbiology laboratory is most likely to enhance blood culture, as SF TAT may result in faster pathogen detection (positive results can

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Section 2:  Infections/Sepsis/Infection Control apply to both fungi and bacteremia), therefore combining blood culture and SF improves pathogen detection.17 The detection limit is 100 CFU/mL for Candida glabrata, Streptococcus spp., and coagulase-negative Staphylococcus and ranges from 3 to 30 for the others, depending on the infectious agent. Limitations are the high costs (€ 150–200 per test), the need for trained personnel, and the lack of information on antibiotic sensitivity. This assay is an important alternative to blood culture, primarily due to its short time to result and high specificity, although further advances in laboratory personnel and workflow are required to improve its suboptimal sensitivity.

Sequencing In comparison to the traditional Sanger identification method, the MicroSEQ 500 kit (PerkinElmer Applied Biosystems, Waltham, MA, USA) and pyrosequencing (Biotage, Uppsala, Sweden) are sequencing technologies that attack microorganisms in CM positive and whole blood in a short time and at a lower cost. The first involves amplification and sequencing of the first 527 bp fragment of bacterial 16S rRNA genes, while the second was used to classify and identify a range of bacterial 16S rDNA fragments. Currently, next generation sequencing (NGS) technology (e.g., Illumina MiSeq) is posing a new challenge in identifying and genotyping viable, dead, and viable but nonculturable pathogens as well as antibiotic resistance markers in a cost-effective and timely manner. The most difficult aspect of using NGS to detect pathogenic nucleic acid in the vast amount of human genomic DNA is detecting very minute levels of pathogenic nucleic acid (Marcello Guido et al, 2016).

PLEX-ID PLEX-ID (Abbott Molecular, Carlsbad, CA, USA) is a revolutionary and universal approach for diagnosing a wide range of infections and four resistance markers (mecA, vanA/B, and blaKPC) straight from a patient’s blood. Automated DNA extraction, PCR setup, PCR amplification, amplicon purification, and PCR/ESIMS are all part of this procedure. It includes a PCR with nine pairs of primers that target 16S rDNA, 23S rDNA, and four internal genes, as well as ESIMS for amplicon analysis.

CONCLUSION The most common causes of sepsis-related mortality appear to be incorrect diagnosis and inadequate antibiotic use. As a result, the necessity to find innovative approaches to improve diagnostic sensitivity and speed has become increasingly pressing. Blood culture has a response period of 2 days or more; additionally, for certain illnesses, this period of time is far too long for doctors to administer a targeted antibiotic treatment. Despite recent advances in

technology, the sensitivity for detecting specific illnesses remains limited, and blood culture contamination is still a major concern. New approaches have recently been developed to minimize the time it takes to diagnose a disease, as well as to improve the sensitivity and clinical benefits of pathogen identification. In comparison to conventional blood culture, more infections and critical resistance genes have been discovered earlier thanks to molecular detection methods. The short TATs of molecular assays could be critical in the management and outcome of sepsis patients, as delayed antibiotic administration drastically raises fatality rates. The inability to provide information on antibiotic susceptibility of the discovered pathogen is a limitation of PCR-based tests. Another disadvantage of these tools is their high cost, which includes the requirement for specialized equipment, reagents, and long-term qualified people. One of the drawbacks of PCR-based assays is their inability to offer information on the pathogen’s antibiotic susceptibility. Another downside of these tools is their high cost, which necessitates the long-term purchase of equipment, reagents, and qualified employees. All episodes of polymicrobial infection showed contradictory results between blood culture and PCR. This finding shows the difficulty in diagnosing polymicrobial sepsis, for example, the fact that blood cultures regularly detect only the fastest growing organism. In two episodes in which PCR detected both S. aureus and CoNS, only CoNS was detected in blood cultures. The BDL of CoNS was >25 times higher than that of S. aureus.28 As a result, despite the benefits of molecular approaches in terms of sensitivity and speed, only blood culture can accomplish the antibiotic resistance spectrum. As a result, none of the molecular tests can completely replace blood culture; rather, they are complementing and must be used in tandem to ensure a correct and timely diagnosis. In order to address the drawbacks of blood culture- and PCR-based tests, more progress will be required in the near future. The new methodologies should help to increase the restricted analytical sensitivity for detecting difficult-to-detect diseases and distinguishing between alive and dead bacteria. NGS technologies might provide rapid pathogen identification and have the potential to disclose pathogen specimens and antimicrobial susceptibility at the same time.

REFERENCES 1. Hollenberg SM, Singer M. Pathophysiology of sepsis-induced cardiomyopathy. Nat Rev Cardiol. 2021;18(6):424-34. 2. Eubank TA, Long SW, Perez KK. Role of rapid diagnostics in diagnosis and management of patients with sepsis. J Infect Dis. 2020;222(Suppl 2):S103-9. 3. Liesenfeld O, Lehman L, Hunfeld KP, Kost G. Molecular diagnosis of sepsis: New aspects and recent developments. Eur J Microbiol Immunol. 2014;4(1):1-25.

Chapter 14:  Syndromic Polymerase Chain Reaction-based Diagnostics in Sepsis 4. Chatterjee S, Bhattacharya M, Todi SK. Epidemiology of adultpopulation sepsis in India: a single center 5 year experience. Indian Soc Crit Care Med. 2017;21(9):573. 5. Nelson GE, Mave V, Gupta A. Biomarkers for sepsis: A review with special attention to India. BioMed Res Int. 2014;2014:264351. 6. Lucignano B, Ranno S, Liesenfeld O, Pizzorno B, Putignani L, Bernaschi P, et al. Multiplex PCR allows rapid and accurate diagnosis of bloodstream infections in newborns and children with suspected sepsis. J Clin Microbiol. 2011;49(6):2252-8. 7. Yanagihara K, Kitagawa Y, Tomonaga M, Tsukasaki K, Kohno S, Seki M, et al. Evaluation of pathogen detection from clinical samples by real-time polymerase chain reaction using a sepsis pathogen DNA detection kit. Crit Care. 2010;14(4):1-9. 8. Septimus EJ. Sepsis perspective 2020. J Infect Dis. 2020; 222(Suppl 2):S71-3. 9. Garibyan L, Avashia N. Research techniques made simple: polymerase chain reaction (PCR). J Invest Dermatol. 2013;133(3):e6. 10. Liu CF, Shi XP, Chen Y, Jin Y, Zhang B. Rapid diagnosis of sepsis with TaqMan‐Based multiplex real‐time PCR. J Clin Lab Anal. 2018;32(2):e22256. 11. Tissari P, Zumla A, Tarkka E, Mero S, Savolainen L, Vaara M, et al. Accurate and rapid identification of bacterial species from positive blood cultures with a DNA-based microarray platform: an observational study. Lancet. 2010;375(9710): 224-30. 12. Buchan BW, Ginocchio CC, Manii R, Cavagnolo R, Pancholi P, Swyers L, et al. Multiplex identification of gram-positive bacteria and resistance determinants directly from positive blood culture broths: evaluation of an automated microarraybased nucleic acid test. PLoS Med. 2013;10(7):e1001478. 13. Poritz MA, Blaschke AJ, Byington CL, Meyers L, Nilsson K, Jones DE, et al. FilmArray, an automated nested multiplex PCR system for multi-pathogen detection: development and application to respiratory tract infection. PLoS One. 2011;6(10):e26047. 14. Ziegler I, Fagerstrom A, Stralin K, Molling P. Evaluation of a commercial multiplex PCR assay for detection of pathogen DNA in blood from patients with suspected sepsis. PLoS One. 2016;11(12):e0167883. 15. Ljungstrom L, Enroth H, Claesson BE, Ovemyr I, Karlsson J, Fröberg B, et al. Clinical evaluation of commercial nucleic acid amplification tests in patients with suspected sepsis. BMC Infect Dis. 2015;15:199. 16. Dubourg G, Raoult D. Emerging methodologies for pathogen identification in positive blood culture testing. Expert Rev Mol Diagn. 2016;16(1):97-111. 17. Korber F, Zeller I, Grunstaudl M, Willinger B, Apfalter P, Hirschl AM, et al. SeptiFast versus blood culture in clinical routine: a report on 3 years experience. Wien Klin Wochenschr. 2017;129(11):427-34. 18. Deepa Gotur B. Sepsis diagnosis and management. J Med Sci Health. 2017;3(3):1-12.

19. Dierkes C, Ehrenstein B, Siebig S, Linde HJ, Reischl U, Salzberger B. Clinical impact of a commercially available multiplex PCR system for rapid detection of pathogens in patients with presumed sepsis. BMC Infect Dis. 2009;9(1):1-7. 20. Trung NT, Thau NS, Bang MH. PCR-based Sepsis@ Quick test is superior in comparison with blood culture for identification of sepsis-causative pathogens. Sci Rep. 2019;9(1):1-7. 21. Jacobi J. Pathophysiology of sepsis. Am J Health Syst Pharm. 2002;59(Suppl 1):S3-8. 22. Turenne CY, Witwicki E, Hoban DJ, Karlowsky JA, Kabani AM. Rapid identification of bacteria from positive blood cultures by fluorescence-based PCR-single-strand conformation polymorphism analysis of the 16S rRNA gene. J Clin Microbiol. 2000;38(2):513-20. 23. Jordan JA, Jones-Laughner J, Durso MB. Utility of pyrosequencing in identifying bacteria directly from positive blood culture bottles. J Clin Microbiol. 2009;47(2):368-72. 24. Kotsaki A, Giamarellos-Bourboulis EJ. Molecular diagnosis of sepsis. Exp Opin Med Diagnos. 2012;6(3):209-19. 25. Sinha M, Jupe J, Mack H, Coleman TP, Lawrence SM, Fraley SI. Emerging technologies for molecular diagnosis of sepsis. Clin Microbiol Rev. 2018;31(2):e00089-17. 26. Han SS, Jeong YS, Choi SK. Current scenario and challenges in the direct identification of microorganisms using MALDI TOF MS. Microorganisms. 2021;9(9):1917. 27. Kim S, Kim J, Kim HY, Uh Y, Lee H. Efficient early diagnosis of sepsis using whole-blood PCR–reverse blot hybridization assay depending on serum procalcitonin levels. Front Med. 2020;7:390. 28. Van den Brand M, Van den Dungen FA, Bos MP, Van Weissenbruch MM, van Furth AM, De Lange A, et al. Evaluation of a real-time PCR assay for detection and quantification of bacterial DNA directly in blood of preterm neonates with suspected late-onset sepsis. Crit Care. 2018;22(1):1-10. 29. Ginn AN, Halliday CL, Douglas AP, Chen SC. PCR-based tests for the early diagnosis of sepsis. Where do we stand? Curr Opin Infect Dis. 2017;30(6):565-72. 30. Yealy DM, Huang DT, Delaney A, Knight M, Randolph AG, Daniels R, et al. Recognizing and managing sepsis: what needs to be done?. BMC Med. 2015;13(1):1-10. 31. Peters RP, Savelkoul PH, Vandenbroucke-Grauls CM. Future diagnosis of sepsis. Lancet. 2010;375(9728):1779-80. 32. Scott LJ. Verigene® gram-positive blood culture nucleic acid test. Mol Diagn Ther. 2013;17(2):117-22. 33. McFall C, Salimnia H, Lephart P, Thomas R, McGrath E. Impact of early multiplex FilmArray respiratory pathogen panel (RPP) assay on hospital length of stay in pediatric patients younger than 3 months admitted for fever or sepsis workup. Clin Pediatr. 2018;57(10):1224-6. 34. Loonen AJ, de Jager CP, Tosserams J, Kusters R, Hilbink M, Wever PC, et al. Biomarkers and molecular analysis to improve bloodstream infection diagnostics in an emergency care unit. PloS One. 2014;9(1):e87315.

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3 S EC TI ON

Pulmonology/Ventilation œ Role of High‑flow Nasal Cannula: Has It Change the Outcome? Ahsan Ahmed, Ahsina Jahan Lopa, Anirban Bose

œ Awake Proning

Shrikant Sahasrabudhe, Sauren Panja, Saswati Sinha

œ Utility of ROX Score in Predicting HFNC Failure Harjit Dumra, Tushar Patel, Mukesh Patel

œ Selecting the Right Noninvasive Ventilation Interface Ranajit Chatterjee, Sivakumar MN, Rekha Das

œ How to Predict the SILI in Noninvasive Ventilation and High-flow Nasal Cannula? Manoj Singh, Jay Kothari, Maharshi Desai

œ Peri-intubation Complications and Management Vandana Sinha, Brajendra Lahkar

œ Impact of Obesity on Difficult Weaning Anand Tiwari, Kapil Zirpe

œ Selecting Appropriate Humidification (Active and Passive) Sharmili Sinha, Ranajit Chatterjee, Bhuvna Ahuja

œ Identifying Pulmonary Embolism in Bedside Where Computed Tomography Pulmonary Angiography is not Possible Deepak Govil, Anant Pachisia, Divya Pal

œ Relevance of Berlin Definition

Rajesh Chawla, Raju Shakya, Aakanksha Chawla Jain

œ Hemodynamics in Severe Acute Respiratory Distress Syndrome Edward Smith, Nitin Arora

œ Lung Transplant: Lessons for the Intensivist

Suresh Rao KG, Santhosh Vilvanathan, KR Balakrishnan

15

Role of High‑flow Nasal Cannula: Has It Change the Outcome?

C H A P T E R Ahsan Ahmed, Ahsina Jahan Lopa, Anirban Bose

INTRODUCTION High‑flow nasal cannula (HFNC) has rapidly gained its popularity during COVID pandemic for managing patients with acute respiratory failure due to severe COVID pneumonia. When ventilators were not available and all intensive care unit (ICU) beds were full, it had helped a lot of patients with acute hypoxemic respiratory failure (AHRF) to be managed in high dependency unit (HDU) bed and thus reduced the burden of ICU and ventilator beds in an already exhausted healthcare system. It has distinct advantage over the other oxygen delivery devices because of its unique effects on respiratory physiology. This review summarizes available data and addresses the wide spectrum of its clinical uses.

PHYSIOLOGY During spontaneous breathing, inspired air is warmed and humidified in nose, pharynx, larynx, and trachea. Conventional oxygen delivery devices deliver cold gas which causes drying up and desiccation of airway mucosa, impaired bronchociliary clearance, and bronchoconstriction. Bubble humidifier is incapable of delivering required humidity to delivered gas particularly when patient’s minute volume and peak inspiratory flow rate are high. HFNC delivers adequately heated and humidified gas with an active humidifier. There is better airway clearance, improved mucociliary function and metabolic cost of the breathing reduced by heated and humidified gas of HFNC.1 Alveolar oxygenation depends upon delivered gas flow rate, fraction of inspired oxygen (FiO2), device interface, and inspiratory flow rate. Inspiratory flow rate is increased in acute respiratory failure. Low flow devices can provide maximum 15 L/min flow and FiO2 up to 100% but higher inspiratory rate dilutes the inspired gas. Intermediate flow device such as Venturi mask can provide fixed FiO2 compromising total flow. On the other hand, HFNC can provide up to 60 L/min flow and FiO2 up to 100%, independent of flow, provided device flow must be greater than patient’s inspiratory flow.1 Conventional oxygen delivery system delivers unstable

and lower than predicted FiO2 while HFNC overcomes this shortcoming.2 HFNC offers resistance to expiratory flow causing increased airway pressure in flow-dependent manner.3 Pharyngeal pressure is increased in mouth closed position than mouth open position.3 Pharyngeal pressure with HFNC is also affected by sex and body mass index (BMI).3,4 End expiratory lung volume (EELV) is increased with HFNC, linearly with flow.4 HFNC reduces anatomical dead space by flow-dependent clearance of carbon dioxide.5 With all these mechanisms, HFNC can reduce respiratory rate, minute ventilation, partial pressure of arterial carbon dioxide (PaCO 2 ), and pH constant ; while improves oxygenation with increase in positive end-expiratory pressure (PEEP), reduces work of breathing, and improves patient comfort.6

CLINICAL SCENARIOS FOR USING HIGH‑FLOW NASAL CANNULA After its successful use in COVID patients, HFNC is also being tried in many other clinical entities of acute hypoxemic respiratory failure. It has shown to be beneficial in patients in severe acute respiratory distress syndrome (ARDS), for preoxygenation of hypoxic patients before intubation, procedures such as bronchoscopy, prevention of reintubation, and even in a subset of patients with hypercapnic respiratory failure. In spite of significant physiological benefits, robust data on outcome, especially mortality benefit, is lacking.

ACUTE HYPOXEMIC RESPIRATORY FAILURE Multiple observational studies showed improvement of oxygenation status with HFNC in AHRF with very limited data on reduction in mechanical ventilation and mortality. FLORALI trial, a multicenter open-label trial, compared the effect of HFNC, noninvasive ventilation (NIV) or conventional oxygen therapy (COT) via nonrebreathing face mask in patients with nonhypercapnic AHRF with no previous history of lung disease. The study showed no

84

Section 3: Pulmonology/Ventilation difference in intubation rate in HFNC group compared to other two groups. However, Dyspnea Score, number of days on ventilator, and 90-day mortality are less in the HFNC group. In post-hoc analysis, reduced intubation rate is found in a subgroup with PaO2/FiO2 ratio 16 hours) significantly reduced mortality in these patients. This has been corroborated further in a meta-analysis3 and a Cochrane review4 thereby placing PP as a strong recommendation in international guidelines on ARDS management. PP refers to placing a patient face down and it is said to improve oxygenation by improving ventilation-perfusion (VQ) matching. Due to its positive physiological effects, it has also been tested in spontaneously breathing patients who are not intubated which is known as “awake proning.” Although there have been studies reporting the use of awake proning in the past, the interest in the same has been rekindled with sudden surge of cases of acute respiratory failure during the COVID-19 pandemic which have overwhelmed the capacity of healthcare systems. Our aim is to address the current evidence, indications, the technical aspects, and the overall utility of awake proning in the present scenario.

PHYSIOLOGIC RATIONALE OF PRONE POSITIONING ■ Improvement of V/Q mismatch and shunt by reducing

alveolar overdistension in the nondependent areas as well as collapse of alveoli in dependent areas. Also there is less compression of dorsal regional lung units leading to homogenization of transpulmonary pressures. ■ Facilitates drainage of secretions from the posterior lung ■ Reduction of ventilator-induced lung injury (VILI) and patient self-inflicted lung injury (P-SILI): There is also a proposed theory of reductions in VILI in ARDS patients put forward by Albert way back in 1997. 5

Similarly patients with acute respiratory failure who are spontaneously breathing have high respiratory drives which can contribute to P-SILI. Reduction of respiratory effort by PP through improved gas exchange may help ameliorate further lung damage. ■ Decreasing lung compression: More uniform distribution of tidal volume and end expiratory lung volume, thus reducing the cyclical opening and closing of alveoli (reduced atelectrauma)6

CURRENT EVIDENCE ON AWAKE PRONING Although PP is now an integral part of the standard of care due to its proven efficacy not only in improving gas exchange in moderate-to-severe ARDS, data on awake spontaneously breathing patients is scarce.

NON-COVID-19 PATIENTS There have been studies in the pediatric population which have shown improvement in oxygenation and lung mechanics in spontaneously breathing infants with pneumonia with prone ventilation.7,8 Similarly there have been several case reports and observational studies on the impact of awake proning in adults with hypoxemic respiratory failure. Valter et al. reported a rapid increase in PaO2 and ability to avoid intubation in all four patients who were subjected to PP with good tolerance and found no adverse effects.9 In another study of 15 adult patients (nine of whom were immunocompromised) with acute hypoxemic respiratory failure, Scaravilli et al. found that prone position was both safe and feasible and improved oxygenation.10 Awake proning when combined with highfrequency percussive ventilation (a form of noninvasive ventilation) has also been found to enhance airway opening, limit potential VILI, and improve clearance of secretions in post-lung transplant recipients. It has been found to improve lung exchange, reduce the work of breathing and respiratory rate and the number of bronchoscopies.11 Ding et al. in a multicenter cohort study in two teaching hospitals studied

Chapter 16:  Awake Proning 20 patients with moderate-to-severe ARDS and aimed to determine whether early institution of PP with high flow nasal cannula (HFNC) or noninvasive ventilation (NIV) could avoid intubation. The main causes of ARDS were influenza and other viral pneumonia. Average duration of prone position was 4 hours per day. Intubation was avoided in 11 patients. All patients with PF ratio 28%.13 These are a result of extrapolation from studies of mechanically ventilated with ARDS in whom prone ventilation is an evidence-based practice. Although limited data on the utility of awake proning exists in spontaneously breathing patients, it is now recommended that hospitalized patients with COVID-19 who require supplemental oxygen which may include high flow nasal oxygen, NIV, or even low flow oxygen are encouraged to spend as much time as possible in prone position. Awake proning has shown to improve oxygenation and in some cases reduce intubation rates. A randomized controlled multinational meta-trial including patients from six superiority trials including patients on HFNC for acute hypoxemic respiratory failure due to COVID-19 were assigned to awake PP or standard of care. Hospitals from Canada, France, Ireland, Mexico, USA, and Spain participated in the study. 1,126 total patients were enrolled with 567 in the awake prone and 559 in the standard of care group. Primary outcome was defined as “treatment failure” which was a composite outcome of intubation or mortality within 28 days of enrollment. Treatment failure occurred in 40% of the awake prone group versus 46% in the standard of care [relative risk (RR) 0.86, 95% confidence interval (CI) 0.75–0.98]. The hazard ratio for intubation was 0.75 (95% CI 0.62–0.91) and that for mortality was 0.87 (95% CI 0.68–1.11) within 28 days whereby indicating that awake proning reduces the risk of treatment failure by reducing intubation rates without any increased risk of harm.14 A prospective before - after single center study conducted in a French hospital included 24 nonintubated patients with confirmed COVID-19 infection and requiring oxygen supplementation and chest computed tomography (CT) findings with posterior lesions. Arterial blood gases were

obtained before PP, during PP, and 6–12 hours after turning to supine position. The main outcome was the proportion of responders defined as a 20% increase in PaO2 between pre-PP and during PP. Secondary outcomes included persistent responders (persistent 20% PaO2 increase between pre-PP and after supination), variation of PaO2 and PaCO2 between prePP, during PP, and after resupination and feasibility (ability to sustain PP >1 hour and 3 hours. 40% of those who tolerated PP showed improved oxygenation however the response was sustained in only half of these patients after return to supine position.15 Another single center study from Italy included 56 patients with confirmed COVID-19 infection on supplemental oxygen or NIV aimed to assess the feasibility and physiologi­ cal effects of PP which was maintained for a minimum of 3 hours. PP was feasible in 83.9% patients and oxygenation substantially improved (PaO2:FiO2 ratio—180.5 mm Hg [standard deviation (SD) 76.6] in supine to 285.5 mm Hg (SD 112.9) in prone position, p 35/min, PaCO2 >48 mm Hg

(6.5 kPa) ■ Immediate need for intubation ■ Persistent shock or arrhythmias ■ Altered mental status/agitation ■ Spinal instability ■ Raised intracranial pressure (ICP) and seizures ■ Recent sternotomy or tracheal surgery ■ Major abdominal surgery ■ Morbid obesity ■ Anterior thoracostomy/air leaks ■ Pregnancy: Second/third trimester.

THE PROCEDURE OF AWAKE PRONING (FLOWCHART 1) ■ Explain the procedure to the patient. ■ The attending staff needs to be trained in the procedure

and capable of monitoring the patient. ■ Provision to identify failure of awake PP and escalation to

invasive ventilation should be present. ■ Ensure oxygen and airway adjuncts and the SpO2 probe are in place from time to time. ■ An alarm bell should be available near the patient and explained to him/her. Timed position changes can be done as follows: ■ 30 minutes to 2 hours lying prone (bed flat) ■ 30 minutes to 2 hours on right side (bed flat) ■ 30 minutes to 2 hours sitting up (30–60°) by adjusting head end of the bed ■ 30 minutes to 2 hours lying on left side (bed flat) ■ 30 minutes to 2 hours prone again ■ Continue to repeat the cycle.

(RR: relative risk)

MONITORING OF THE PATIENT ■ Ensure that the patient is comfortable and care to avoid

pressure injury. ■ Closely monitor vitals, sensorium, and signs of respira-

tory distress. ■ Clear protocol to identify failure of awake proning and

alert the critical care team must exist. ■ Watch closely for desaturation, hemodynamic instability,

and arrhythmia.

COMPLICATIONS ■ Venous stasis ■ Pressure sores ■ Dislodgement of venous access ■ Nerve compression

Chapter 16:  Awake Proning ■ Arrhythmia ■ Hypoxia ■ Vomiting ■ Exposure of medical personnel.

FUTURE DIRECTIONS Several randomized controlled trials (RCTs) are ongoing which aim to address the effect of awake proning not only on oxygenation but also on how it may impact patient-centered outcomes some of which are mentioned below. ■ OPTIPRONE study: PP during high flow oxygen therapy in acute hypoxemic respiratory failure (NCT 03095300). ■ Pro Cov: PP in spontaneously breathing nonintubated COVID-19 patients (NCT 04344106). ■ APPROVE-CARE: Awake PP to reduce invasive ventilation in COVID-19 induced acute respiratory failure (NCT 04347941). ■ COVI-PRONE: Awake prone position in hypoxemic patients with coronavirus disease 19 (NCT 04350723).

CONCLUSION Awake proning seems to be a safe, simple, and a low cost intervention which can be performed in several areas in the hospital even outside the critical care areas. By improving oxygenation at least in the patients with moderate ARDS and by its propensity to reduce the intubation rates in a carefully selected set of patients, it has the potential to reduce the demand on invasive mechanical ventilation. Thus, it may ease the pressure on the intensive care services as well as avoid the complications associated with invasive ventilation. The results from the ongoing trials will likely further elucidate the unresolved issues associated with this maneuver.

REFERENCES 1. Bryan AC. Conference on the scientific basis of respiratory therapy. Pulmonary physiotherapy in the pediatric age group. Comments of a devil’s advocate. Am Rev Respir Dis. 1974;110(6 Pt 2):143-4. 2. Guérin C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, et al. Prone positioning in severe acute respiratory distress syndrome. N Eng J Med. 2013;368(23):2159-68. 3. Sud S, Friedrich J, Adhikari N, Taccone P, Mancebo J, Polli F, et al. Effect of prone positioning during mechanical ventilation on mortality among patients with acute respiratory distress syndrome: a systematic review and meta-analysis. CMAJ. 2014;186(10):381-90. 4. Bloomfield R, Noble D, Sudlow A. Prone position for acute respiratory failure in adults. Cochrane database of systematic reviews. 2015;2015(11):CD008095.pub2

5. Cornejo RA, Diaz JC, Tobar EA, Bruhn AR, Rames CA, Gonzalez RA, et al. Effects of prone positioning on lung protection in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2013;188(4):440-8. 6. Glenny RW, Lamm WJ, Albert RK, Robertson HT. Gravity is a minor determinant of pulmonary blood flow distribution. J Appl Physiol. 1991;71(2):620-9. 7. Chaisupamongkollarp T, Preuthipan A, Vaicheeta S, Chantarojanasiri T, Kongvivekkajornkij W, Suwanjutha S. Prone position in spontaneously breathing infants with pneumonia. Acta Paediatr. 1999;88(9):1033-4. 8. Tulleken JE, van der Werf TS, Ligtenberg JJM, Fijen JW, Zijlstra JG. Prone position in a spontaneously breathing neardrowning patient. Intensive Care Med. 1999;25(12):1469-70. 9. Valter C, Christensen AM, Tollund C, Schønemann NK. Response to the prone position in spontaneously breathing patients with hypoxemic respiratory failure. Acta Anaesthesiol Scand. 2003;47(4):416-8. 10. Scaravilli V, Grasselli G, Castagna L, Zanella A, Isgrò S, Lucchini A, et al. Prone positioning improves oxygenation in spontaneously breathing nonintubated patients with hypoxemic acute respiratory failure: A retrospective study. J Crit Care. 2015;30(6):1390-4. 11. Feltracco P, Serra E, Barbieri S, Milevoj M, Michieletto E, Carollo C, et al. Noninvasive high-frequency percussive ventilation in the prone position after lung transplantation. Transplant Proc. 2012;44(7):2016-21. 12. Ding L, Wang L, Ma W, He H. Efficacy and safety of early prone positioning combined with HFNC or NIV in moderate to severe ARDS: a multi-center prospective cohort study. Crit Care. 2020;24:28. 13. Bamford P, Bentley A, Dean J, Whitmore D, Wilson-Baig N. Ics guidance for prone positioning of the conscious COVID patient. 2020. 14. Ehrmann S, Li J, Ibarra-Estrada M, Perez Y, Pavlov I, McNicholas B, et al. Awake prone positioning for COVID19 acute hypoxaemic respiratory failure: a randomised, controlled, multinational, open-label meta-trial. Lancet Respir Med. 2021;9(12):S2213-2600. 15. Elharrar X, Trigui Y, Dols AM, Touchon F, Martinez S, Prud’homme E, Papazian L. Use of prone positioning in nonintubated patients with COVID-19 and hypoxemic acute respiratory failure. JAMA. 2020;323(22):2336-8. 16. Coppo A, Bellani G, Winterton D, Di Pierro M, Soria A, Faverio P, et al. Feasibility and physiological effects of prone positioning in non-intubated patients with acute respiratory failure due to COVID-19 (PRON-COVID): a prospective cohort study. Lancet Respir Med. 2020;8(8):765-74. 17. Ponnapa Reddy M, Subramaniam A, Afroz A, Billah B, Lim ZJ, Zubarev A, et al. Prone positioning of nonintubated patients with coronavirus disease 2019-a systematic review and metaanalysis. Crit Care Med. 2021;49(10):e1001-14. 18. Sodhi K, Chanchalani G. Awake proning: Current evidence and practical considerations. Indian J Crit Care Med. 2020;24(12):1236-41.

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17

Utility of ROX Score in Predicting HFNC Failure

C H A P T E R Harjit Dumra, Tushar Patel, Mukesh Patel

INTRODUCTION Heated humidified high-flow nasal cannula (HFNC) has revolutionized management of acute hypoxemic respiratory failure (AHRF) patients. Physiologic studies have shown that as compared to conventional oxygen therapy, high flow in HFNC generates a positive end-expiratory pressure (PEEP) effect leading to increased end-expiratory lung volume (EELV) and tidal volume all of which contributes to improved ventilation, oxygen delivery, decreased work of breathing (WOB), better airway secretion clearance, and improved patient comfort.1 In 2015, Frat et al. published the FLORALI trial where they randomized over 300 patients who had AHRF to receive conventional oxygen therapy, noninvasive ventilation or HFNC. In this study, use of HFNC was associated with lower risk for intubation particularly in a subset of patients with partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) < 200 mm Hg. This was also associated with improved ventilator free days and lower mortality risk. This clearly indicated that HFNC was a safe and effective tool in reducing the need for mechanical ventilation (MV).1,2 All this evidence has led to HFNC being given a strong recommendation for use in patients with hypoxemic respiratory failure in the recently published guidelines in Intensive Care Medicine in 2020 as well as in 2021 update of the Surviving Sepsis Campaign Guideline.3,4 However, one of the most difficult decisions in the intensive care unit (ICU) is to decide when to intubate and initiate MV in a spontaneously breathing patient with acute respiratory failure (ARF). While HFNC might decrease the need for MV in quite a number of patients, it can also lead to undue delay in intubation in some. This could lead to adverse outcomes. The problem with HFNC is that we are flying blind. While on invasive or noninvasive MV there’s an interface which provides clinicians with immense amount of patient data that not only helps in modifying ventilator settings but also guides clinicians in real time about which direction the patient is heading. The lack of such an interface

makes it extremely challenging to do so on HFNC. Hence, there is an urgent need to identify accurate predictors for initiating MV in spontaneously breathing patients with ARF. Some of the common variables which indicate clinical worsening and need for MV in patients of ARF on HFNC include: (1) worsening oxygenation [PaO2 < 60 mm Hg, saturation of peripheral oxygen (SpO2) < 90% with HFNC flow > 30 L and FiO2 of 100%), (2) respiratory acidosis [pressure of arterial carbon dioxide (PaCO2) >50 mm Hg, venous partial pressure of carbon dioxide (PvCO2) > 55 mm Hg, pH < 7.25), (3) respiratory rate (RR) > 30 breaths/minute, (4) persistence of thoracoabdominal asynchrony, (5) retained secretions, and (6) lack of decrease in the RR after HFNC. In addition to these respiratory parameters, some small retrospective studies have also shown that additional organ failures such as hemodynamic, neurological disturbance [Glasgow Coma Scale (GCS) < 12], and high Sequential Organ Failure Assessment (SOFA) score could also predict HFNC failure.5,6 All of these till date, however, have not been discriminant enough to unequivocally identify patients who would require subsequent intubation. Hence, there is a pressing need for an objective decision making tool which can provide a solution to this day-to-day dilemma and standardize decision making. For a consid­ erable period of time, we have relied on various indices in the ICU, to guide patient management at bedside. The respiratory rate and oxygenation (ROX) index is once such tool which is easy, feasible, and reliably predicts need for MV in patients of hypoxemic respiratory failure on HFNC.5

WHAT DOES RESPIRATORY RATE AND OXYGENATION STAND FOR? The acronym ROX stands for respiratory rate and oxygenation. The ROX index is defined as ratio of SpO2/FiO2 to the RR. It was introduced for the first time by Roca et al. when they published the results of their prospective observational study. This study carried out over a period of 4 years, included 157 patients with severe pneumonia and

Chapter 17:  Utility of ROX Score in Predicting HFNC Failure ARF on HFNC treatment. In this study, a ROX index > 4.88 measured after 12 hours of HFNC treatment was associated with a considerable decrease in need for MV and hence could identify patients who could continue to receive HFNC beyond 12 hours.1,2,5 This index was more accurate at predicting HFNC failure then either of the two variables (i.e., SpO2/FiO2, and RR) independently.2

FURTHER IMPROVING THE RESPIRATORY RATE AND OXYGENATION INDEX So is one study enough to prove the functionality of the ROX index? Roca et al. published a validation study in 2019, involving 191 patients with pneumonia and ARF and further delineated other parameters for the ROX index. The authors found that ROX was better than looking at SpO2/FiO2, RR, PaCO2, flow, SpO2, FiO2, and lactate to predict the need for MV. ROX index > 4.88 at 2 hours had a hazard ratio of 0.434, at 6 hours hazard ratio of 0.304, and at 12 hours hazard ratio of 0.291, clearly indicating a lower risk of intubation on HFNC. HFNC failure was indicated by a ROX index of 12 5 mEq/L before transplant with a strategy of strict monitoring intra- and postoperatively and controlling sodium levels if 10 mm Hg has been shown to be detrimental to graft function. Regardless hypoxia should be avoided to preserve the graft. Noninvasive ventilation/high-flow nasal cannula (NIV/HFNC) is an option to support such patients temporarily.

Infections and Prophylaxis Postoperative infections can be a major cause of morbidity and prolong ICU stay. Preoperative colonization with multi-drug resistant organism (MDRO) has been shown to be associated with postoperative MDRO infections. Donor-derived infections are also possible in the DDLT scenario. Screening the deceased donor for infections by blood and urine and ET cultures is always a good strategy

to follow. Prophylaxis will depend on local and patient factors. A high MELD patient with recent (within 3 months) hospital admissions and treated with antibiotics will need a carbapenem depending on local flora. A straightforward low MELD hepatocellular carcinoma with no hospitalization or colonization a β-lactam/β-lactamase inhibitor (BL/BLI) with gram-positive cover for 48 hours postoperative suffices. Antifungal prophylaxis is indicated for ALF and ACLF as they are at a very high risk of both Candida and mold infections in the first 3–4 weeks post-transplant. An echinocandin for 2–3 weeks post-transplant is recommended as per the European Association for the Study of the Liver (EASL) guidelines. Herpes simplex virus (HSV) and cytomegalovirus (CMV) are two viral reactivations causing mortality and morbidity post-transplant. CMV prophylaxis is an exhaustive topic in itself but it suffices to say high-risk patients should be on valganciclovir prophylaxis.

Post-transplant Graft-related Complications Detailed discussion of graft-related complications is beyond the scope of this chapter. Postoperative hemorrhage, primary nonfunction, small for size syndrome, acute cellular rejection, hepatic artery thrombosis, portal vein thrombosis, outflow obstruction, and bile leaks are possible complications in first phase post-LT. Each of them requires early identification and brisk correction to save the graft function in the long run. Daily Doppler for first 3–5 days in LDLT setting is imperative to pick up vascular complications early. Daily or twice daily liver enzymes can help in early recognition of acute cellular rejection. Primary nonfunction will require urgent relisting and retransplantation although it is one of the rarer complications.8

Neurological Complications The spectrum of neurological complications post-LT is wide. Tacrolimus-induced posterior reversible encephalopathy syndrome (PRESS), seizures and encephalopathy, tacrolimus-induced tremors and hyperirritability, visual hallucinations, and cortical blindness. Osmotic demyelination occurs with a frequency of 1–3.5% post-LT, especially in alcoholics. It is essential to be cautious of drug interactions of CNI to avoid sudden surges in their levels, even though neurotoxicity is not dose related but idiosyncratic in nature. Changing from tacrolimus to cyclosporine is the most common remedy for tacrolimus-related neurotoxicity and vice versa.

Acute Kidney Injury Incidence of AKI ranges from 20 to 50% post-LT depending on the definition used in various studies. AKI remains a major issue to tackle post-LT. Many patients have hepatorenal

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Section 14:  Transplant/Organ Donation syndrome (HRS) AKI preoperative, and are more prone to postoperative AKI. Multiple modifiable and nonmodifiable factors predispose to postoperative AKI. There is increased mortality associated with AKI. Recent survey involving 13,400 LT patients across continents showed incidence of AKI as 40% and AKI needing RRT about 7%. Both groups had higher mortality and higher graft loss. 30-day mortality was 16% and 1-year mortality was 31%. Odds ratio for mortality in patients with AKI was 2.9 and 8.9 for those on RRT.5

CONCLUSION Meticulous intensive care is needed perioperatively for LT patients. Acute liver failure is the most challenging condition one can handle in an ICU. Proper management in the ICU to control intracranial pressure sepsis and hemodynamics followed by a successful transplant in indicated cases has improved survival of ALF drastically in the last one decade. ACLF is now an emerging challenge for transplantation. Patients are sicker and frailer and case selection is very important for acceptable results post-transplant. Diabetes mellitus (DM), CAD, obesity, and chronic kidney disease (CKD), increasingly coexisting in these patients, make perioperative management complex, requiring a truly multidisciplinary coordinated effort for eventual success.

REFERENCES 1. Ruf AE, Kremers WK, Chavez LL, Desclazi VI, Podesta LG, Villamil FG. Addition of serum sodium into MELD score















predicts waiting list mortality better than MELD alone. Liver Transplant. 2005;11(3):336-43. 2. Artru F, Louvet A, Ruiz I, Levesque E, Labreuche J, UrsicBedoya J, et al. Liver transplantation in the most severely ill cirrhotic patients: a multicenter study in acute-on-chronic liver failure grade 3. J Hepatol. 2017;67:708-15. 3. Kardashian A, Ge J, McCulloch CE, Kappus MR, Dunn MA, Duarte-Rojo A, et al. Identifying an optimal liver frailty index cutoff to predict waitlist mortality in liver transplant candidates. Hepatology. 2021;73:1132-9. 4. Thongprayoon C, Cheungpasitporn W, Lertjitbanjong P, Aeddula NR, Bathini T, Watthanasuntorn K, et al. Incidence and Impact of Acute Kidney Injury in Patients Receiving Extracorporeal Membrane Oxygenation: A Meta-Analysis. J Clin Med. 2019;8(7):981. 5. McPhail MJ, Wendon JA, Bernal W. Meta-analysis of performance of Kings’s College Hospital Criteria in prediction of outcome in non-paracetamol-induced acute liver failure. J Hepatol. 2010;53(3):492-9. 6. Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology. 2013;144(7):1426-37,e1-9. 7. Zampieri FG, Machado FR, Biondi RS, Freitas FGR, Veiga VC, Figueiredo RC, et al. Effect of Intravenous Fluid Treatment With a Balanced Solution vs 0.9% Saline Solution on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial. JAMA. 2021;326(9):818-29. 8. Feltracco P, Barbieri S, Galligioni H, Michieletto E, Carollo C, Ori C. Intensive care management of liver transplanted patients. World J Hepatol. 2011;3(3):61-71.

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Heart Transplant: What Intensivist Must Know?

C H A P T E R Bhagyesh Shah, Dhiren Shah, Niren Bhavsar

INTRODUCTION In the era of organ transplantation being explored for all the possible reasons, end-stage heart failure has been the major reason for heart transplant throughout the world being well sought after in certain class of symptomatic patients despite of well-optimized mechanical and medical support.1 Orthotopic heart transplant is done when a braindead donor’s family donate his/her heart to an eligible recipient with heart failure. Long-term outcomes after transplantation have improved with the advances made in transplant candidate selection, surgical techniques, immunosuppressive modalities, and postoperative care. With 1 year survival at 85–90% and median survival of 12–14 years, heart transplant has proven its worth. Worldwide >125,000 heart transplants have been performed with North America being the leader. Heart transplantation In India has been on rise since last 8–10 years. In India till date, we have performed around 1,100 heart transplants, with annually around 150 transplants. For better outcomes in heart transplantation, the role of intensivist is of paramount importance, both preprocedural (during brain-dead donor

Fig. 1: Multipronged role of intensivist in heart transplant patient care.

identification and optimization) and postsurgery while recipient is in the ICU.

INDICATION OF HEART TRANSPLANT AND RECIPIENT EVALUATION The American College of Cardiology/American Heart Association (ACC/AHA) guidelines include the following indications for cardiac transplantation:2 ■ Refractory cardiogenic shock requiring intra-aortic balloon pump (IABP) counter pulsation or left ventricular assist device (LVAD) ■ Cardiogenic shock requiring continuous intravenous (IV) inotropic therapy (i.e., dobutamine, milrinone, etc.) ■ Peak VO2 (VO2max) 30% alveolar surface may be seen.

Also look for 20% or more hemosiderin-laden macrophages (siderophages) as demonstrated by Prussian blue staining of BAL. Consider BAL sending for multiplex polymerase chain reaction (PCR) (e.g., Biofire pneumonia plus panel). Latter when available can potentially provide microbiological diagnosis within an hour along with presence of genes for antibiotic resistance. BAL cytology with hypercellularity and >20% lymphocytosis and a decreased CD4/CD8 ratio is seen in COP. Transbronchial bronchoscopic biopsy can potentially aggravate the situation due to pneumothorax but are diagnostic for COP and DPTS.15-18 First step in management is physiological stabilization (in tandem with diagnostic procedures). Start oxygen (after checking SpO2 and immediate ABG) with nasal prongs or face mask. If patient is still distressed, consider NIV with full face mask or helmet interphase. If there is no hypercarbia, HFNC is a good alternative. Patient needs to be moved into a respiratory high-dependency unit (HDU) or intensive care unit (ICU) early for careful monitoring. Hemodynamic status must be evaluated early. If blood pressure (BP) is low or arterial lactate >4 mmol/L or urine output 65 mm Hg. If respiratory distress persists or worsens or patient has altered sensorium or needs more than minimal inotropic support, early intubation and mechanical ventilation (MV) needs to be instituted. Apply lung protective ventilation. Add sedatives (midazolam and propofol) and pain reliever (fentanyl). Patients with acute respiratory distress syndrome (ARDS) may also need neuromuscular paralysis. Severe lung injury in long-term >240 days postallogeneic HSCT recipients, otherwise eligible for aggressive interventions, may benefit from ECMO (survival 46%).19 Attention to mouth care, prevention of pressure sores, early enteral feeding, delirium assessment and treatment, etc., are useful. Standard nursing care and attention to nosocomial infection prevention are needed.

Specific Treatment ■ Antibiotics: Start empirical antibiotics early based on

possible etiological agents (depends on duration since transplant, prophylaxis being received, recent use of antibiotics, level of immunosuppression used, and neutropenia). Make every attempt to obtain microbiological specimens before first antibiotic dose. Deescalate or modify once microbiological information is available.

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Section 14:  Transplant/Organ Donation In case of secondary deterioration (presumed infection induced), obtain fresh specimens of blood, lower respiratory tract specimen, and even urine for stains and cultures and add broader spectrum empirical antibiotics based on institution guidelines to be modified based on laboratory results. Co-trimoxazole should be considered even based on radiological evidence (diffuse opacity with peripheral sparing) and clinical likelihood even before microbiological confirmation. ■ Corticosteroids: They are very useful for PERS and moderately for DAH. High dose like 1–2 mg/kg methylprednisolone twice a day for 3 days and then taper off over next few days. For DPTA, a dose of 1 mg/kg of methylprednisolone is used. Also, low-dose steroids may help in case of persistent hypotension. If patient was already on long-term steroids, similar of slightly higher doses must be continued during the acute disease. Steroids also help in case of PCP pneumonia. For COP 0.5–1.0 mg/kg, prednisolone is to be initiated and tapered over several months. Drug-induced lung injury (cyclosporine, fludarabine, and sirolimus) may also respond to steroids. ■ In case of DAH treatment may include platelet trans­ fusions, therapies such as aminocaproic acid and recombinant factor VIIa and cytokine antagonists (etanercept and cyclophosphamide) with variable success. ■ Most cases of venous thromboembolism occur within 6–12 months of HSCT. Treatment has to be decided on case-to-case basis. ■ Treatment options include reduction of immunosuppression alone as pre-emptive therapy, administration of rituximab, or a combination of both may stop rapidly progressive multiorgan failure and death.20

CONCLUSION Hematopoietic stem cell transplantation number and indications have been increasing over the years and so have reco­gnition of associated pulmonary complications. With better techniques and ability to deal with infections, noninfectious complications have been relatively growing faster. Initial stabilization needs to happen in tandem with definitive diagnosis which then allows specific treatment and prognostication. Collaboration is needed between hematologist, oncologist, pulmonologist, and intensivist to manage these cases.

REFERENCES 1. Baldomero H, Niederwieser D, Bazuaye N, Bupp C, Chaudhri N, Corbacioglu S, et al. One and half million hematopoietic stem cell transplants (HSCT). dissemination, trends and potential to improve activity by telemedicine from the worldwide network for blood and marrow transplantation (WBMT). Blood. 2019;134(Suppl 1):2035.

2. Indian Society for Blood and Marrow Transplantation. ISBMT registry data (unpublished). [online] Available from: https:// www.isbmt.org/. [Last accessed February 2022]. 3. Haider S, Durairajan N, Soubani AO. Noninfectious pulmonary complications of hematopoietic stem cell transplantation. Eur Respiratory Rev. 2020;29(156):190119. 4. Khurshid I, Anderson LC. Non-infectious pulmonary complications after bone marrow transplantation. Postgrad Med J. 2002;78(919):257-62. 5. Capizzi SA, Kumar S, Huneke NE, Gertz MA, Inwards DJ, Litzow MR, et al. Peri-engraftment respiratory distress syndrome during autologous hematopoietic stem cell transplantation. Bone Marrow Transplant. 2001;27(12):1299-303. 6. De Lassence A, Fleury-Feith J, Escudier E, Beaune J, Bernaudin JF, Cordonnier C. Alveolar hemorrhage: diagnostic criteria and results in 194 immunocompromised hosts. Am J Respir Crit Care Med. 1995;151(1):157-63. 7. Peña E, Souza CA, Escuissato DL, Gomes MM, Allan D, Tay J, et al. Noninfectious pulmonary complications after hematopoietic stem cell transplantation: Practical approach to imaging diagnosis. Radiographics. 2014;34(3):663-83. 8. Soubani AO, Pandya CM. The spectrum of noninfectious pulmonary complications following hematopoietic stem cell transplantation. Hematol Oncol Stem Cell Ther. 2010;3(3):143-57. 9. Aguilar-Guisado M, Jiménez-Jambrina M, Espigado I, Rovira M, Martino R, Oriol A, et al. Pneumonia in allogeneic stem cell transplantation recipients: A multicenter prospective study. Clin Transplant. 2011;25(6):E629-38. 10. Cordonnier C. Pneumonia after hematopoietic stem cell transplantation. In: Ljungman P, Snydman D, Boeckh M. (Eds). Transplant Infections. Switzerland: Springer, Cham; 2016. 11. Yadav H, Peters SG, Keogh KA, Hogan WJ, Erwin PJ, West CP, et al. Azithromycin for the treatment of obliterative bronchiolitis after hematopoietic stem cell transplantation: a systematic review and meta-analysis. Biol Blood Marrow Transplant. 2016;22(12):2264-9. 12. Or R, Gesundheit B, Resnick I, Bitan M, Avraham A, Avgil M, et al. Sparing effect by montelukast treatment for chronic graft versus host disease: a pilot study. Transplantation. 2007;83(5):577-81. 13. Bergeron A, Chevret S, Chagnon K, Godet C, Bergot E, de Latour RP, et al. Budesonide/formoterol for bronchiolitis obliterans after hematopoietic stem cell transplantation. Am J Respir Crit Care Med. 2015;191(11):1242-9. 14. Greer M, Riise GC, Hansson L, Perch M, Hämmäinen P, Roux A, et al. Dichotomy in pulmonary graft-versus-host disease evident among allogeneic stem-cell transplant recipients undergoing lung transplantation. Eur Respir J. 2016;48(6):1807-10. 15. Sircar M, Jha OK, Chabbra GS, Bhattacharya S. Noninvasive ventilation assisted bronchoscopy in high risk hypoxemic patients. Indian J Crit Care Med. 2019;23(8):363-7. 16. Jha O, Kumar S, Mehra S, Sircar M, Gupta R. Helmet NIV in acute hyoxemic respiratory failure due to Covid- 19: Change in PaO2/FiO2 ratio a predictor of success. Indian J Crit Care Med. 2021;25(10):1135-44.

Chapter 77:  Lung Complications after Hematopoietic Stem Cell Transplant 17. Sircar M, O Jha, Singh J, Yadav S, Kaur R. Prospective cohort study of Impact of BAL Biofire Filmarray pneumonia panel on microbial diagnosis and antibiotic prescription in ICU. Crit Care. 2020;24 (Suppl 1):446. 18. Sircar M, Ranjan P, Gupta R, Jha OK, Gupta A, Kaur R, et al. Impact of bronchoalveolar lavage multiplex polymerase chain reaction on microbiological yield and therapeutic decisions in severe pneumonia in intensive care unit. J Crit Care. 2016;31(1):227-32.

19. Wohlfarth P, Beutel G, Lebiedz P, Stemmler HJ, Staudinger T, Schmidt M, et al. Characteristics and outcome of patients after allogeneic hematopoietic stem cell transplantation treated with extracorporeal membrane oxygenation for acute respiratory distress syndrome. Crit Care Med. 2017;45:e500-7. 20. Xuan L, Jiang X, Sun J, Zhang Y, Huang F, Fan Z, et al. Spectrum of Epstein–Barr virus-associated diseases in recipients of allogeneic hematopoietic stem cell transplantation. Transplantation. 2013;96(6):560-6.

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Approach to Donor-derived Infection and Colonization in the Intensive Care Unit

C H A P T E R Parikshit S Prayag, Vasant Nagvekar

INTRODUCTION

BACTERIAL INFECTION/COLONIZATION IN Transplantation, both solid organ as well as bone marrow, THE DONOR is on the rise across the globe, especially in India. Successful prevention and management of infections forms the cornerstone of a transplant program. It is important to recognize colonization of the donor with bacteria as well as infections (bacterial, fungal, viral, and parasitic) in a timely manner. Proper protocols must be established to identify, prevent, and treat donor-derived infection and colonization. It is important to know which organs can be accepted in this setting. This also includes putting into place robust screening protocols. This chapter will deal with important issues in the peritransplant setting such as screening donors, identifying infected organs, accepting or refusing organs, which are colonized and reducing the risk of donor-derived infections, with a focus on the intensive care unit (ICU) setting.

DONOR-DERIVED INFECTIONS Numerous infections can be transmitted from the donor to the recipient, and hence, a detailed donor evaluation must be conducted. This is important from the point of view of identifying these infections and preventing transmission to the recipient (Table 1).

In an Indian setting, bacterial infection or colonization of the donor can be commonly found. This is further compounded by the fact that many of the isolates, especially gram-negative organisms found in this setting can be multidrug resistant. Hence, it is important to recognize which organs can be transplanted and to have the proper antimicrobial protocols in place. The approach is different for different scenarios:

Donor with Bacteremia In general, bacteremia in the donor is not a contraindication for transplantation. In a study assessing the outcome of transplantation of organs procured from bacteremic donors, the outcomes of transplantation were not affected by the presence of donor bacteremia.1 In a study from Italy, there were 14 recipients who received an organ from a high-risk donor (bacteremia or colonization of the transplanted organ with carbapenem-resistant gram-negative organisms). Proven transmission occurred in 4 out of the 14 high-risk recipients because donor infection was either not identified or there was no prompt communication. These recipients did not receive optimum post-transplant antibiotic therapy.

TABLE 1: Potential donor-derived infections in the transplant setting. Bacteria

Viruses

Fungi

Parasites

• Gram-negative infections including multidrug-resistant pathogens • Gram-positive infections including Staphylococcus, Enterococcus (vancomycin-resistant Enterococcus), Listeria • Mycobacterial infections • Rickettsial infections, Borrelia, Brucella species • Nocardia • Syphilis

• HIV • Hepatitis viruses B, C, and E • Influenza • Adenovirus • CMV • HSV • ? COVID-19

• • • • •

• • • •

(CMV: cytomegalovirus; HIV: human immunodeficiency virus; HSV: herpes simplex virus)

Candida Aspergillus Mucorales Cryptococcus Histoplasma

Malaria Toxoplasma Schistosoma Strongyloides

Chapter 78:  Approach to Donor-derived Infection and Colonization in the Intensive Care Unit Transmission did not occur in any high-risk recipient who received the optimum antimicrobials for at least 7 days.2 If feasible, delaying transplantation till the donor has received at least 48 hours of the appropriate antimicrobial therapy (based on susceptibility results) is prudent. Also, in the setting of bacteremia, a reasonable protocol is to administer the appropriate antibiotics (with demonstrated sensitivity) to the recipient for at least 7 days. Decisions to prolong this therapy to 14 days should be made on a caseto-case basis.

Donor with Bacterial Meningitis A donor with bacterial meningitis is not a contraindication for transplantation. Several studies have shown that organs from donors with bacterial meningitis can be transplanted without adverse outcomes.3-5 Donors should be on the appropriate antibiotics for at least 24–48 hours prior to procuring the organs and these should be continued in the recipient for about 7–10 days. Efficient communication is an integral part of this protocol and microbiologists as well as infectious diseases physicians should be consulted. Susceptibility as well as penetration into the central nervous system should be considered before choosing the antimicrobials. When meningitis is caused by highly virulent pathogens such as Listeria or Mycobacterium tuberculosis, some transplant centers consider it to be a contraindication for organ transplant.

Donor with Colonization or Infection of the Transplanted Organ As described above, in the study from Italy, transmission occurred in recipients when they were treated with inappropriate or short courses of therapy.2 Hence, if an organ with bacterial colonization is transplanted, it is imperative to communicate properly and involve experts, to optimize the management of recipients. A transplant infectious diseases physician should be involved in this process.

Donor with Colonization Elsewhere (Other Than the Transplanted Organ) This will not be a contraindication for transplantation. Also, in this situation, unnecessary usage of antibiotics must be avoided. This should be assessed on a case to case basis. Most donors in the ICU are at a risk for colonization, and this increases with other factors such as prolonged ICU stay, multiple antibiotics, indwelling devices, and duration of mechanical ventilation. Donor colonization (proven or suspected) at a site other than the transplanted organ needs careful evaluation by a transplant infectious diseases physician to see if targeted therapy is needed in the perioperative period for the recipient. This information should be clearly relayed to the treating teams.

Donor with Evidence of Syphilis Both treponemal and nontreponemal tests should be used as a part of an algorithm to determine the presence of syphilis in the donor. Current evidence suggests that a donor with active syphilis need not be excluded as long as the recipient gets adequate therapy in the post-transplant setting.6

Tuberculosis Donors with active tuberculosis (TB) are generally a contraindication for transplantation. Thorough assessment of donors in the ICU must be conducted to rule out active TB and should involve a transplant infectious diseases physician.

VIRAL INFECTION IN THE DONOR Human Immunodeficiency Virus A donor who is human immunodeficiency virus (HIV) positive remains a contraindication for a seronegative recipient. There are research trials underway to assess whether a seropositive patient can be a donor for a seronegative recipient.

Hepatitis Viruses Donors infected with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) should not be excluded. However, to determine the feasibility of such transplants, various factors need to be considered and this should be done by a relevant expert. In addition, donors who are currently negative, but have risk factors for acquisition of HIV/HBV or HCV should not be excluded, but the risk should be communicated to the recipient so that enhanced surveillance can be practiced. Such adult donors include: ■ Donors with high-risk sexual behavior ■ Long-standing hemodialysis patients ■ Donors who have injected drugs for nonmedical reasons. ■ Donors who have been treated for other sexually acquired infections in the preceding 12 months.

Coronavirus Disease (COVID-19) There is a theoretical risk of transmission of COVID-19 from the donor to the recipient is based on the fact that viral ribonucleic acid (RNA) is detected in organs that can be transplanted (e.g., lung, heart, kidney, and intestine) and in other sites (i.e., blood and urine).7,8 Donors who have active COVID-19 (clinically, proven by testing or radiographically) or who have had infection in the preceding 21 days should be excluded. 9 Also, donors who have been exposed to individuals with known or suspected COVID-19 in the preceding 14 days should be excluded.9

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Donor with Vaccine-induced Thrombosis and Thrombocytopenia There is insufficient data to conclude whether a donor with thrombosis secondary to COVID-19 vaccination can be included as an organ donor. In a study involving donors with vaccine-induced thrombosis and thrombocytopenia (VITT), 21 of 27 (78%) allografts had satisfactory function after a median follow-up of 19 days post-transplantation.10 Every effort must be made to exclude thrombosis in the graft, and can involve the use of Doppler as well as histopathological evaluation with a biopsy. Anti-PF4 antibodies can induce platelet activation and thrombosis, and hence, platelet transfusion should be avoided as far as possible. Anticoagulation regimens should generally include agents other than heparin. However, detailed counseling and consenting has to be a part of such protocols where there is inadequate clarity. Donors with unexplained encephalitis should generally be excluded.

Dengue Virus Cases of transmission of the dengue virus from the donor to the recipient have been described.11 Although there are no official recommendations at this point of time, in endemic areas such as India, the transplant teams should be aware of the possibility of such transmissions. Donors with active dengue infection are best avoided. Though cytomegalovirus and Epstein-Barr virus are not contraindications for organ donation, the serostatus helps in planning further prophylaxis in the recipients.

FUNGAL INFECTIONS IN THE DONOR Candida Donors with untreated candidemia should be excluded. Donors who have had adequate treatment and documented eradication of candidemia are usually considered to be low risk, and can be included, though the data is sparse. It would be reasonable to include these and administer appropriate antifungal therapy to the recipient in the peritransplant period. In the absence of documented infection in the recipient, empiric antifungal therapy can be discontinued at 2 weeks, and routine prophylactic guidelines (which may vary across centers) should be followed. Candida isolated from the preservation fluid, or in the donor urine cultures in cases of kidney transplants, should be treated for 2 weeks in the recipients, unless there is evidence of continued infection or a robust reason to prolong antifungal therapy. Colonization at distant sites need not always be treated, and decisions should be taken after consulting a transplant infectious diseases physician.

Renal and urinary penetration of antifungal agents should be considered, especially when dealing with fluconazole resistant species. Usually, lung transplant centers use at least 3 months of antifungal prophylaxis. If candida isolated in the donor respiratory cultures is not covered as a part of the routine post-lung transplant antifungal prophylaxis, then antiCandida therapy should be used till bronchoscopy has confirmed the integrity of the bronchial anastomosis. A more prolonged course can be used for recipients of bilateral or right lung transplants and in patients receiving depleting induction agents.

Mold Infections Mold infections, such as Aspergillus and mucormycosis in the donor are generally considered to be a contraindication for transplantation. Contamination of the preservation fluid can be a mode of transmission, leading to invasive mold infections in the recipients. Steps to identify and prevent such occurrences must be taken and appropriate communication must ensue, so that the recipient receives mold active therapy.

Donor with Cryptococcal Infection The chances of transmission to the recipient are considerable, and hence, a donor with active cryptococcal disease is usually avoided. In cases, where the donor has been treated adequately and fungal eradication has been documented, transplantation can be considered. This should be done in consultation with a transplant infectious diseases expert.

PARASITIC INFECTIONS IN THE DONOR Certain parasitic infections can be transmitted from the donor to the recipient. Local knowledge of the endemic parasites is crucial. Appropriate screening protocols can be then put into place. Donors can be screened for strongyloides, which can be transmitted to the recipient, and can cause severe disease. Antibody results should not delay transplantation, but if positive, preventive ivermectin is a safe and effective approach for the recipient. Donors in the ICU with active malaria should be excluded. Donors with a strong suspicion for visceral leishmaniasis (VL) or proven VL should be generally excluded. These discussions should involve all the concerned teams.

SUMMARY OF THE APPROACH TO DONOR INFECTION/COLONIZATION ■ Active bacteremia/meningitis in the donor is not a

contraindication as long as the donor has received the appropriate antibiotics for 48 hours, and the information is relayed properly so that the recipient is treated.

Chapter 78:  Approach to Donor-derived Infection and Colonization in the Intensive Care Unit ■ Approach to an organ colonized with bacteria which is

transplanted should be similar to donor bacteremia. ■ Donor colonization at a site other than the transplanted

organ is not a contraindication and unnecessary antibiotic use should be avoided. ■ Donors with active TB, severe malaria, dengue, mold infections should generally be avoided. ■ Donors with active COVID-19 within the preceding 21 days or potential exposures within the prior 14 days are usually excluded. ■ Donors with VITT should be included only after a thorough evaluation, multidisciplinary consultation, and extensive counseling. ■ Donors with candidemia can be included if they have received adequate therapy with eradication of infection. ■ Each center must develop a clear protocol in accordance with the local transplant authorities. ■ Involvement of a transplant infectious diseases expert is invaluable, if such expertise is available.

CONCLUSION It is important to recognize infections and colonizations promptly in the donor. This is a fine balance between not rejecting an organ in a set up where recipients have to endure long waiting periods and ensuring safety of transplantation. Local authorities, treating teams, and infectious diseases specialists have to act as a team and ensure prompt communication and an evidence-based approach.

REFERENCES 1. Freeman RB, Giatras I, Falagas ME, Supran S, O’Connor K, Bradley J, et al. Outcome of transplantation of organs procured from bacteremic donors. Transplantation. 1999;68:1107-11.

2. Mularoni A, Bertani A, Vizzini G, Gona F, Campanella M, Spada M, et al. Outcome of transplantation using organs from donors infected or colonized with carbapenem-resistant gram-negative bacteria. Am J Transplant. 2015;15(10):2674-82. 3. López-Navidad A, Domingo P, Caballero F, González C, Santiago C. Successful transplantation of organs retrieved from donors with bacterial meningitis. Transplantation. 1997;64:365-8. 4. Paig I JM, Lopez-Navidad A, Lloveras J, Mir M, Orfila A, Quintana S, et al. Organ donors with adequately treated bacterial meningitis may be suitable for successful transplantation. Transplant Proc. 2000;32:75-7. 5. Satoi S, Bramhall SR, Solomon M, Hastings M, Mayer AD, de Goyet JV, et al. The use of liver grafts from donors with bacterial meningitis. Transplantation. 2001;72:1108-13. 6. Screening of donor and recipient prior to solid organ transplantation. Am J Transplant. 2004;4(Suppl 10):10-20. 7. Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA. 2020;323:1843-4. 8. Tavazzi G, Pellegrini C, Maurelli M, Belliato M, Sciutti F, Bottazzi A, et al. Myocardial localization of coronavirus in COVID-19 cardiogenic shock. Eur J Heart Fail. 2020;22:911-5. 9. American Society of Transplantation. (2020). SARS-CoV-2 (Coronavirus, 2019-nCoV): Recommendations and guidance for organ donor testing. [online]. Available from: https://www. myast.org/sites/default/files/Donor%20Testing_100520_ revised_ReadyToPostUpdated10-12.pdf [Last accessed December, 2021]. 10. UK Donor VITT Transplant Study Group, Greenhall GHB, Ushiro-Lumb I, Pavord S, Currie I, Perera MTPR, et al. Organ transplantation from deceased donors with vaccineinduced thrombosis and thrombocytopenia. Am J Transplant. 2021;21(12):4095-7. 11. Cedano JA, Mora BL, Parra-Lara LG, Manzano-Nuñez R, Rosso F. A scoping review of transmission of dengue virus from donors to recipients after solid organ transplantation. Trans R Soc Trop Med Hyg. 2019;113(8):431-6.

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Antiviral Drugs in Transplant Recipients

C H A P T E R Rajeev Soman, Sujata Rege, Geethu Joe

INTRODUCTION

Resistance

Solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients are uniquely predisposed to develop clinical illness, often with increased severity, due to a variety of common and opportunistic viruses. Patients may acquire viral infections from the donor (donor-derived infections), from reactivation of endogenous latent virus, or from the community. Treatment for viruses with proven effective antiviral drug therapies should be complemented by reduction in the degree of immunosuppression.1 For others with no proven antiviral drugs for therapy, reduction in the degree of immunosuppression remains as the sole effective strategy for management. Prevention of viral infections is therefore of utmost importance, and this may be accomplished through vaccination, antiviral strategies, and aggressive infection control measures.2 Knowledge of nucleotide sequences, domains of structural, and enzyme proteins have enabled the design of antiviral drugs that target different steps of the viral-host interaction and replication cycle. A combination of such agents appear to be more effective in certain viral infections. Viruses can also be neutralized by antibodies and cellmediated immunity which have found application in certain situations.

Mutations in UL97 CMV phosphotransferase (conferring resistance to GCV/vGCV but not to cidofovir and foscarnet) and UL 54 CMV DNA polymerase (high level GCV resistance, cross-resistance to cidofovir).

ANTIVIRAL DRUGS FOR CYTOMEGALOVIRUS3 Ganciclovir and Valganciclovir Mechanism of Action Ganciclovir (GCV) is converted intracellularly to monophosphate form by viral kinase. Cellular kinases catalyze the formation of di- and triphosphate [guanosine triphosphate (GTP)] forms which concentrate 10-fold greater in cytomegalovirus (CMV)-infected cells. GTP preferentially inhibits viral DNA polymerases as well as blocks chain elongation. Valganciclovir (vGCV) is an oral prodrug that is rapidly converted to GCV.

Pharmacokinetics and Pharmacodynamics Valganciclovir is absorbed orally with bioavailability of 60% (when administered with food) and hydrolyzed to GCV in the intestinal wall and liver. Ganciclovir is excreted unmodified in urine and has higher intracellular half-life. Clearance of GCV correlates to glomerular filtration rate (GFR), hence dosage adjustment is required with impaired renal function. Hemodialysis decreases serum concentration by 50%, hence dosing postdialysis is recommended.

Administration and Dosage ■ Ganciclovir: Intravenous (IV) and intraocular. IV: 5 mg/

kg 12 hourly induction therapy followed by 24 hourly maintenance therapy. ■ Valganciclovir: Oral 900 mg twice daily induction therapy followed by once daily maintenance.

Toxicity and Monitoring ■ Bone marrow suppression: GCV and vGCV are asso-

ciated with bone marrow suppression, particularly leukopenia, and are contraindicated when absolute neutrophil count (ANC) 7–8 mm generally indicates obstruction.

Pancreas (Fig. 6) ■ The head, neck, body, and tail are visualized at bedside. ■ Hypoechoic areas around the pancreas and an

inhomogeneous pancreatic echo texture along with a change of normal shape of the pancreas are seen. ■ Increase in thickness of head, neck, body, or tail are noted (head > 2.6 cm and body > 2.2 cm). ■ Presence of collections in the peripancreatic area is noted (pseudocysts or necrotic collections) and if indicated, drainage procedures can be done with ultrasound guidance. ■ Pancreatitis is all easily visualized at bedside.

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Intra-abdominal Clinical

Cardiovascular System Clinical

■ Distension of abdomen, localized guarding, and raised

■ Fever, arrhythmias, clubbing, new onset murmurs

enzymes. ■ Purulent collections, many times subdiaphragmatic are the cause of fever in certain groups and can be seen very well at bedside. ■ Bowel pathologies may be picked up but this requires some specializations. ■ Dilated bowel loops (normal small intestine up to 3–4 mm and large intestine up to 4–5 mm). ■ Five layers of the intestine, i.e., premucosal, mucosal, intramucosal, muscular, and serosal layers can be seen.13 ■ Compressibility is usually reduced, note can be made of collections in the lumen or within the layers, as well as visualization of peristalsis can be done. ■ Contrast-enhanced ultrasound helps us to visualize the bowel wall microperfusion.14 ■ Ulcerative colitis and Crohn’s disease can be diagnosed. ■ Appendicitis (an often fluid-filled cord-like roundish structure with a diameter of >6 mm and lacking peristalsis) as well as diverticular disease (round hypoechoic ring with varying thickness, likened to bubbles along the wall of the bowel) may be identified at bedside (Fig. 7).

splenomegaly as well as culture positivity may be seen. ■ Common causes of undifferentiated fever in the critical

care setting include infective foci on the valves. ■ Endocarditis and mass-like lesions can be reasonably

well appreciated by transthoracic echocardiography (Fig. 9).3 ■ Quantification of the possible etiology is possible (e.g., large friable masses likely go in favor of fungal cause, right-sided endocarditis commonly seen in drug abuser, and likely Staphylococcus as cause). ■ Looking for vegetations, measuring their sizes, attachments, bases, and location can give invaluable clues in approach to such patients. ■ We can also assess for valve abscesses and prosthetic valve pathologies at bedside by the use of ultrasound.

Skin and Soft Tissue (Fig. 8) Clinical ■ Redness pain swelling discharge may be present. ■ Generalized thickening and increase in echogenicity of

the area with hypoechoic strands representing fluid are noted. ■ Cellulitis is typically diagnosed by the crazy pavement appearance on ultrasound. This is also known as cobblestone appearance.11 ■ Swelling within the fascial planes can help diagnose fasciitis.

Fig. 8: Skin and soft-tissue edema.

Fig. 7: Perisplenic collection.

Fig. 9: Aortic valve endocarditis.

Chapter 106:  Approach to Undifferentiated Fever in the ICU by POCUS: A New Way? ■ Myxomas in the heart chambers or rarely malignant

processes within the heart are seen. ■ The myocardium can present with a speckled appearance

sometimes leading us to a possible cause of myocarditis.

Pericardium (Fig. 10) ■ Clinically beck’s triad may be seen. ■ The pericardium can also be well seen at the bedside by

the use of POCUS. ■ We can evaluate for pericardial effusions, and by the appearance of the fluid and make important conclusions about etiology (clear fluid likely transudative, septate effusion likely infective, hazy effusions likely infective or blood). ■ Ultrasound can further facilitate a guided diagnostic tap of the fluid for evaluation.

Pulmonary Embolism Clinical ■ Unilateral limb swelling, unexplained dyspnea, and

hypoxia may be present. ■ Indirect evidence of pulmonary embolism as the cause of

fever can be sought at bedside, evidence of enlargement of the right ventricle, right atrium, and the “D” sign, along with the evidence of a thrombus in an extremity vessel make the diagnosis of pulmonary embolism very likely. ■ Some observers mention commonly seeing an A profile, sometimes a C profile where a pulmonary infarct is setting in.

Musculoskeletal Clinical ■ Soft tissue swelling pain may be present. ■ Collections around long bone fractures and intramuscu-

lar hematomas can be seen prominently as many times mixed echogenic collections.

■ Aspirations may be done safely at bedside under ultra-

sound guidance. ■ Joint effusions, their quantity and volume can be done at

bedside, and guided aspirations safely performed.

Paranasal Sinuses Clinical ■ Swelling and tenderness along the sites of the sinuses

(mainly maxillary) can be elicited in the conscious patient. ■ Many times indwelling nasogastric tubes and recently the scare of rhinocerebral mucormycosis should prompt the physician to make an evaluation of the sinuses as well. ■ Complete opacification of the sinuses is called the complete sinusogram (vase shaped) and incomplete opacification is called the incomplete sinusogram. These indicate the amount of fluid or secretion filling in the maxillary sinuses.4

Perioral Clinical ■ Pain, difficulty in chewing, swallowing, jaw area swelling,

and swellings in the soft tissues around the oral cavity may be noted. ■ POCUS can help identify fever due to pathologies around perioral area, tooth abscesses can be easily seen at bedside. These are seen as filling defects adjacent to the bone. ■ Collections in the subcutaneous areas, their measurements and progressive spread can be closely monitored and seen at bedside (Ludwig’s angina).

MISCELLANEOUS CAUSES ■ Pancreatitis (described in previous section) ■ Acute febrile disease many times due to inflammation

may be seen early in the course of pancreatitis. ■ The pancreas can be reasonably well examined at the

bedside. ■ The swelling of the pancreas can be measured by

various normograms, as well as search can be done for peripancreatic collections as well as pancreatic pseudocysts. ■ If infected necrosis is suspected, an ultrasound-guided aspiration can be easily done under guidance.

THROMBOSIS ■ Prominent among noninfectious causes are thrombotic

Fig. 10: Pericardial effusion.

lesions. ■ At the bedside, POCUS can identify deep vein thrombosis reasonably accurately.

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Section 18: Radiology ■ The compression test is done to achieve a diagnosis in

the extremities.

■ Oral malignant processes near mandible or tongue can be

seen well, as are some other malignancies like sarcoma.

■ Thrombotic foci may be located in both the upper and

■ Lung masses (Fig. 12), if superficial, can be picked up

lower extremity veins as well as the arterial systems (Fig. 11).11 ■ Superficial thrombophlebitis, sometimes also responsible for fever and can be seen as thickened vessel walls on the ultrasound. ■ Rarely, we may locate thrombi in the pulmonary vessels, commonly located by using the parasternal short-axis view at pulmonary artery level, where we are able to see the main pulmonary artery and its bifurcation.

bedside as also lesions (primary or metastatic) within solid organs such as liver, spleen, kidneys, or others (Fig. 13).

MALIGNANCIES

LINE-RELATED SEPSIS (FIG. 14) Clinical ■ Redness, pain discharge, and tenderness around the area

of the line. ■ This important cause of undifferentiated fever is

sometimes overlooked by the clinician.

■ Fever due to underlying malignant processes many times

flummoxes the clinician. ■ POCUS can help identify nodes, percutaneous aspira-

tions can be easily performed for identifying etiology.

■ Ultrasound evaluation can help in identifying possible

infective foci in the line: Soft tissue swellings at port of entry and evidence of edema as seen

z

Fig. 11: Free mobile clot in femoral vein.

Fig. 13: Metastases in liver.

Fig. 12: Mass in lung.

Fig. 14: Line sepsis biofilm.

Chapter 106:  Approach to Undifferentiated Fever in the ICU by POCUS: A New Way? ■ All infective/inflammatory processes may not present as

fever and should be kept in mind. ■ Ultrasound cannot rule out drug-related fevers. ■ Wise use of the POCUS can indeed improve outcomes.

REFERENCES

Fig. 15: Dengue, gallbladder, and ascites.

By tracing the path of the cannula, we may be able to locate “films” which begin to accumulate around/on the lines. ■ These “biofilms” are also likely foci of infection and merit consideration of line removal. z

TROPICAL FEVER HELP (FIG. 15) Clinical ■ Febrile illness with associated hepatosplenomegaly,

rashes, jaundice, joint swellings, and altered sensorium may be seen. ■ Description of the ultrasound features in dengue has been studied. ■ Typical among the findings are: z Evidence of “leaking” or polyserositis seen as ascites and pleural effusions z Thickening of the gallbladder wall (acalculous cholecystitis)12 ■ The appearance of the gallbladder has been described as a cobblestone appearance. ■ Some authors have found a correlation between thickened gallbladder wall and low platelet counts. ■ However, these findings are not exclusively seen in dengue and may be seen in other diseases as well.

CONCLUSION ■ POCUS is an invaluable tool in the bedside assessment

of undifferentiated fever in ICU. ■ A large number of pathologies can be effectively screened

by a thorough examination. ■ Clinical examination, robust laboratory interpretation,

and evaluation are strongly recommended with ultrasound for better results.

1. Niven DJ, Laupland KB. Pyrexia: aetiology in the ICU. Critical Care. 2016;20:247. 2. Robba C, Goffi A, Geeraerts T, Cardim D, Via G, Czosnyka M, et al. Brain ultrasonography: methodology, basic and advanced principles and clinical applications. A narrative review. Intensive Care Med. 2019;45:913-27. 3. Sordelli C, Fele N, Mocerino R, Weisz SH, Ascione L, Caso P, et al. Infective endocarditis: echocardiographic imaging and new imaging modalities. J Cardiovasc Echogr. 2019;29(4):149-55. 4. Neagos A, Dumitru M, Vrinceanu D, Costache A, Marinescu AN, Cergan R. Ultrasonography used in the diagnosis of chronic rhinosinusitis: From experimental imaging to clinical practice. Exp Ther Med. 2021;21(6):611. 5. Yikilmaz A, Taylor GA. Sonographic findings in bacterial meningitis in neonates and young infants. Pediatr Radiol. 2008;38(2):129-37. 6. Vidili G, Sio ID, D’Onofrio M, Mirk P, Bertolotto M, Schiavone C, et al. SIUMB guidelines and recommendations for the correct use of ultrasound in the management of patients with focal liver disease. J Ultrasound. 2019;22(1):41-51. 7. Mongodi S, Via G, Girard M, Rouquette I, Misset B, Braschi A, et al. Lung ultrasound for early diagnosis of ventilatorassociated pneumonia. Chest. 2016;149(4):969-80. 8. Zhou J, Song J, Gong S, Hu W, Wang M, Xiao A, et al. Lung Ultrasound combined with procalcitonin for a diagnosis of ventilator-associated pneumonia. Respir Care. 2019;64(5):519-27. 9. D’Amato M, Rea G, Carnevale V, Grimaldi MA, Saponara AR, Rosenthal E, et al. Assessment of thoracic ultrasound in complementary diagnosis and in follow up of communityacquired pneumonia (CAP). BMC Med Imaging. 2017; 17:52. 10. Javaudin F, Marjanovic N, de Carvalho H, Gaborit B, Le Bastard Q, Boucher E, et al. Contribution of lung ultrasound in diagnosis of community-acquired pneumonia in the emergency department: a prospective multicentre study. BMJ Open. 2021;11:e046849. 11. O’Rourke K, Kibbee N, Stubbs A. Ultrasound for the evaluation of skin and soft tissue infections. Mo Med. 2015;112(3): 202-5. 12. Santhosh VR, Patil PG, Srinath MG, Kumar A, Jain A, Archana M. Sonography in the diagnosis and assessment of dengue fever. J Clin Imaging Sci. 2014;4:14. 13. Andrzejewska M, Grzymisławski M. The role of intestinal ultrasound in diagnostics of bowel diseases. Prz Gastroenterol. 2018;13(1):1-5. 14. AlAli M, Jabbour S, Alrajaby S. ACUTE ABDOMEN systemic sonographic approach to acute abdomen in emergency department: a case series. Ultrasound J. 2019;11:22.

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19 S EC TI ON

Present and Future Challenges in ICU Organization and Management œ Organizational Challenges of Intensive Care Unit in India during the COVID-19 Pandemic: How to Prepare? Ratender K Singh, Om P Sanjeev, Chandrakanta Singh

œ Managing Change in Intensive Care Unit: Why Won’t Doctors Do What They’re Told? Gauri R Gangakhedkar, Jigeeshu V Divatia

œ The Current State of Clinical Information Systems in Critical Care in India Anuj Clerk, Biren Chauhan, Krunalkumar Patel

œ Challenges and Issues in Intensive Care Nursing in India: How to Overcome Them? Susruta Bandyopadhyay, Manoj Kumar Rai, Manish Bharti

œ Gut Dysfunction in Intensive Care Unit: Recent and Future Advances in Diagnosis and Management Avinash Tank, Kalpesh Shah, Rajeev Kumar Bansal

œ Intensive Care Management of Acute Liver Failure: What is New? Lalita Gouri Mitra, Juhi Chandwani, Amit Singhal

œ Caring for the Dying Patient in Indian Intensive Care Unit: Quality of Care, Ethical, and Legal Challenges Abhishek Prajapati, Rachit Patel, Bhalendu Vaishna

œ Pregnancy-associated Severe Sepsis: Present State and Challenges Anjan Trikha, Prachee Makashir, Sunil T Pandya

107

Organizational Challenges of Intensive Care Unit in India during the COVID-19 Pandemic: How to Prepare?

C H A P T E R Ratender K Singh, Om P Sanjeev, Chandrakanta Singh

INTRODUCTION The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on our health infrastructure has been challenging and a wake-up call to speed up the entire process of its transformation for any future pandemics. The state of poor health infrastructure as witnessed during coronavirus disease 2019 (COVID-19) needs to be rejuvenated by appropriate allocation of funds to the tune of at least 5% of gross domestic product (GDP) sustained over decades.1 Severe demand–supply imbalance of intensive care units (ICUs) was observed during the COVID-19 pandemic globally. India too suffered as many sick patients could not be provided ICU care primarily due to the poor ICU bed to hospital bed ratio. In a preprint data published in 2020, it was estimated that India has approximately 1.9 million hospital beds, 95,000 ICU beds, and 48,000 ventilators.2 Other than scarcity of ICU beds, heterogeneous distribution within the country, quality of ICUs, wide variability in paymentbased access, vaguely defined qualification, training, and credentialing of ICU doctors/nurses are major challenges that already existed even before the COVID-19 pandemic.

To begin with, the current proportion of ICU to hospital beds must be increased from 10–15% to 30% seeing the current COVID-19 situation and any future similar pandemics to fulfil the unmet demands immediately. Simultaneously tremendous efforts must also be made to improve both the quality and quantity of the human resource for these ICUs to uphold the desired standards of ICU care. Technological advancements in telehealth must be used to its fullest potential for improving the reach and quality for our generations to come.

CHALLENGES AND IMPROVEMENT STRATEGIES FOR INTENSIVE CARE UNIT Several challenges have been encountered by COVID-ICUs at all fronts, namely infrastructure, manpower, equipment, etc. Major challenges faced by these of COVID-ICUs are detailed in Table 1. Possible, achievable, and sustainable reforms are required to meet the future needs of qualityassured and surge-congruent ICUs. A need-based strategic and reorganizational approach is presented here in Table 1.

TABLE 1: Challenges and strategies to better prepare intensive care units (ICUs) for future pandemics. Characteristics

Challenges faced in COVID-ICUs

Strategies to better prepare ICUs for future pandemics

Initial planning • Unknown nature of virus, disease, • Nomination of team leader/ risk of transmission and absence of a coordinator definitive treatment instilled fear and • Assessment, planning, teamwork misconceptions amongst HCWs dynamics, accountability, • Existing poor and fragmented health logistics required needs for all infrastructure due to poor investment aspects of ICU care must be in health meticulously done • Scaling up the infrastructure in limited • Planning for surge capacity time was challenging • Optimally trained ICU human resource in sufficient numbers was a major limitation • Logistics were based on assumptions about case load and case mix

• Population-based region, city, state, and countrybased models of ICUs and their optimal distribution be determined in advance • Mandatory credentialing and certification of all ICUs • Focus on building modular ICUs that are easy to install and scalable in short time • Incorporate expandable spaces in initial design layout for ICUs • Identify in advance expandable pool of hybrid ICUs, trained manpower, and equipment that can be used if needed • Evidence-based triaging be mandated for admissions to ICUs to make best use of scare resources • Advanced planning for surge capacity at all levels Contd...

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Section 19:  Present and Future Challenges in ICU Organization and Management Contd... Characteristics

Challenges faced in COVID-ICUs

Strategies to better prepare ICUs for future pandemics

• Arranging for logistics with simultaneous lockdown was a bottleneck • Pandemic preparedness of hospitals, emergencies, and ICUs was found wanting

• Validated models for predicting case load be made available in time for better planning and implementation • SOPs for pandemics and/or other disasters must be prepared in advance with clear roles and responsibilities

Initial planning

Infrastructure Proportion of ICU beds/hospital beds Gross demand–supply imbalance, more so • Increased allocation of ICU beds to at least 30% of in the second wave hospital beds • Identify expandable pool of ICU beds both within and outside ICUs • Level of ICU care • Number of beds/units

Distinction between the levels of ICU care could be hardly implemented or maintained as “some care was better than no care” for needy patients

Maintaining levels of ICU care is advisable for better allocation of scarce logistics, human resources, and patient needs

Site/location of ICU

• Most current ICUs are not strategically located for dealing with pandemics • Larger emergencies with larger/ multiple ICUs at front end of hospital not available at most centers • Often ICUs placed within difficult-toaccess complexes located far off from emergency, OTs, and diagnostic blocks, not amenable to structural alterations for preventing cross-contamination in COVID-19

• Creation of large front-end emergency block with larger or multiple ICUs within it as is desired for disasters is needed with separate entry and exit for patients and HCWs and BMW disposal • Diagnostic and therapeutic intervention areas should be in close vicinity to this block

ICU design

• Physical partitioning is desirable for optimal IPC • Mostly halls with wall-based head-end measures, provided easy visibility of patients is not panels were prevalent in most ICUs hampered from nursing station • Partition between patients were either nonexistent or only by curtains in most • Negative- and positive-pressure isolation rooms must be planned and constructed at the initial ICUs stages of ICU construction itself for better isolation • Negative-/positive-pressure isolation of infected/contagious or immunosuppressed rooms were not available at most centers patients

Zones of ICU

• Because of the fear factor, zone distribution within ICUs was maintained owing to restricted movement • Family support areas were either nonexistent or distantly placed from the ICUs

Conventional zones of ICUs need to be expanded from three to five, namely, grossly contaminated, contaminated, buffer, clean, and HCWs donning/ doffing (separate) zones other than family support zones should be more clearly defined and maintained

Environmental requirements

• The set standards of heating ventilation and air-conditioning (HVAC) for ICUs were suboptimal at most centers • The air quality index (AQI) of most COVID-ICUs not known • Tolerance to humidity and temperature differed between patients and HCWs due to wearing of PPE • Poor visibility due to either improper wearing of goggles, poor-quality goggles, and/or poor control of temperature and humidity remained a niggling issue

• HVAC systems of ICU must be in accordance with set standards • Higher rate of air changes of at least six cycles per hour with two cycles from outside fresh air or 15 cycles per hour are preferable • HVAC maintenance and upkeep must be a priority • Doffing areas are hazardous areas for HCWs and should be optimally ventilated and stationed at a distance from the ICUs • Crowding at these areas should be avoided by staggered doffing of HCWs at the end of a shift

Contd...

Chapter 107:  Organizational Challenges of Intensive Care Unit in India during the COVID-19 Pandemic: How to Prepare? Contd... Characteristics

Challenges faced in COVID-ICUs

Strategies to better prepare ICUs for future pandemics

• Availability of common ICU equipments was initially below par • Pace of installation of invasive ventilators and the training required to run them by less-trained ICU staff proved challenging at most centers • Availability of video laryngoscopes was also an issue initially • Availability of invasive ventilators with capability of NIV mode was also an issue and resulted in much use of single-tube BiPAP devices which were an inferior choice • Helmet–mask interface though preferable for NIV was used minimally due to nonavailability and cost • HFNC though in much demand was initially in limited supply and also costly and on many instances was initiated without due consideration to the amount of oxygen consumed in background of oxygen crunch • Oxygen wastage was an issue at most centers • Difficult-to-maintain supply chain of lifesaving antimicrobials, remdesivir, steroids, tocilizumab, low-molecularweight heparin, etc. • ABG machines were installed at sites distant from ICU, leading to issues with transportation, sample processing, and reporting of ABG samples at most centers • Dedicated renal replacement therapy (RRT), USG, and X-ray machines were not available at many centers compromising ICU care

• Pooling of lifesaving equipments with advanced surge capacity planning • Have an active biomedical engineering wing for regular upkeep and maintenance of vital equipment • Having a central log of all such vital equipment and their functional status will help quicker relocation and utilization • Equipments with multitasking capabilities should be preferred, like ventilators with both NIV mode and IMV basic modes for ICUs • All ICU equipments should be compatible with available hospital information systems for easier data transfers • Better technologies adopted to improve equipment/ patient ratios • Module-based scalable monitoring solutions should be adopted for greater flexibility • Medical equipments with reasonable battery backup are preferable • Appropriate use of antimicrobials and other lifesaving drugs must be promoted, monitored, and audited regularly • Oxygen is a vital resource and its wastage should be avoided

ICU equipment Ventilators, monitors, infusion pumps, USG, X-ray, RRT, drugs, etc.

Human resource Intensivist or critical care specialist

• Trained intensivists in requisite numbers • Need to identify trained intensivists within the system and use them more diligently in times of need as they for full-time coverage were not available are and will continue to be in short supply • Often, inexperienced ICU physicians • Their expertise should be made readily available were on floor being guided by their to less trained on-floor staff, via intelligent use of more trained seniors via use of varied telemedicine resources communication devices for episodic • Identify an expandable pool of specialists from consultations only Critical Care Medicine, Emergency Medicine, Anesthesiology, and Pulmonary Medicine • Organize regular academic meetings amongst these specialties as they will be your most valuable resource for ICUs

Resident/junior doctors

• A mix of residents of clinical (ICU and Emergency and ICU rotations should become a regular non-ICU) and nonclinical specialties had to feature of training for residents across the specialty and be posted for an extended period of time subspecialties • There were not enough trained ICU residents to provide quality ICU services round the clock Contd...

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Challenges faced in COVID-ICUs

Strategies to better prepare ICUs for future pandemics

Nursing

• In public hospitals, 1:1 nursing is not available at most centers • Often the ratio of 1:5–7 was observed even for ventilated patients • Similar to intensivists and resident doctors, a mixed pool of nurses from ICU segment and non-ICU segment were deployed inside ICUs

Policy of rotation of nurses for emergency and ICU training must become mandatory to increase awareness about Airway, Breathing, and Circulation; hemodynamic monitoring and lifesaving emergency, and ICU drugs and equipment

Respiratory therapist/ physiotherapist/nutritionist

Pooling of this manpower will be helpful Not available at most centers, hence this work was also relegated to nurses and residents; chest and limb physiotherapy were severely compromised, resulting in poor outcomes. Similar difficulties faced with enteral/parenteral nutritional support

Psychological counsellor

Nonavailability led to poor psychological Need to be considered an integral part of the ICU team support of all three stakeholders, i.e., patients, and used more often their relatives, and healthcare providers

Human resource

Disaster preparedness Fire

• Major fire outbreaks reported at several ICUs in India • Fire safety norms not adhered to or only minimally implemented • Upkeep and maintenance not guaranteed

• Any new, even if it is a temporary ICU needs strict adherence to fire safety norms • Upkeep and maintenance service records mandatory

Interrupted oxygen supply

• Oxygen reserves stretched to the limit in second wave when demands far exceeded the supply • Oxygen cylinder-based supply proved precarious at several ICUs and situation became panicky in several hospitals, as reported in media • Liquid oxygen supply was only available at major hospital ICUs, and they too scrambled to maintain their supply due to overwhelming demand • Clearly demand–supply imbalance was created due to faulty planning and overwhelmed demands • Timely extraordinary efforts by both state and central government averted the inevitable oxygen crisis throughout India

• Oxygen wastage is very common in any hospital setting • Oxygen stewardship programs are needed to increase awareness • Every ICU must try and keep a record of oxygen consumption • Oxygen monitoring nurses can help stem the wastage • Oxygen delivery devices which minimize wastage must be promoted

Major power failure

• Inadequate battery backup of lifesaving equipments during power failure compromised functionality • Lack of generator supply with UPS backup jeopardized safety of equipments at several ICUs

• Backup power should be made mandatory for most of the feasible ICU equipments • At hospital level, there must be a power backup facility in case of failure

Communication systems

Centralized and state-of-art public address systems • Absence of a centrally located public should be made mandatory for hospitals, ICUs and and staff address system hampered Emergencies communication between patients and HCWs and amongst HCWs both within and outside COVID-ICUs • This lack of communication made working in COVID-19 hospitals and ICUs a struggle and in times of crisis help was not available as desired Contd...

Chapter 107:  Organizational Challenges of Intensive Care Unit in India during the COVID-19 Pandemic: How to Prepare? Contd... Characteristics

Challenges faced in COVID-ICUs

Strategies to better prepare ICUs for future pandemics

• Fragmented teams–fragmented communications led to suboptimal care • Owing to safety concerns, families of COVID patients could not be allowed within the ICUs at most centers • Expectantly so, there were unending demands for communication with their loved ones admitted in the ICU through voice and video calls • Customized solutions were adopted at some centers using telemedicine

• Conscious patients allowed to keep their mobiles with them for direct communication with their families • Telemedicine can provide may be the much-needed family access to patients and vice versa

Disaster preparedness Human violence which includes violence by relatives/political activists of patients on HCWs

Infection prevention and control (IPC) • Cleaning and disinfection • Biomedical waste (BMW) disposal • Prevention care bundles for CRBSI/ VAP/CAUTI • FASTHUGBD • Safe injection practices

• Difficult to maintain the higher and more stringent IPC practices in context of COVID • Limitations of logistics, infrastructure, and HCWs failed to implement even the most basic IPC measures in the COVID-ICUs • Preventive care bundles could be partially implemented that too only by trained ICU staff • Elements of standard ICU care were also only partially implemented • More often than not, all above important aspects remained ignored and/or unmonitored

• Provision of adequate number of trained staff • Additional staff monitoring and auditing these activities • Provision of CCTV surveillance to ensure compliance • Regular training of staff about these aspects of ICU care

• Not yet equipped for telemedicine in ICUs • Provision of CCTV surveillance to strengthen the compliance to improve standards of ICU care was requested by government but not complied with at most centers • Piles and piles of paper records were difficult to sustain and maintain • Electronic medical record (EMR) in ICUs hardly available • Difficulties of data compilation, integration, collation, and analysis were hurdles to care and research in COVID-19

• Telehealth surge has been witnessed during COVID19 and is going to be even more utilized in coming times • Paperless-ICUs are the way ahead • Tele-ICU services can help circumvent many shortcomings noticed in COVID-ICUs • Tele-ICUs can help minimize the risk to HCWs and emphatically utilize the services of senior intensivists • ICU-specific EMRs soon will become a reality in most ICUs • Digital health is coming of age in India with the right push at the right time

Telemedicine Tele-ICUs

(ABG: arterial blood gas; BiPAP: bilevel positive airway pressure; COVID: coronavirus disease; CAUTI: catheter-associated urinary tract infection; CCTV: closed-circuit television; CRBSI: catheter-related bloodstream infection; HFNC: high flow nasal cannula; HCW: healthcare worker; IMV: intermittent mandatory ventilation; NIV: noninvasive ventilation; OT: operation theater; PPE: personal protective equipment; SOP: standard operating procedure; USG: ultrasound; UPS: uninterruptible power supply system; VAP: ventilator-associated pneumonia)

CONCLUSION Expectations from society for upholding the higher standards of ICU care, despite the overwhelming demands and poor infrastructure, could be fulfilled to some extent. However, bitter lessons learnt by COVID-ICUs should be taken as an opportunity to better ourselves for future needs. Technological advancements in telemedicine have and will continue to lead the way for any future pandemics. Telehealth

surge was observed during COVID-19 and is expected to continue rising further as the set standard in health care. The experience gained using telemedicine in COVID-19 needs to be furthered and extended to the non-COVID-ICUs as well to overcome the heterogeneity in delivery of critical care services in India. Health care in India needs structural, organizational, operational, and technological overhaul to meet the rising ICU demands.

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REFERENCES 1. World Health Organization. (2003). How much should countries spend on health? [online] Available from https:// www.who.int/health_financing/en/how_much_should_ dp_03_2.pdf [Last accessed March, 2022]. 2. Kapoor G, Hauck S, Sriram A, Joshi J, Schueller E, Frost I, et al. (2020). State-wise estimates of current hospital beds, intensive care unit (ICU) beds and ventilators in India: Are we prepared for a surge in COVID-19 hospitalizations?

[online] Available from https ://www.medrxiv.org/ content/10.1101/2020.06.16.20132787v1 [Last accessed March, 2022].

SUGGESTED READING 1. Arabi YM, Azoulay E, Al-Dorzi HM, Phua J, Salluh J, Binnie A, et al. How the COVID-19 pandemic will change the future of critical care. Intensive Care Med. 2021;47:282-91. 2. https://egazette.nic.in/WriteReadData/2020/219374.pdf.

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Managing Change in Intensive Care Unit: Why Won’t Doctors Do What They’re Told?

C H A P T E R Gauri R Gangakhedkar, Jigeeshu V Divatia

INTRODUCTION Scientific and technological advances have transformed the healthcare sector. Consumerization of healthcare, changing economic and institutional facets, and the widespread permeation of insurance in healthcare have altered both the spectrum and the nature of services provided by the healthcare providers. The healthcare sectors in rapidly growing low- and middle-income countries, which are becoming global centers of technological and organizational innovation, have been particularly impacted by these changes.1 Incorporation of these advances into healthcare services is not an easy task given the distinct socioeconomic and infrastructural constraints in these countries. To facilitate the incorporation of the changes brought on by the advances, the concept of professional health managers has become popular. Health managers help organize and provide cost-effective and efficient healthcare, taking the pressure off healthcare workers who are also being increasingly burdened by documentation and administrative tasks as well as participation in management-led qualityimprovement initiatives.2 Of all the components that make up the healthcare systems, the intensive care units (ICUs) are among the most complex and expensive. The innate complexity of the ICU stems from multiple causative factors such as critically ill patients with acute life-threatening illnesses, high mortality rates, unpredictable outcomes at work, dynamic interdepartmental team structures, and the immense emotional burden to provide clear and honest information to vulnerable patients and their families.1,3 Continuous change is integral to the ICU culture; however, acceptance and incorporation of anything new contradict the basic human need for a stable environment.2 Available literature suggests that doctors rely more on knowledge gained from their past experiences, education, and information from journals than they are at accepting and adhering to new protocols. However, presenting them

with evidence to support the need for the change appears to make it easier for doctors to accept new evidence and protocols.4 In this chapter, we attempt to highlight factors that affect the acceptance of change and make the acceptance of these changes challenging. We will also attempt to suggest means by which doctors could possibly find it easier to accept and adapt to change easily.5 We have identified four major domains which in clinicians might encounter challenges in consolidating changes that emerge with evolving evidence and thus have trouble doing what they are told. Implementing evidence-based practices (EBPs): EBPs truly form the core of modern medicine. The formal definition for EBP is the conscientious, explicit, and judicious utilization of current evidence to make decisions that improve the care of individual patients. It represents an attempt to accurately understand medical developments, and apply newer principles as they evolve, to provide the best care for the patients.6 Evidence-based practice utilization, based on inter­ national standards, has been shown to reduce costs, improve patient and family satisfaction, and enhance the quality of patient care.7 In fact, a review by Pronovost et al. estimated that 167,819 lives can be saved annually, in the United States alone, with the implementation of key EBPbased intervention to target major ICU causes of mortality such as sepsis, adult respiratory distress syndrome (ARDS), and inadequate glycemic control.8 Conventionally, clinical decisions are usually based on traditional teaching, intuition, information obtained from peers or colleagues, and information from procedure manuals and application of EBP may appear to de-emphasize the value of these sources. However, it must be remembered that EBP holds no value unless implemented against the backdrop of strong clinical expertise. While EBP allows integration of research evidence with clinical expertise and patient values, its application and adaptation are unlikely to

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Section 19:  Present and Future Challenges in ICU Organization and Management be effective or sustainable, unless it is applied in the right setting by the right clinicians on the right patients, as is represented in Figure 1.6 Barriers to implementation of EBP on an individual level include lack of familiarity with EBP, individual flawed perceptions of EBP, or lack of credible information sources of evidence. Jordan et al. found that a significant number of doctors thought that the available information was overwhelming and difficult to synthesize, which suggested an inability to critically appraise, validate, and comprehend the information in order to make a clinical decision.7 This is a perception that requires immediate rectification since preappraised literature is available on websites such as the Cochrane database of systematic reviews, UpToDate, The Bottom Line, and the ACP journal club, free of cost or at a small price. The authors thus propose a six-step plan to understand and implement EBP (Fig. 2). Pharma-funded trials and possible financial incentives evoke a rather skeptical view on available literature. As a clinician, being a skeptic allows you to critique the available

Fig. 1: Evidence-based medical decisions.

Fig. 2: Six-step plan to implement evidence-based practice (EBP) into clinical practice.

evidence and only accept it if a definitive advantage is evident. Unfortunately, this means that sometimes good evidence gets ignored and pathophysiologic reasoning or biologic plausibility is given precedence.9 On the contrary, trials showing overwhelmingly negative outcomes, such as the ones proving the impact of starches on the kidney, seem to be accepted easily.10 The only plausible explanation behind this seemingly easy acceptance of negative studies is that when faced with a dilemma, a clinician will always choose the safest alternative for their patient. Additionally, incorporation of EBM into practice incorporates a commitment to regularly review the available literature to assess validity. This needs to regularly review evidence and the brevity of validity of most of the evidence, be it guidelines or that from other scientific papers that could also be perceived as a deterrent to EBM. Lack of support from management, poor facilitation, lack of authority to change practice, high workload, and inadequate infrastructure were found to be major organizational barriers to the implementation of EBP. Implementing new protocols: While prima facie, there appears to be no difference between EBP and protocolized care, it must be understood that protocolized care represents an effective way to incorporate EBP into practice, and EBP involves regularly updating the protocols to reflect the latest evidence. Protocols and checklist consist of simple measures that are “bundled” and have shown improved outcomes. Protocols standardize care of patients with similar diseases and hence increase the consistency of behavior. They allow the nursing and paramedical staff to work with directives in the absence of doctors.11 Additionally, they reduce the risk of errors by reducing the pressure of performing unfamiliar tasks at critical times and create additional defenses to prevent errors.12 Multiple studies and reviews have validated the immense contribution that protocols have had in improving outcomes in critically ill patients.13-15 Since caring for critically ill patients demands management of multiple severe problems with a slim margin of error, incorporation of protocols has the potential to replace idiosyncratic behaviors. However, they serve as a guide for classical situations, when in reality, clinical practice consists of complex and unpredictable scenarios, for which the approaches may have to be tailored.4 Furthermore, the evidence proving that protocols are associated with markedly improved outcomes does not assess the impact of individual components on outcomes; the bundle is assessed only in its entirety leading to impact misattribution, where each individual component is credited with having been responsible for the benefit.16,17 An observational study conducted in Pennsylvania ICUs showed that the implementation of protocols that are known to improve outcomes was seen in 14–41% of

Chapter 108:  Managing Change in Intensive Care Unit: Why Won’t Doctors Do What They’re Told? the ICUs though the protocols were available in 96% of them.18 The possible reason for this is that implementation of exhaustive checklists may increase the complexity of given tasks, making it difficult to accomplish particularly in high-volume or high-functioning ICUs. Consequently, even in the face of evidence to suggest that protocols and checklists have shown to vastly improve outcomes, one must remember that protocols promote safety, not excellence! When we consider employing protocols to clinical practice, it becomes important to fit the available resources with the protocol implementation desirable, to prevent protocol misalignment.17 Maitland et al. found that using “fluid bolus techniques” to resuscitate critically ill children in a resource-poor setting did not lead to the intended benefit, since facilities such as invasive monitoring and mechanical ventilation were not easily available.18 Though there is evidence that checklists and protocols are excellent tools to monitor the state of a system, their successful implementation depends on achieving the right balance between standardization and in providing the physicians with some decision-making latitude. 4 In other words, the real challenge is to not allow patient care to become a series tick boxes which treats patients as an abstract image rather than individuals. Implementing technology: One of the most important challenges that ICU physicians face is the need to continually learn and imbibe evolving healthcare technology in order to undertake their professional tasks, to the best of their competence.19 Adopting new technology can be taxing since it entails approval by team members, meeting budgetary requirements, developing the requisite infrastructure, and training of team members. Financial constraints, deficient infrastructure, information technology (IT) workforce shortages, and untrained and reluctant staff members are at the forefront of challenges in implementation of new technology. Besides these challenges, introduction of any new technology can disrupt the delivery of care and can also lead to new, unforeseen errors which impact the safety and quality of clinical care or even lead to patient harm. Unfamiliarity with the software leading to an increased requirement of time to carry out otherwise simple tasks, administering medications twice, and entering orders for incorrect patients are often seen when the team is new to a technology. In fact, up to 21 studies have identified delay in providing care, due to unavailable or inaccessible software, power failures, or computer viruses preventing access.20 All of this could give rise to a growing feeling of frustration, a sense of futility, and a convoluted perception that the technology is a waste of time, thus leading to creation of workarounds to avoid using the software.

When the introduction of a new technology is a management initiative, its acceptance becomes easier if it is introduced after looking into the perceived facilitators and barriers to implementation.21,22 Furthermore, a detailed assessment regarding the actual needs of the center would ensure that the programs are accurately structured to meet the center’s needs.23 This is predominantly true about technologies that have long learning curves and whose functionality is likely to increase over time. When the team members perceive a technology as having little value or impact, its implementation is met with resistance. All these factors possibly explain why technology initiatives that are led by nurses or physicians, rather than administration' lead to better outcomes. Providing initial training on a device, availability of technology support staff to assist novices, and the availability of continued guidance along with refresher courses have a significant impact on widespread acceptance.21 It is these differences in implementation that possibly lead to the same technology to thriving in one institution yet failing in another. Interpersonal relations/conflicts: The ICU, as a workplace, is dynamic not just because of how rapidly the condition of the patients changes but also because the ICU has multidisciplinary teams whose members work together regularly, disband, and regroup together repeatedly. 23 Multidisciplinary teams where each team member provides a distinct approach and perspective toward a uniform goal, i.e., better patient outcomes, have been the characteristics of critical care. A fundamental component of effective teamwork in the ICU thus becomes fluid leadership, with an identification of common goals. Fluid team leadership involves assessing a given scenario and patient requirements to dictate which team member, with their training and understanding, would be the best to lead the treatment plan at that point. Unfortunately, this unique structuring could also entail an incomplete grasp of the other team members’ background and understanding of the situation. Given the highly volatile environment where stakes and tensions remain high, the changing interpersonal dynamics can make the ICU a place rife with conflicts. Team conflicts can be classified as task or relationship conflicts. Disagreement about tasks at hand such as team strategy and policy development leads to task conflicts while relationship conflicts consist of disagreements due to differences in personality, personal values, and beliefs.23 Team conflicts can be used to clarify misunderstandings and disagreements about roles and tasks. Relationship conflicts unlike task conflicts are invariably detrimental to team performance and hence patient outcomes.23 They lead to situations where actions of the team members are viewed with suspicion. As a consequence, conflicts have

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Section 19:  Present and Future Challenges in ICU Organization and Management the potential to alter team dynamics and communication, decrease trust and team performance, and lead to poor mental health among professionals.24 Failure to collaborate and communicate effectively could lead to patient care decisions being taken in isolation and without taking into account the perspectives of all team members.24 Conflicts in the ICU have been shown to be strongly associated with burnout syndrome in nurses and physicians. A multicentric study by the European Society of Intensive Care Medicine (ESICM) carried out in 323 ICUs in 24 countries showed that 72% of the respondents reported at least one conflict over one 24-hour period evaluation.3 While 70% of respondents reported that these conflicts had possibly a harmful effect on the quality of care provided, 44% of respondents reported a possible harmful effect on patient survival.3 Understanding the root cause of conflicts and domains of patient care that are affected is crucial. It will help attending physicians, nurse managers, and quality management programs implement appropriate countermeasures more efficiently. Task conflicts provide an excellent opportunity to revisit and review policies to improve outcomes. Team identification, regular debriefings, and policy review meetings can help reduce relationship conflicts. Furthermore, since death of the patients is one of the strongest risk factors leading to team conflicts and physician burnout, it may be advisable to ensure that the same team member is not in charge of several dying patients at the same time. When dealing with patients who are dying, having the entire team formulate an approach to explain the principles of palliative care to the family significantly increases team identification and decreases conflicts while simultaneously improving the quality of care.3

Forming a core project implementation team that regularly reviews project status and plans next steps, enrolling enthusiastic experts, provides regular updates, use of digital tools such as online forums, applications that show individual contributions, and outcomes in real time, and reinforcing the importance of the initiative by mentors or team, the ICU director, and key unit leadership personnel, holds the key to success.5,25 However, this is easier said than done, since ensuring the same requires extensive interdisciplinary leadership and collaboration. Rather than a chain of events, implementing change consists of a never-ending cycle as represented in Figure 4.26

MANAGING CHANGE IN INTENSIVE CARE UNIT

Fig. 3: Choosing the right intervention.1 (HCP: healthcare provider)

Implementing sustainable changes in the ICU practices is not limited to simply introducing amendments but necessitates focused efforts to plan, implement, and evaluate interventions or the so-called Plan-Do-Study-Act (PDSA), as a continuous quality improvement initiative as recommended by the Institute of Healthcare Improvement (IHI). It would probably help to understand that implementing an effective and sustainable change begins much before the introduction of the idea for the change, i.e., of the PDSA cycle. The planning of the change is indubitably the most important part of the process. It involves understanding the history and evolution of the health sector in that particular region, the functioning and culture of the same, studying potential innovations that could be effective based on the current set of challenges, analysis of infrastructural and managerial policies that influence health system performance, and understanding of health system stewardship.1 The fundamental components to choosing the right intervention are shown in Figure 3.

Fig. 4: Implementing effective change.

Chapter 108:  Managing Change in Intensive Care Unit: Why Won’t Doctors Do What They’re Told? Organizational changes have been shown to be associated with psychological uncertainty since the changes affect the work, role, and overall life of the involved team members. They could also lead to work-related stress, decreased productivity, emotional exhaustion, mental health problems, and a myriad of other problems.2 Bureaucratized and hierarchical organizations tend to be less flexible. Therefore, they are less amenable to change and less likely to empower staff. Literature regarding acceptance of change suggests that physicians were more likely to respond with skepticism or suspicion to management-led changes.2 Any changes initiated by healthcare providers themselves are usually the easiest to implement and resistance is rarely encountered. For management-led changes, clear advanced intimation to allow time for preparation, and providing evidence which shows identifiable value in improving patient outcomes, goes a long way in easing the acceptance (see Fig. 3). Implementing effective change has been described as unfreezing old behaviors, introducing new ones, and refreezing them.19 To ensure that changes brought on by administration or management are as physician friendly as they are patient-centric, the Swedish government has introduced the concept of “trust-based governance.” “Trust-based governance” aims at integrating aspects of professional logic with managerial logic, and thus provides an effective solution to healthcare professionals using auditing, control, and performance management.2 Though it encourages the presence of healthcare managers, the system encourages doctors to use their expertise and discretion to independently treat complex patients and make decisions based on their knowledge and skills rather than limit them in a rigid hierarchy.

CONCLUSION To summarize, each ICU represents a microcosm of the healthcare sector with multidisciplinary teams, distinct work cultures, and varied infrastructural and socioeconomic limitations. Thus, while implementing any new strategy, it must be borne in mind that bringing about any such alteration would require a change in the ICU work culture and impact the daily behavior of all the team members. Furthermore, implementing effective and sustainable longterm solutions for change consists of evaluating each setup for its requirements and identifying challenges that would be encountered during implementation. The ideal solution is one, which while holding patient interests at heart, represents an amalgamation between technological, protocolized, evidence-based or people-oriented interventions.

REFERENCES 1. Bloom G, Wilkinson A, Bhuiya A. Health system innovations: adapting to rapid change. Global Health. 2018;14(1):29.

2. Nilsen P, Seing I, Ericsson C, Birken SA, Schildmeijer K. Characteristics of successful changes in health care organizations: an interview study with physicians, registered nurses and assistant nurses. BMC Health Serv Res. 2020;20(1):147. 3. Azoulay E, Timsit JF, Sprung CL, Soares M, Rusinová K, Lafabrie A, et al. Prevalence and factors of intensive care unit conflicts: The Conflicus study. Am J Respir Crit Care Med. 2009;180(9):853-60. 4. Rycroft-Malone J, Fontenla M, Bick D, Seers K. Protocol-based care: impact on roles and service delivery. J Eval Clin Pract. 2008;14(5):867-73. 5. Michailidou E. Change management in ICU. Am J Biomed Sci Res. 2020;8:524-9. 6. George EL, Tuite P. A process for instituting best practice in the intensive care unit. Indian J Crit Care Med. 2008;12:82-7. 7. Jordan PJ, Bowers C, Morton D. Barriers to implementing evidence-based practice in a private intensive care unit in the Eastern Cape. South Afr J Crit Care. 2016;32(2):50-4. 8. Pronovost PJ, Rinke ML, Emery K, Dennison C, Blackledge C, Berenholtz SM. Interventions to reduce mortality among patients treated in intensive care units. J Crit Care. 2004;19: 158-64. 9. Ebell M, Shaughnessy A, Slawson D. Why are we so slow to adopt some evidence-based practices? Am Fam Physician. 2018;98:709-10. 10. Zarychanski R, Abou-Setta AM, Turgeon AF, Houston BL, McIntyre L, Marshall JC, et al. Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic review and meta-analysis. JAMA. 2013;309(7):678-88. 11. Matlakala MC, Bezuidenhout MC, Botha AD. Challenges encountered by critical care unit managers in the large intensive care units. Curationis. 2014;37(1):1146. 12. Drews F, Wallace J, Benuzillo J, Markewitz B, Samore M. Protocol adherence in the intensive care unit. Hum Factors Ergon Manuf. 2012;22(1):21-31. 13. Chang SY, Sevransky J, Martin GS. Protocols in the management of critical illness. Crit Care. 2012;16(2):306. 14. Blackwood B, Alderdice F, Burns K, Cardwell C, Lavery G, O’Halloran P. Use of weaning protocols for reducing duration of mechanical ventilation in critically ill adult patients: Cochrane systematic review and meta-analysis. BMJ. 2011;342:c7237. 15. de Moraes AG, Holets SR, Tescher AN, Elmer J, Arteaga GM, Schears G, et al. The clinical effect of an early, protocolized approach to mechanical ventilation for severe and refractory hypoxemia. Respir Care. 2020;65(4):413-9. 16. Girbes ARJ, Marik PE. Protocols for the obvious: Where does it start, and stop? Ann Intensive Care. 2017;7:42. 17. Kavanagh BP, Nurok M. Standardized intensive care. Protocol misalignment and impact misattribution. Am J Respir Crit Care Med. 2016;193(1):17-22. 18. Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011;364(26):2483-95. 19. Al-Abri R. Managing change in healthcare. Oman Med J. 2007;22(3):9-10. 20. Kim MO, Coiera E, Magrabi F. Problems with health information technology and their effects on care delivery and patient outcomes: a systematic review. J Am Med Inform Assoc. 2017;24:246-50.

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Section 19:  Present and Future Challenges in ICU Organization and Management 21. Langhan ML, Riera A, Kurtz JC, Schaeffer P, Asnes AG. Implementation of newly adopted technology in acute care settings: a qualitative analysis of clinical staff. J Med Eng Technol. 2015;39:44-53. 22. Gabriel MH, Jones EB, Samy L, King J. Progress and challenges: implementation and use of health information technology among critical-access hospitals. Health Aff (Millwood). 2014;33(7):1262-70. 23. Guenter H, van Emmerik H, Schreurs B, Kuypers T, van Iterson A, Notelaers G. When task conflict becomes personal: The impact of perceived team performance. Small Group Res. 2016;47:569-604.

24. Cullati S, Bochatay N, Maître F, Laroche T, Muller-Juge V, Blondon KS, et al. When team conflicts threaten quality of care: A study of health care professionals’ experiences and perceptions. Mayo Clin Proc Innov Qual Outcomes. 2019;3(1):43-51. 25. Kleinpell R, Zimmerman JJ. Implementing clinical practice changes in critical care: lessons learned in a national collaborative of over 60 ICU teams. Anaesthesiol Intensive Ther. 2017;49(5):437-40. 26. Institute for Healthcare Improvement. (2005). Science of improvement: how to improve. [online] Available from: http:// www.ihi.org/resources/Pages/HowtoImprove/Scienceof ImprovementHowtoImprove.aspx [Last accessed March, 2022].

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The Current State of Clinical Information Systems in Critical Care in India

C H A P T E R Anuj Clerk, Biren Chauhan, Krunalkumar Patel

INTRODUCTION Medical field is advancing rapidly and so it is obvious that the quantum of information is rising at a galloping rate. Ever-growing volumes of information, not only about patients’ clinical data sets but also about administrative areas (quality, safety, codes, equipment, maintenance, etc.), is increasing fast. Keeping track of the dynamics of change in all these data sets is beyond the capacity of a human being, unless one takes resort to computerized information systems. Computer-based clinical information system (CIS) helps not only to acquire and manage data but also facilitate assimilation into actionable intervention regimes, which are then made available to the bedside team for timely actions for better patient care. Recognizing the importance of CIS, the American Board of Medical Specialties has added Certificate in Clinical Informatics in their list and all modern hospitals have the post of Chief, Clinical Information Services. In India, due to heterogeneity in resource allocation for CIS in various critical care units, we have all states of CIS in our intensive care units (ICUs), right from fully automatized paperless ICUs to all paper without any computer systems. Recently, there has been massive upsurge in the use of computer technology in the healthcare sector. Changes happening at the national government-sponsored healthcare sector have given a new boost to the use of already progressive computer-based health information in the private sector. This chapter will give information on the currently available CIS in India with a mix of clinicians as well as administrators’ viewpoints.

CIS AT A LARGE-SCALE NATIONAL LEVEL AND ITS PROJECTED IMPACT AT HOSPITAL LEVEL Taking cues from the National Health Policy, 2017 (NHP 2017), the government of India launched a health scheme called “Ayushman Bharat Pradhan Mantri Jan Arogya Yojana (PM-JAY)” which is a classic example of large-scale use of health information technology (IT).1 This scheme is technology driven, digitally equipped, completely paperless,

and seamlessly integrated with its empanelled healthcare providers. This giant health information system not only made possible collection of such a large metadata but also information so collected and collated are of great value to public health researchers for better planning of future healthcare needs of the country. In September, 2021, the government announced Ayushman Bharat Digital Mission (ABDM) to bridge gaps among various stakeholders of the healthcare ecosystem. Building blocks of ABDM will be Unique Health ID for every citizen, robust Health Facility Registry (HFR) and Healthcare Professionals Registry (HPR) and digitally stored Patient Health Records (PHR). The changes in health care at the top (national level) are expected to percolate as mandatory digitalization of many aspects of health care. Many hospital information systems (HISs), also called CIS, which are already in use, will get a boost. This is a much-needed thrust to resolve intersystem software mismatch, which prevents assimilation of healthcare data not only between hospitals but also country at large. In the current scenario, no hospital, clinic or nursing home, or ICU can afford to lag behind in adopting and upskilling themselves in use of CIS.

CLINICAL INFORMATION SYSTEM: WHY IN MODERN ICU? As time is muscle in acute coronary syndrome, brain in stroke, time is life in ICUs. To deliver optimal care, any intensive care professional has to collect data from various screens [monitors, intra-aortic balloon pump (IABP), injection pumps, air mattress pump, warmer, ventilator, extracorporeal membrane oxygenation (ECMO) console, etc.], various sources [bedside charts, past records, films, X-ray, computed tomography (CT) scan, magnetic resonance imaging (MRI), etc.], and various reports (pathology, radiology, operating room notes, emergency room notes, catheterization laboratory notes). Then he/she needs to analyze these collected data to reach a conclusion and make and document a treatment plan. Optimal

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Section 19:  Present and Future Challenges in ICU Organization and Management implementation of treatment plans and regimes is the final step. The effect of patient management needs to be analyzed using the same information from CIS. To do this in a timely manner with a cacophony of alarms in intensive care has become challenging or at times impossible for an average human being. Automatization of these tasks requires compilation of information in CIS at the onset but software incompatibilities between data sources are prohibitive. Many inputs are subjective with marked interobserver variability, which makes datasets inaccurate at best and makes a standard (computerized) algorithmic approach misleading. Dynamic dataset in intensive care setting (ICS) needs integration of timed physiologic inputs in many linear as well as nonlinear analytical tools, which is impossible for routine software, designed mainly for commercial and stock-keeping purposes. 2,3 Thus, one needs a CIS designed to serve clinicians’ need in ICU. Many of large corporates or medical colleges have purchased commercially available ones or got their software designed indigenously. These software not only facilitate day-today functioning but also pave the way for generation of a large database (BIGDATA) which can be used for machine learning and application of artificial intelligence to create better and cost-effective services. Integration of biomedical and healthcare data has potential to revolutionize the medical therapies and personalized medicine, but it requires a cautious approach to prevent derailment of the established healthcare system.4 At inception, such CIS was limited to clinical tasks like ordering, display of laboratory results or radiology images, and at times printing discharge summaries from the system. Now modern CIS has evolved to semiautomatic (requires manual data entry by ground team) or fully integrated and automatic systems. India being the providers of IT professional to the world, it is obvious that we have a large number of agencies making software solutions today. As the number of CIS available in the market increases, one needs guidance of selecting which one suits best for their unit or institute at large.

CURRENT CIS (HIS) SOFTWARE’S BASIC FEATURES AND COST CONUNDRUM Every IT solution has broadly two major aspects—software and hardware. CIS is software aspect and hardware is there to support and extract maximum benefits of CIS software. Every software solution has again two major areas to look into. Back end is like the brain of the system and front end is the body of the system. Every software is run on fundamental blocks of logic and rule. So, any CIS software one is looking at has to be validated from logic and rule that has gone into developing CIS software. This helps one to critically evaluate and choose from the currently available CIS solutions (Fig. 1).

Fig. 1: Fundamental blocks of a clinical information systems. (BI: business intelligence) TABLE 1: Few of the currently available clinical information system (CIS) providers globally and locally. Multinational global companies

India-specific companies and their HIS software

• • • • • • • •

• • • • • • • • • • • •

Cerner Corporation Allscripts Athenhealth Epic Systems Microsoft Salesforce SAP IBM

TCS Medmantra Wipro HIS Attune Akhil Suvarna HIS eClinicalworks Manorama Infosolutions Palash Healthcare Birlamedisoft Gemini Medstar HIS eHospital

(HIS: hospital information system)

CIS SOFTWARE SOLUTION PROVIDERS AND COST COMPARATIVES Global companies offering CIS software solutions are much more costly (anywhere around 75 lakhs or more) when compared to Indian companies. Indian providers are costeffective in short as well as long run. Few large hospital provider chains also have an in-house team of software developers and use their homegrown CIS as it is highly customized to their requirements (Table 1). On an average, global CIS providers are—five to six times more costly as compared to their Indian counterparts. Recently, subscription-based models have come up where companies do charge on use basis or per bed per day basis which apportions cost for the buyer over a period of time. However, one has to compare features offerings versus initial cost, plus yearly maintenance cost, and cost of initial capital that goes behind implementing CIS software in a hospital. From an administrator’s eyes, one needs to evaluate the cost of CIS in terms of man-hours saved, value addition to customers, system efficiency and tangible and intangible savings, quality care outcomes, etc., for better decisionmaking while purchasing suitable HIS.

Chapter 109:  The Current State of Clinical Information Systems in Critical Care in India

HOW TO EVALUATE A GIVEN CIS? A MATRIX SYSTEM

CIS SOFTWARE SOLUTION—360° EVALUATION MATRIX

Before making purchase of CIS software, one has to enlist their own requirements and expectations from CIS software. Requirements must be well elaborated and documented keeping not only past experiences or present needs but future needs as well. Growth plans of the hospital or ICU must take precedent while listing down the requirements. Major thrust has to be on both clinical and nonclinical workflows where HIS software can come in to simplify, streamline, and act as an enabler rather than hindrance. The requirement matrix has to be contextual, realistic, and simplified. The matrix has to be from the perspective of patient and end user and not only from the clinician or management perspective. This is the common error one should get rid of while enlisting requirements for HIS software. One can group the requirements under patient management system, clinical management system, patient support system, and administrative system. Once the requirement list is ready, multiple HIS software solution providers can be requested for the demonstration where critical features can be evaluated. Evaluation should be done jointly by Chief Operative Officer, Medical Director, and multidisciplinary team comprising mid-level managers, end users, diverse team of clinicians, and top management.

Table 2 shows the matrix for analysis of evaluation of CIS software. Shortlisted CIS software can be taken up for further discussions and negotiation on cost, features, migration, and implementation exercise, etc., to close the purchase. On-site visit to the places where the solution is being practiced will be more rewarding and revealing.

HIS SOFTWARE SOLUTION—ADOPTION CYCLE To reach to the desired end result of any HIS (CIS), one is expected to pass through the adoption cycle shown in Figure 2.

Challenges during Adoption of a New CIS Software No adoption process of new CIS software is free from challenges and hurdles. Time and cost overrun are the end result of poor planning and preparedness. CIS purchase is only one part of CIS adoption. The real challenge lies during the migration and implementation phase. Few common challenges faced by any healthcare institution and possible solutions are given in Table 3. Multidisciplinary team approach form beginning, involving larger team and empowering them, creating change managers within system and nurturing vendor association as key stakeholder will ease out these challenges along with sound planning and leading the change from the front.

Limitations of Using CIS in Modern ICUs Morrison et al., studied effect on interpersonal communi­ cation and hurdles in ICU round in their 25 bedded ICU in before and after introduction of fully integrated electronic patient record. They did it by recording ICU

Fig. 2: Process of selection and implementation cycle for clinical information system (CIS). (AI: artificial intelligence; BI: business intelligence; HIS: hospital information system; MIS: management information system; ML: machine learning)

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Section 19:  Present and Future Challenges in ICU Organization and Management TABLE 2: Clinical information system software solution—360o evaluation matrix. 360° HIS software evaluation matrix Performance scoring (Likert scale) Demo HIS 1

Group and subgroups

Key aspects

Patient management system

• Emergency department workflow • OPD workflow • IPD workflow

Clinical management system

• • • •

Support services management

• Radiology workflow • Pharmacy workflow • Allied clinical and nonclinical services workflow

Inventory management

Supply chain module

Revenue cycle management

• • • •

MIS reports console

Daily/weekly/monthly reports and data for decision-making

Analytics/BI

Analytics and performance management

Modules

Patient/user/department/administration

Database administration

Data capturing, data processing, storage, privacy, security, retrieval, analytics

Vendor support

Requirement understanding, HIS configuration, workflow validation, training, hardware compatibility, integration, interoperability, scalability

Migration support

360° migration, pre- and postmigration support

Implementation support

Pre- and postimplementation support

Licenses and upgradation support

• Compliance and updates as and when arrives to optimize • HIS performance

Demo HIS 2

Demo HIS 3

Demo HIS 4

ICU workflow Ward workflow OT workflow Laboratory sciences workflow

Registration and admission Billing Claims management Finance and accounts

(BI: business intelligence; HIS: hospital information system; IPD: inpatient department; ICU: intensive care unit; MIS: management information system; OPD: outpatient department; OT: operation theater)

rounds on video and interpreted for study parameters.5 After implementation, the doctor who stood in front of the computer (rather than large ICU charts and files) had data visible to him only and rest could see hardly anything. Due to this, others could no longer focus on the patient data. It was noted that team members had difficulty in entering the conversation and impairing communication. It took almost 1 year for the team to readjust themselves by juniors taking print from the system, physician standing back a little, and larger fonts and enlarged images being used on the screen so that everyone can see. Questions were invited at the end of each patient in order to facilitate discussion. Thus, one would expect new problems generated due to implementation of new CIS in a system.6 However, one

must be ready to modify or adapt oneself and CIS with everchanging information load from various courses in ICU.

LEGAL REQUIREMENTS FOR DATA STORAGE AND RETRIEVAL Various central and state laws make it imperative for hospital to maintain electronic health records (EHRs) of their patients and must produce to competent authority as and when required by law. Patients must get their health records on demand. Protecting personal health data of every patient is very essential and legally binding. The IT Act, 20007 largely governs the data security and exchange in all sectors including health care. In addition, the Ministry

Chapter 109:  The Current State of Clinical Information Systems in Critical Care in India TABLE 3: Hurdles and proposed solutions while adopting clinical information system in intensive care unit. Problems faced by ICU team while switching over to new CIS System-related

Possible solutions

Hardware shortage, wear and tear

Optimal planning, timely upgrade

Network issues (not able to retrieve stored data on time)

Better planning hardware at inception

Data migration from old to new CIS

Anticipate and make action plan before implementation

Not able to fix software glitches on time especially after hours

Optimal IT team backup (24 × 7)

End-user access and allowance by system

Optimize access privileges from outset

Limitation in privileges to access core system by ground team. Wait for next working day

Telecomputing even after hour support

Teething trouble during introduction

Anticipate and make provisions for added support

Not storing data

Technical support, options of backing up on local system

Data protection

Password protection

Initially heavy dependence on CIS support team of vendor and time Have local IT team trained so system get independent from vendor delays in getting solutions to problems support after a deadline Not in system so cannot do

Availability of alternative path to perform and timely integration in the system

End user-related Typing speed and errors

Time and proactive attitude to adopt CIS

Cannot make drawing in notes, software, and hardware limits

Draw on paper, scan, and attach

Lack of end-user training and its effectiveness

Optimal and repetitive training of ground team Have adequately trained trainers first

Only one member can use a system at a time

Optimal planning and redesign the way ground team functions

Too slow or resistant in adopting new technology

Repeated training and support by IT team

Not willing to adopt and gets irritated

Adopt or perish pressure from the authorities

Password sharing

Team morale and discipline building with new CIS

Makes system limitation or failure scapegoat for all shortfalls

On-site IT support and alternative pathway for execution of essential tasks

Misuse of internet access

Optimal credentialing and firewalls

Blames system but never helps in optimizing CIS

Team ownership of CIS (software adapted to your needs)

(CIS: clinical information system; ICU: intensive care unit; IT: information technology)

of Health and Family Welfare (MoHFW) has drafted and proposed DISHA Act (Digital Information Security in Healthcare Act) to govern data security in the healthcare sector. Through the DISHA Act,8 the government intends to setup the National Digital Health Authority to promote and adopt eHealth Standards, enforcing data privacy and security for EHRs and storage and exchange of EHRs. Recent development around data security, safety, and usage of data on various social media platforms posed major challenge and threat to national security and paved way for The Personal Data Protection Bill, 2019, 9 which after enacting into an act will have impact on digital health records too. Globally and nationally, data security and privacy is a major concern and evolving very rapidly and in the Indian context, a regulatory framework at multiple levels is a near-future possibility. This is going to impact

the way health care is practiced and delivered by hospitals. This emphasizes the need for formal training of medical students on EHRs, data privacy, security, and usage and exchange of health data of patients.

CONCLUSION Clinical information system in critical care is need of the hour and must be adopted carefully. Utmost care needs to be exercised while selecting and adopting a CIS. Storage and retrieval of data from the database to facilitate its use for research, machine learning, or application of artificial intelligence is often a neglected aspect. With introduction of ABDM, we anticipate uniform integration of healthcare data across systems (private and government) and across the nation that can pave way for new era in healthcare management.

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REFERENCES 1. Ministry of Health and Family Welfare, Government of India. (2017). National Health Policy, 2017. [online] Available from: https://www.nhp.gov.in/nhpfiles/national_health_ policy_2017.pdf [Last accessed March, 2022]. 2. Buchman TG. Novel representation of physiologic states during critical illness and recovery. Crit Care. 2010;14(2):127. 3. De Georgia MA, Kaffashi F, Jacono FJ, Loparo KA. Information technology in critical care: Review of monitoring and data acquisition systems for patient care and research. Scientific World J. 2015;2015:727694. 4. Dash S, Shakyawar S, Sharma M, Kaushik S. Big data in healthcare: management, analysis and future prospects. J Big Data. 2019;6(1):54. 5. Morrison C, Jones M, Blackwell A, Vuylsteke A. Electronic patient record use during ward rounds: a qualitative study of interaction between medical staff. Crit Care. 2008;12(6):R148.

6. Lapinsky SE. Clinical information systems in the intensive care unit: primum non nocere. Crit Care. 2009; 13(1):107. 7. Ministry of Electronics & Information Technology, Government of India. (2000). Information Technology Act 2000. [online] Available from: https://www.meity.gov.in/ content/informa­tion-technology-act-2000 [Last accessed March, 2022]. 8. Ministry of Health and Family Welfare, Government of India. (2017). Digital Information Security in Healthcare, Act [Draft for Public Consultation], 2017. [online] Available from: https:// www.nhp.gov.in/NHPfiles/R_4179_1521627488625_0.pdf [Last accessed March, 2022]. 9. PRS Legislative Research. (2019). The Personal Data Protection Bill, 2019. [online] Available from: https://prsindia. org/billtrack/the-personal-data-protection-bill-2019 [Last accessed March, 2022].

110

Challenges and Issues in Intensive Care Nursing in India: How to Overcome Them?

C H A P T E R Susruta Bandyopadhyay, Manoj Kumar Rai, Manish Bharti

WHAT IS CRITICAL CARE NURSING?

Training of the Critical Care Nurses

Critical care nursing has been identified as a specialized job for >50 years. It was not difficult to understand that the intensive care units with their load of sick patients and their array of gadgets would require a special group of nurses. Presently the training standards for such nurses and their pattern of employment varies from country to country. Indian Society of Critical Care Medicine (ISCCM) in its Experts Committee Statement on intensive care unit (ICU) planning and designing states that the ICUs need one is to one nursing for the very critical patients (like those who are on mechanical ventilation) and at least two nurses for three patients for the less critical ones.1 However, it does not state the training standards for these nurses. The Society on its part runs a training and diploma course for the critical care nurses.

The training standards of such nurses also vary from country to country. While in USA, the nurses need to have a 2 years training before appearing for the exit examination, in Canada, they need just an orientation session lasting a few days. The Australian College of Critical Care Nursing issued a position statement in 2006, which have been subsequently updated several times. This statement discusses the commitments of a critical care nurse, it also emphasizes the need for a clinical learning environment. It divides the level of training in the entry level, the postgraduate level, and the specialist level. This model has been later adapted by a few other countries.3

MANNING IN CRITICAL CARE NURSING Even across the first world countries, there are wide vari­ abilities in the patient-to-nurse ratio, training standards, and training methods for the critical care nurses. For example, in the USA, 37% of the nurses are attached to the ICUs which would mean a total number of around 200,000, however when one looks into the number of nurses who are members of the American Association of Critical Care Nursing (AACCN), the actual number may be around 2% of the total nursing strength. In Canada, the number of critical care nurses is 18,000, in UK, it is about 3,000, in Europe around 20,000, and in Australia around 10,000. The patient–nurse ratio also varies. Although the standard recommendation is, one to one nursing for very critical patients, often the ratio slips to one registered nurse (RN) for two such patients, in USA, UK, and other countries. Sometimes the number of nurses are made up with enrolled nurses (ENs) who work under the supervision of the RNs, the latter being trained to a level of university graduation.2

Attrition of the Nursing Force A major ailment of nursing and more so of critical care nursing is high rates of attrition. It has been seen the turn­ over is the highest among critical care nurses, in an average around 26%. The “Intention to Leave” (ITL) is seen as a spectrum, from the ITL the department/unit to ITL the hospital to ITL the nursing career. This phenomenon is particularly harmful for the critical care units as it takes time and effort to train critical care nurses. The major issues influencing the ITL are job satisfaction, workplace comfort and safety, remuneration, career opportunities, family workplace balance, etc. The job satisfaction is not welldefined and include many aspects such as work environ­ ment, power to take decisions, and learning opportunities.4

Nursing in India The British realized the importance of building a nursing workforce in India. However, there was initially many reservations against taking up nursing as a career among the Indians. The social stigma, religion, and caste issues delayed the progress of this effort. After independence, the Indian Nursing Council was founded in 1950. Initially, they proposed a three and a half-year long General Nursing and Midwifery (GNM) diploma and a 2-year long Auxiliary

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Section 19:  Present and Future Challenges in ICU Organization and Management Nursing and Midwifery (ANM) diploma. Later a BSc, an MSc degree, an MPhil, and a PhD were added to the list of Nursing Qualifications. Recently, the Government of India has also initiated a course for nurse practitioners. However, even today the nurse-to-population ratio remains inadequate, 1.7 per 1,000 people instead of the stipulated 2.5. There are major differences between the urban and rural nurse population ratios. India is also losing a major number of nurses to more affluent countries as there is a general short­ age of nurses across the globe. Although the condition in India is nowhere near the Philippines where 84% of the nursing force have migrated to other countries. (This has prompted persons from other professions including doctors in Philippines to retrain themselves as nurses and then migrate.) Still India needs another 2.4 million nurses to set its nurse:patient ratio right.5 The various nursing courses in India are given in Table 1.

Critical Care Nursing in India The Indian Nursing Council gives a 1-year diploma course in critical care nursing. The Indian Society of Critical Care also has a diploma course (Indian Diploma in Critical Care Nursing). The Nurse Practitioner in Critical Care Nursing course has been introduced by the Government of India since 2017, 24 nursing colleges are offering this course and the first batch has passed out in 2020. Critical Care Nursing Society in India is vital to nurses. It was registered on 21 November 2011. It publishes the bimonthly Journal of Critical Care Nursing. It offers the Certificate Program in Critical Care Nursing (3 years), Fellowship in Critical Care Nursing (1 year), and Diploma in Critical Care Nursing (6 months). Both the Critical Care Nursing Society and ISCCM publish their own journals and the ISCCM’s journal is indexed. Although there has been all these progress in the educational aspects of the critical care nursing, the induction of such trained nurses into the system has not been done systematically. There are still no standards of critical care nursing nor are the domains of a nurse holding a degree of critical care nursing well demarcated.6 The national accreditations board for the hospitals (NABH) has stipulated the nurse–patient ratios in different areas of critical care (Table 2). TABLE 1: The various nursing courses in India. S. No.

Course

Number of institutions

Number of seats

1

ANM

1,927

55,254

2

GNM

3,040

122,017

3

BSc

1,752

88,211

4

MSc

611

11,853

(ANM: Auxiliary Nursing and Midwifery; BSc: Bachelor of Science; GNM: General Nursing and Midwifery; MSc: Master of Science)

Problems Ailing the Nursing Sector and Critical Care Nursing Although there are some 300,000 seats for nursing in various institutes, the gap between the demand and supply of the nursing personnel remains high. The majority of the institutes provide the GNM, ANM, and the BSc courses. There is less demand for the higher courses and specializations as the career opening for these qualified nurses is still inadequate. There is also some general loss of interest in nursing as a career. This can be attributed to several factors, long and arduous working hours, relatively less remuneration, short and straight career path (the more ambitious often have a singular goal of getting a foreign placement), workplace violence, and insecurity. Those who do take up critical care nursing as a career face some other problems too. As already mentioned the domain of a critical nurse and a critical care nurse practitioner still remains ill demarcated. Ongoing training facilities such as CME (continuing medical education) are lacking. There are very few research opportunities for the nurses. Last but not the least, the attrition rate is the highest among the nurses working in the critical care area.7

The Way Forward There has been an increasing stress on the development of the nursing sector in the recent years. Particularly, the stipulation of the National Accreditation Board for Hospitals (NABH) on nursing numbers and standards have made it mandatory for the hospitals to have adequate trained nurses. The recent reforms by the government like introduction of the courses like nurse practitioners may further open up career opportunities for the interested students. The organizations like the NABH may bring in stipulations which will demarcate the areas and responsibilities for the critical care nurses. Many of the teaching institutions for the nurses are using highly qualified nurses for dual purpose of nursing and teaching. This increases their utilization, responsibility, and remuneration. It also creates excellent learning environments for the students. The standards of education and training for the aspirants for critical care nursing should be more regularized and structured. Perhaps the different organizations who are training critical care nurses should TABLE 2: The nurse–patient ratios in different areas of critical care. S. No.

Department, area

Nurse:patient ratio per shift

1

ICU:Ventilated beds

1:1

2

ICU:Other beds

1:2

3

High dependency units

1:3

4

Emergency room: Ventilated

1:1

5

Emergency room: Others

1:4

Chapter 110:  Challenges and Issues in Intensive Care Nursing in India: How to Overcome Them? join hands in this effort. More efforts should be given in regular training, skill learning programs for the nurses. More researches in nursing issues should be encouraged.7 We are hoping for brighter days.

REFERENCES 1. Rungta N, Zirpe KG, Dixit SB, Mehta Y, Chaudhry D, Govil D, et al. Indian Society of Critical Care Medicine Experts Committee consensus statement on ICU planning and designing, 2020. Indian J Crit Care Med. 2020;24(Suppl 1):43-60. 2. Gill FJ, Leslie GD, Grech C, Latour JM. A review of critical care nursing staffing, education and practice standards. Aust Crit Care. 2012;25(4):224-37.

3. Rn JG, Rn FL, Rn DM, Wilson L, Mned RN, Blakeman R. Position Statement ACCCN Position Statement on Critical Care On behalf of the Australian College of Critical Care Nurses. 2017. 4. Cortese CG. Predictors of critical care nurses’ intention to leave the unit, the hospital, and the nursing profession. Open J Nurs. 2012;2(3):311-26. 5. Gill R. Nursing Shortage in India with special reference to International Migration of Nurses. Soc Med. 2011;6(1): 52-9. 6. Gnanadurai A. Critical care nursing in India. Crit Care Nurs Clin North Am. 2021;33(1):61-73. 7. Verma A, Gomez TFH. Nursing reforms Paradigm shift for a bright future. 2016;(August):1-50.

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Gut Dysfunction in Intensive Care Unit: Recent and Future Advances in Diagnosis and Management

C H A P T E R Avinash Tank, Kalpesh Shah, Rajeev Kumar Bansal

INTRODUCTION

Microbiota 1

Gut dysfunction is common in ICU patients and it is estimated that around 62% of patients develop at least one GIT symptom for at least 1 day.2 This is partly linked to the belief that chronic kidney disease in critically ill patients leads to increased permeability in the intestines3 as well as due to compromised immunity in these patients. These factors lead to high rates of GIT infections, and along with morphological changes in the intestinal mucosa, significantly contribute to gut dysfunction, 4 leading to microbial alterations and deterioration of the patient’s health.3 The prognosis in such patients is generally poor1 and a common endpoint is multiorgan failure.4 Broadly, gut dysfunction can be defined as an impairment of GIT function and digestion. In certain critically ill patients, this may also be a sign of end-organ failure or a sign of a chronic underlying disease. Gut dysfunction includes problems with gut motility, impairment in gut absorption capability, fistulae in the gut lining,1 compromise in mucosal barrier integrity,5 changes in the microbiota, and raised intra-abdominal pressure. These impairments can quickly turn into life-threatening situations.1 Currently, there are no standardized scales to quantify the level of gut dysfunction severity.6

Approximately 40 trillion microbes inhabit the human gut.3 This microbiota is essential for human existence and contributes to the proper GIT function.1

Immunity One prominent fact about the gut is that it has the highest number of lymphocytes compared to all other organs in the human body. These lymphocytes are known to produce antimicrobial peptides which help fight against any invading pathogenic attack.

GUT DYSFUNCTION Gut dysfunction is a chronic condition and can often be an early manifestation of a deteriorating critically ill patient or may present as a sole condition itself (Fig. 1). Gut dysfunction may manifest as gut bleeding, breach in the intestinal tract, gut dysmotility, diarrhea, vomiting, increased intraluminal gut pressure, infection, and feeding intolerance. The main etiology for this is increased permeability of the GIT epithelium in critically ill patients which in turn gives way to the easy modification of gut

ELEMENTS OF THE GUT Epithelium The GIT is lined by a single-cell layer of epithelium with a surface area about of 30 m2 which is equivalent to the area of half a badminton court. The gut epithelium is known to produce cytokines and peptides and acts as the first line of defense from invading pathogens. The epithelium is covered by a layer of mucus which prevents any contact of epithelium with the GI acidic components. The renewing capacity of the gut epithelium is remarkable and most cells take around a weeks’ time to renew completely.

Fig. 1: Normal gut epithelium versus gut epithelium in critical illness.3

Chapter 111:  Gut Dysfunction in Intensive Care Unit: Recent and Future Advances in Diagnosis and Management microbiota. Reduced immunity in critically ill patients is another major contributing factor for gut infections. In fact, the causes of changes of the gut microbial ecosystem are quite complicated. This is especially true for ICU patients who are usually subjected to lots of factors that may predispose the gut environment to changes. These factors involve medications such as antibiotics, protonpump inhibitors and opioids, and enteral/parenteral routes of feeding.3 Additionally, gut dysfunction is often occult and difficult to estimate in severity.5 Gut dysfunction often leads to numerous additional illnesses in the patient,3 first by compromising the nutrition of the patient5 and second intestinal toxins formed due to dysbiosis spread easily to the rest of the body through various portals such as the blood and lymphatic supply.7 ■ In good health (left), intestinal stem cells divide and to the top of the villus. A continuous mucus layer surrounds the epithelium as a barrier against luminal microbes which are even recognized by secretory immunoglobulin A (IgA). Permeability is mediated via the tight junction (inset) that selectively allows solutes and water through but blocks larger molecules. ■ In critical illness (right), proliferation lessens and apoptosis occurs resulting in a shorter villus length. A damaged, nonuniform mucus layer is seen. The damaged tight junction allows for hyperpermeability and reduced gut barrier function allowing bacteria to translocate into the lamina propria. The main issue with gut dysfunction is slow gastric emptying. Conditions such as high glucose levels, opioid drugs, raised intracranial pressure, abnormal electrolyte levels, ischemia, burns, etc., contribute to this. In certain cases, gut dysfunction might even be related to aspiration pneumonia.8 The exact mechanism of the disease is not yet clear, 5 but the biggest challenge is to prevent GIT dysmotility.

hyperpermeability, mucosal changes, and low immunity. Barrier dysfunction can be detected with electron microscopy, but the drawback is that this procedure needs a biopsy.1

Gastrointestinal Tract Dysmotility

According to latest research, an abdominal ultrasound can show significant findings of gastric emptying, gut movement alterations, and changes in intestinal dimensions and may also help detect any perforations with an ultrasound Doppler. Ultrasound may also be used in the placement of the feeding tubes.

Gastrointestinal tract dysmotility is a common condition seen in critically ill patients.8 The current estimates suggest that about 60% of ICU patients end up with GIT dysmotility.9 GIT dysmotility can further be divided into upper GIT dysmotility and lower GIT dysmotility.8 One of the most common reasons for upper GIT dysmotility is the use of opioid in ICU patients5 and its most common manifestation is vomiting; however, other manifestations may also include nausea and intolerance to feeding.8

Diarrhea Recent studies suggest using diarrhea as an indicator of malabsorption. Diarrhea may also suggest feeding intolerance, but the data in this regard are very limited. Diarrhea may also be a symptom of nonocclusive mesenteric ischemia.1

Gut-lymph Hypothesis The gut-lymph hypothesis suggests that the mesenteric lymphatics cause spread of toxins from the GI tract to the lungs. Several studies have supported this theory and one countermeasure to prevent this situation is ligation of mesenteric lymphatic vessels which may otherwise commonly lead to sepsis.3 As a matter of fact, sepsis happens to be the major cause of mortality for acute intestinal failure patients.7

MANAGEMENT Investigations Gastric Residual Volume Gastric residual volume (GRV) is a common measure of gastric emptying. Increased GRV is an indication of feeding intolerance. However, this technique has several limitations as it cannot be used due to aspiration risk, and the measurements are still unclear.10 The scoring system on GI failure grades gut injury based on the severity of symptoms (Table 1).10

Ultrasound

TABLE 1: Gastrointestinal tract failure score.10 Criteria

Score

Normal

0

Gut Barrier Dysfunction

Enteral feed (missed) 1.5] and hepatic encephalopathy (HE) in a patient with an otherwise healthy liver and with illness of aspartate aminotransferase (AST). Hepatitis A virus (HAV) immunoglobulin M (IgM), hepatitis B surface antigen (HBsAg), hepatitis B core antigen (HBc) IgM, anti-hepatitis C virus (HCV), anti-hepatitis E virus (HEV), cytomegalovirus (CMV) IgM, Epstein–Barr virus (EBV) IgM, herpes simplex virus (HSV) IgM, varicella-zoster virus (VZV) IgM, anti-HIV (human immunodeficiency

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Section 19:  Present and Future Challenges in ICU Organization and Management virus) may be positive. A low level of Factor 5 with HE may be predictive of mortality, in viral hepatitis. ■ Acetaminophen: Low bilirubin, very high AST >3,500 IU/L and high INR. Check for elevated serum and urine paracetamol levels, acidosis on arterial blood gas measurement is an important prognostic indicator. z Acute fatty liver of pregnancy/HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome: Aminotransferases 0.8 preoperatively is associated with worse outcomes. Auxiliary LT can be considered in some patients and main advantage remains not requiring lifelong immunosuppressants.21

CONCLUSION Acute liver failure is a potentially reversible severe lifethreatening condition from various etiologies. Timely intensive care support is essential as it rapidly progresses to

multiorgan failure and brain stem herniation due to severe encephalopathy. In recent times with better understanding of the pathophysiology, improvements in intensive care management, and increased availability of transplants, outcomes have improved significantly. No single prognostic model discriminates those who will spontaneously recover and those who will require transplant. Biomarkers such as caspase-cleaved and uncleaved cytokeratin K18 (referred to as CK18) and HLA-DR monocyte expression have shown promising results in detecting spontaneous recovery from ALF but need further studies. LT remains the key and intensive critical care is needed to bridge ALF patients to transplant; however, potential candidates must be evaluated rapidly and serial assessment for surgical fitness is required to ensure good outcomes postsurgery.

REFERENCES 1. Bernal W, Wendon J. Acute liver failure. N Engl J Med. 2013;369(26):2525-34. 2. Donnelly MC, Hayes PC, Simpson KJ. The changing face of liver transplantation for acute liver failure: Assessment of current status and implications for future practice. Liver Transpl. 2016;22(4):527-35. 3. O’Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet. 1993;342(8866):273-5. 4. Davies LC, Jenkins SJ, Allen JE, Taylor PR. Tissue-resident macrophages. Nat Immunol. 2013;14:986-95. 5. Antoniades CG, Quaglia A, Taams LS, Mitry RR, Hussain M, Abeles R, et  al. Source and characterization of hepatic macrophages in acetaminophen induced acute liver failure in humans. Hepatology. 2012;56(2):735-46. 6. Seetharam A. Intensive care management of acute liver failure: Considerations while awaiting liver transplantation. J Clin Transl Hepatol. 2019;7(4):384-91. 7. Aziz R, Price J, Agarwal B. Management of acute liver failure in intensive care. BJA Education. 2021;21(3):110-6. 8. McPhail MJ, Farne H, Senvar N, Wendon JA, Bernal W. Ability of King’s college criteria and model for end-stage liver disease scores to predict mortality of patients with acute liver failure: A meta-analysis. Clin Gastroenterol Hepatol. 2016;14(4):51625.e5.

Chapter 112:  Intensive Care Management of Acute Liver Failure: What is New? 9. Ichai P, Legeai C, Francoz C, Boudjema K, Boillot O, Ducerf C, et al. Patients with acute liver failure listed for superurgent liver transplantation in France: Reevaluation of the clichyvillejuif criteria. Liver Transpl. 2015;21(4):512-23.  10. Price J, Hogan BJ, Agarwal B. Acute liver failure: prognosis and management. In: Feagan BG, Kahrilas PJ, Jalan R, McDonald JWD, (Eds). Evidence-based gastroenterol hepatology, 4th edition. John Wiley &Sons; 2019. pp. 374-83. 11. Romero M, Palmer SL, Kahn JA, Ihde L, Lin LM, Kosco A, et al. Imaging appearance in acute liver failure: correlation with clinical and pathology findings. Dig Dis Sci. 2014;59(8):1987-95. 12. American Association for the Study of Liver Diseases. Acute liver failure update 2011. [online] Available from: http://www. aasld.org/practiceguidelines/Documents/AcuteLiver FailureUpdate2011.pdf. [Last accessed March 2022]. 13. Gonzalez SA. (2017). Acute liver failure. BMJ Best Practice. [online] Available from: https://bestpractice.bmj.com/topics/ en-us/1010. [Last accessed March 2022]. 14. Cardoso FS, Marcelino P, Bagulho L, Karvellas CJ. Acute liver failure: An up-to- date approach. J Crit Care. 2017;39:25-30. 15. Slack AJ, AuzingerG, Willars C, Dew T, Musto R, Corsilli D, et al. Ammonia clearance with haemofiltration in adults with liver disease. Liver Int. 2014;34(1):42-8.

16. Lele AV, Wilson D, Chalise P, Nazzaro J, Krishnamoorthy V, Vavilala MS. Differences in blood pressure by measurement technique in neurocritically ill patients: A technological assessment. J Clin Neurosci. 2018;47:97-102. 17. Karvellas CJ, Cavazos J, Battenhouse H, Durkalski V, Balko J, Sanders C, et al. Effects of antimicrobial prophylaxis and blood stream infections in patients with acute liver failure: a retrospective cohort study. Clin Gastroenterol Hepatol. 2014;12(11):1942-9. 18. Butterworth RF. The concept of “the inflamed brain” in acute liver failure: mechanisms and new therapeutic opportunities. Metab Brain Dis. 2016;31(6):1283-7. 19. Karvellas CJ, Subramanian RM. Current evidence for extracorporeal liver support systems in acute liver failure and acute-on-chronic liver failure. Crit Care Clin. 2016;32(3):439-51. 20. Larsen FS, Schmidt LE, Bernsmeier C, Rasmussen A, Isoniemi H, Patel VC, et al. High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial. J Hepatol. 2016;64(1):69-78. 21. Rela M, Kaliamoorthy I, Reddy MS. Current status of auxiliary partial orthotopic liver transplantation for acute liver failure. Liver Transplant. 2017;22:1265-74.

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113

Caring for the Dying Patient in Indian Intensive Care Unit: Quality of Care, Ethical, and Legal Challenges

C H A P T E R Abhishek Prajapati, Rachit Patel, Bhalendu Vaishnav

INTRODUCTION End-of-life care (EOLC) in an intensive care unit (ICU) poses a daily challenge for clinicians across the world. A clear understanding of global and local ethical, legal, sociocultural, and spiritual considerations is required for improving standard of care. Medical interventions at the time of death can prolong the lives of people, often without assurance of meaningful existence of quality of life. It is an important obligation of a critical care expert to guide the relatives to take appropriate decision within permissible legal and ethical provisions so as to facilitate comfortable dying process and death. The legal issues relevant at EOLC are advance directives, euthanasia, withholding and withdrawing life-sustaining treatment from adults, and substitute decision-making for adults. The ethical issues include compromised autonomy, loss of personal identity, poor symptom management, and shared decision-making. This chapter discusses the current scenario about major legal and ethical challenges in Indian ICUs and shares authors’ experiences about incorporation of several EOLC practices which stem from integrating the wisdom of Indian traditions with mainstream EOLC for enhancing quality of care.

LEGAL CHALLENGES Euthanasia Euthanasia, defined as the administration of a lethal drug by a physician as an act of mercy at the patient’s request (to cause latter’s death), has no legal acceptance in India. The Law Commission of India in their 196th report clearly separated euthanasia from end-of-life decisions (EOLD).1 Withdrawal or withholding of life-support measures/treatment in a compos mentis patient is fundamentally different from euthanasia, which indicates assisted dying or an act of assistance by a healthcare worker for bringing about death.2 However, in situations when the patient is unable to express his own right, the Law Commission (2006) did not allow the family members any access to the right of withdrawal or withholding of life-support measures. In end-of-life situations,

the patient is hardly capable to decide about EOLD, which makes EOLD nearly impractical in ICU.3 A report of the Law Commission (2012), after the Aruna Shanbaug judgment, endorsed “passive euthanasia” on humanitarian grounds and for protecting doctors who honestly act in the best interests of patients. 4 Passive euthanasia, also known as “negative euthanasia,” involves withholding of medical treatment or withholding lifesupport system for continuance of life rather than active intervention to enhance the dying process. This report endorsed safeguards advocated in the Aruna Shanbaug case, but for proceeding it concurred with the previous report. This landmark ruling has provided some light on issue of lawfulness of “involuntary passive euthanasia.”5 In her case, the Court ruled that withholding or withdrawal of life support was not illegal and should be allowed in certain circumstances. It further recommended a court procedure for all EOLD on incapacitated patients. The protocol to be followed in case of obtaining a legal sanction for passive euthanasia was quite practically impossible to implement in emergency and critical situations. Errors in diagnosis/treatment or prognostication may lead to premature decisions about end of life. Personal– emotional and socioeconomic reasons may drive the family to choose discontinuation of treatment even when it is objectively premature.

Advance Medical Directives or the Living Will6 In Common Cause vs. The Union of India, a landmark judgment declared advance medical directives (AMD) and foregoing of life support (FLS) to be constitutionally valid when applied to incompetent patients.6 It is a landmark judgment in response to a petition to declare right to die with dignity as a fundamental right within the fold of right to live with dignity. In Clause 177, the Supreme Court of India mentioned that there is an obligation on the part of the caregivers (both family and physician) and the State to safeguard the right to die with dignity and to receive palliative care. It accepts that a competent person can reveal

Chapter 113:  Caring for the Dying Patient in Indian Intensive Care Unit: Quality of Care, Ethical, and Legal Challenges his choice to refuse treatment when the decision is required to be made. Not following the same would constitute denial of the fundamental right to Autonomy and Privacy. The Court mentioned the following procedure for making AMD operational in India: ■ It should be a written document which indicates the decision relating to the circumstances in which withdrawing or withholding of medical treatment can be resorted to. ■ It should be signed by the executor in presence of two attesting witnesses and countersigned by the Judicial Magistrate First Class (JMFC). ■ The JMFC shall preserve one copy (hardcopy and digital format), hand over one copy to the registry of the jurisdictional District Court, and apprise immediate family members about the existence of this document. ■ One copy shall also be handed over to the designated officer of the local authority (local Government/ Municipality/Municipal Corporation/Panchayat) and one to the family physician if available. ■ In the event of a terminal illness of the executor, the treating physician will ascertain the authenticity thereof from the JMFC before acting upon it. ■ Once the option of refusal or withdrawal of medical treatment is finalized by the treating physician, a Medical Board constituted by hospital visits the patient in the presence of relative and forms an opinion on refusal/ withdrawal of further treatment. ■ After approval from the Hospital Medical Board, the physician/hospital will inform the Jurisdictional Collector about the decision. ■ The Collector shall then constitute a Regional Medical Board which shall visit the hospital. If it agrees with the decision of the Medical Board of the hospital, the Chief District Medical Officer (CDMO) shall inform the decision of the Board to the JMFC. ■ The JMFC will then visit the patient and authorize the decision of the Board. The Executor can revoke the document before it is implemented at any stage. This overall tedious procedure is practically difficult to implement. The complex pathway of going through two sets of medical boards and the legal procedures would delay the FLS procedure and the relief from avoidable suffering. Author’s comments: The Indian Society of Critical Care Medicine (ISCCM)—The Indian Association of Palliative Care (IAPC) recommend2 that a team of doctors for such decisions include caregivers across disciplines. The process should involve seeking a second opinion or involving a medical board or ethics committee within the hospital in the decision-making only if there is a conflict between family and healthcare professionals. Involving the legal fraternity (jurisdictional collectors and judicial

magistrate of first class or the High Court) should only be required in case the conflicts persist after a second opinion and the intervention of the medical board or ethics committee.

ETHICAL ISSUES AND SOCIAL CHALLENGES The four core components of medical ethics are: (1) Autonomy—patient has the right to accept or reject the treatment; (2) Beneficence—a doctor should act in the best betterment of the patient; (3) Nonmaleficence—first, do not harm; and (4) Justice—it concerns the distribution of health resources equally. Two further components of medical ethics are: (1) Dignity—the patient and healthcare workers treating the patient have the right to dignity and (2) Truthfulness and honesty—the concept of informed consent and being honest.7 Studies have shown marked differences in global practices of EOLC. Phua et al. found that withdrawing and withholding ventilation are considered ethically similar in western countries but not so in Asian countries.8 According to their study, whereas majority of clinicians would not initiate life-prolonging measures, only one fifth would be comfortable in withdrawing the same. Asian ICU physicians tended to be more aggressive in their treatment compared with their western counterparts. The reasons for the same are multifactorial: (1) Difficult/ uncomfortable conversations between the ICU physician and family members, (2) physicians’ perceived legal risks, (3) distrust of families toward ICU teams, (4) lack of awareness about the patient’s healthcare wishes due to lack of culture of making advanced directive wishes, and (5) familial piousness and reverence. Most physicians also are apprehensive that withdrawal of support would either lead to cancellation of their license or prosecution or the act be considered against the law. This notion is reinforced by absence of any legislation on this issue. Furthermore, in nongovernment settings the decisions regarding continuation/discontinuation of treatment are heavily influenced by financial factors. The classic example of it is the widespread use of LAMA (leaving against medical advice) for the discontinuation of therapy on the grounds that the patient requested it. LAMA is an easy way where ethical principles are distorted and on the request of the patient or his family, the physician transfers his responsibility on to patients. Facilitating LAMA is indeed based on financial realities of patients/relatives. It is necessary for the clinician to be a part of shared decisionmaking in this situation. It is an ethical imperative, but its legal provisions remain ambiguous. We must move to the pluralistic model, which is a shared-based decision mode.6 A structured outline of the 11 elements of EOLC which can address various ethical issues is provided in Box 1.

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Section 19:  Present and Future Challenges in ICU Organization and Management BOX 1: End-of-life care pathway—11 elements.2   1. Physician’s objective and subjective assessment of the dying process/medical futility. Consensus among all caregivers   2. Honest, accurate, and early disclosure of the prognosis to the family   3. Discussion and communication of all modalities of end-of-life care (EOLC) with the family   4. Shared decision-making consensus through open and repeated discussions   5. Transparency and accountability through accurate documentation   6. Ensure consistency among caregivers   7. Implementing the process of withholding or withdrawing life support   8. Effective and compassionate palliative care of the patient and appropriate support to the family   9. After death care 10. Bereavement care support 11. Review of the care process

CARE OF A DYING PATIENT: REDEFINING NARRATIVE In moments of grief, human beings turn to wider and deeper existential dimensions of life to seek succor. However, medical professionals are not adequately trained nor tuned to offer nonabandonment response appropriately. Nonabandonment is one of a physician’s central ethical obligations; it reflects a longitudinal commitment both to care about patients and to jointly seek solutions to problems with patients throughout their illnesses.9 In endof-life situations, this response assumes greater significance because the focus shifts from recovery to comfort.10 The VALUE pneumonic helps in shaping a strong and caring nonabandonment response.11 V: Value statements by family members A: Acknowledge family members’ emotions L: Listen to family members U: Understand who the patient is as a person and how decisions are made in the family E: Elicit questions from family members A critical care specialist is placed in a unique position to fulfill this obligation for the suffering humanity, which no one else can. End-of-life care decisions are heavily influenced by the context, culture, and spiritual beliefs of people and clinicians. An Indian sick person is surrounded by a large family at his home till the point when he is ultimately hospitalized. “Union with the divine,” “being at peace,” and “preserving dignity” are the three core principles of spirituality that an Indian looks for at the end of life, no matter the process of death.12 Indian spiritual perspective has always held a view that man is not a mere biophysical entity; he is a soul—a spark of the

Divine immanent in every human being—who is sheathed by body, mind, and emotions and his care and well-being extends beyond physical frame. As clinicians, we are trained with an emphasis on the biophysical model of health and avoid any exploration of death as a process of Life. Almost all religions describe it to be a process and a journey of the soul to the world’s beyond and emphasize creation of a respectful and peaceful environment at the time of death. Incorporation of practices, such as customized prayer session, expanded visitation by family members, offering music, and soft and empathetic communication, can lead to improved achievement of quality parameters. They can help in “redefining” the “death narrative.” These measures provide an inner strength to maintain a sense of control, comfort, connectivity (to the Divine), and identity during this time of crisis. Our firsthand experiences in EOLC based on cognizance of this core conviction are shared here. They are a “personcentric” approach founded on recognizing spiritual needs and in connecting with the bereaved family in sharing grief as any human being should do. ■ Dialogue beyond illness as a part of quality care: Adaptation of the “ABCDs” of dignity-conserving care (attitudes, behaviors, compassion, and dialogue) founded on principles of Indian philosophy offers a promise to improve quality of death.13 We conducted detailed interviews of 15 preterminal patients focusing on their life experiences, wishes for future and family, and expression of gratitude. The very discussion brought about a glow on their face and strength in their voice and their suffering seemed to have lessened. The memoirs of the discussion were a great contentment to their family after death. In end-of-life moments, to look beyond disease and its cure is more than ever necessary; by connecting one to a larger reality of life, it helps psychological adaptation to factuality of death. ■ Spiritual assessment: Spiritual assessment as part of a medical encounter is a practical first step in incorporating consideration of a patient’s spirituality into medical practice at all stages of care, particularly in EOLC. We carried out assessment of spirituality in 30 ICU patients using HOPE questionnaire. The HOPE questions provide a formal tool that may be used in this process. “HOPE” denotes a questionnaire for spiritual assessment as part of a medical encounter. H—sources of hope, strength, comfort, meaning, peace, love, and connection; O—the role of organized religion for the patient; P—personal spirituality and practices; E—effects on medical care and EOLD.14 Our study revealed that critically ill patients have huge dependence on Higher powers along with longing for support from family and healthcare team. The patients value very much the act of praying and reported that they would find better fulfillment in the journey through illness if the treating team shared such acts.

Chapter 113:  Caring for the Dying Patient in Indian Intensive Care Unit: Quality of Care, Ethical, and Legal Challenges

Fig. 1: Code Krishna veneration tray.

Fig. 2: Code Krishna in non-COVID ward.

Code Krishna: Blending Spiritual Wisdom with Modern Care15 We have institutionalized a practice named “Code Krishna” as an attempt to solemnize the event of death and respect cultural convictions of community at the Shree Krishna Hospital, Karamsad, for every death taking place in the hospital since 2016. Process: It comprises of the treating team paying its respects and homage to the departed soul and empathizing with the bereaved family. The visible component of the practice includes members of the treating team assembling at the bedside of the deceased; team and bereaved relatives offering floral tributes to the deceased, and reciting a prayer according to the family’s religious faith followed by a few minutes of meditative silence (Figs. 1 to 3). The invisible component of the practice includes respectful body language for the deceased, sharing bereaved family’s grief, and creating a solemn environment and a silent space amidst the action-packed environment even in a critical care unit. This forms the core of Code Krishna. Uniqueness: By relying on the medical team exclusively (and not on any pastoral services) in this process, we ensured that the first commiserations for a bereaved family are those who have fought as competent professionals to save a patient’s life, and at core being simply human, join head and heart together with the family when the destiny pronounces death. Apart from solace to the family, it also helped the treating team to overcome its own suppressed grief, reflect on meaning of life, and prevent desensitization to death events. Evidence of success: We gathered responses of 57 stakeholders through a semistructured questionnaire. More than 90% healthcare professionals concurred with its relevance and its positive impact. Responses from the bereaved family were: “It was beyond my wildest imagination that the treating team will pray for my mother at the time of death, care of the dying has to be like this alone” was the comment expressed

Fig. 3: Code Krishna in COVID intensive care unit.

by one patient’s relative. “The peace experienced during Code Krishna was so unique!”—reported one nurse. “It took away all my stress and frustration and made me feel like a simple human being!”—noted one critical care expert. The ward boy too would spontaneously join the veneration as an act of sanctifying death. Alumni of our institution reported that they have continued this practice in their work fields— carrying the flame forward. Considering that the prime purpose of hospital is to offer healing comfort, practice such as Code Krishna can go a long way in improving the quality of death through a simple yet profound act of sharing feelings surrounding a painful event of death. We believe and have experienced too that soliciting and fulfilling culture-specific wishes help to create healing moments in the story of each dying person, besides easing emotional trauma and achieving closure.

CONCLUSION Although peaceful and dignified death is a patient’s right and an intensivist’s obligation, legal, ethical, administrative, educational, and attitudinal impediments hamper its fulfillment. Recognition and respect of Indian cultural

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Section 19:  Present and Future Challenges in ICU Organization and Management ethos and standard operating guidelines can offer several initiatives for betterment of EOLC. The practice of humancentric communication, with respect to spiritual needs, and care of death, dying, and beyond through a protocol-based approach (“Code Krishna”) have the ability to redefine the death narratives and impart a stamp of quality care. Healing comes not from the head but from the heart.16

REFERENCES 1. 196th Report on Medical Treatment of Terminally Ill Patients (Protection of Patients and Medical Practitioners). (2006). Available from: https://lawcommissionofindia.nic.in/reports/ rep196.pdf [Last accessed March, 2022]. 2. Myatra SN, Salins N, Iyer S, Macaden SC, Divatia JV, Muckaden M, et al. End-of-life care policy: An integrated care plan for the dying: A Joint Position Statement of the Indian Society of Critical Care Medicine (ISCCM) and the Indian Association of Palliative Care (IAPC). Indian J Crit Care Med. 2014;18(9):615-35. 3. Carlet J, Thijs LG, Antonelli M, Cassell J, Cox P, Hill N, et al. Challenges in end-of-life care in the ICU. Statement of the 5th International Consensus Conference in Critical Care: Brussels, Belgium, April 2003. Intensive Care Med. 2004;30:770-8. 4. Passive Euthanasia-A Relook. 241st Report of Law Commission of India. (2012). [online] Available from: http:// www.lawcommissionofindia.nic.in/reports/ rep241.pdf [Last accessed March, 2022]. 5. Aruna Ramakrishna Shanbaugh vs. The Union Of India and Ors. 2011 4 SCC 454 & 524. Also:AIR 2011 SC 1290. 6. Reportable in the Supreme Court of India Civil Original Jurisdiction. Common Cause s Versus The Union of India and Another. Writ Petition (Civil) No. 215 of 2005. [online] Available from: https://main.sci.gov.in/

supremecourt/2005/9123/9123_2005_Judgement_09Mar-2018.pdf [Last accessed March, 2022]. 7. Sharma H, Jagdish V, Anusha P, Bharti S. End-of-life care: Indian perspective. Indian J Psychiatry. 2013;55(Suppl 2):S293-8. 8. Phua J, Joynt GM, Nishimura M, Deng Y, Myatra SN, Chan YH, et al.; ACME Study Investigators and the Asian Critical Care Clinical Trials Group. Withholding and withdrawal of lifesustaining treatments in intensive care units in Asia. JAMA Intern Med. 2015;175(3):363-71. 9. Quill TE, Cassel CK. Nonabandonment: a central obligation for physicians. Ann Intern Med. 1995;122(5):368-74. 10. Macaden SC, Salins N, Muckaden M, Kulkarni P, Joad A, Nirabhawane V, et al. End of life care policy for the dying: consensus position statement of Indian association of palliative care. Indian J Palliat Care. 2014;20(3):171-81. 11. Cook D, Rocker G. Dying with dignity in the intensive care unit. N Engl J Med. 2014;370(26):2506-14. 12. Inbadas H, Seymour J, Narayanasamy A. Principles of spiritual care in end-of-life care in India: A historical-cultural investigation. BMJ Support Palliat Care. 2014;4 (Suppl 1):A18. 13. Chochinov HM. Dignity and the essence of medicine: the A, B, C, and D of dignity conserving care. BMJ. 2007;335(7612): 184-7. 14. Anandarajah G, Hight E. Spirituality and medical practice: using the HOPE questions as a practical tool for spiritual assessment. Am Fam Physician. 2001;63(1):81-9. 15. Vaishnav B, Nimbalkar S, Desai S, Vaishnav S. Code Krishna: an innovative practice respecting death, dying and beyond. Indian J Med Ethics. 2017;2(4):289-92. 16. Sri Aurobindo Ashram. (2004). The Mother, Collected Works of The Mother, 16, 19. Pondicherry: Sri Aurobindo Ashram Publication Department. [online] Available from: https:// www.sabda.in/catalog/show.php?id=cwm [Last accessed March, 2022].

Pregnancy-associated Severe Sepsis: Present State and Challenges

114 C H A P T E R

Anjan Trikha, Prachee Makashir, Sunil T Pandya

INTRODUCTION

BOX 1: Obstetric risk factors for sepsis.

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) Committee defines sepsis as “a life-threatening organ dysfunction caused by a dysregulated host response to infection”.1 Maternal sepsis can occur during pregnancy, childbirth, postabortion, or postpartum period. Maternal physiological changes result in masking of usual signs and symptoms of sepsis. This makes the management of obstetric patients with sepsis and septic shock is very challenging. Failure to recognize maternal sepsis leads to delay in treatment and therefore high maternal, fetal morbidity and mortality. The majority of parturients are young and healthy, however, the maternal mortality rates continue to be high and sepsis is one of the most important preventable causes for this. Incidence of sepsis in pregnancy varies between the developed and the developing world. In two recent studies from India (both North and South India) this incidence varied between 94/1000 and 165/1000 2 live births. Both the studies are from tertiary care centers implying that the incidence may be much more in rural areas. Complications caused by sepsis in pregnancy are—premature birth, fetal infections, increased fetal mortality, and maternal mortality.

Patient-related Risk Factors for Sepsis

RISK FACTORS AND CAUSES FOR SEPSIS

CURRENT STATUS

The pathogenesis due to infection includes pneumonia and genital tract infections.3 Group A Streptococci and Escherichia coli are the predominant pathogens.4 E. coli (37% of maternal sepsis cases) can lead to chorioamnionitis following prelabor, preterm rupture of membranes, and fetal death.4 Viral infections are becoming increasingly prevalent, especially with the newer strains (H1N1, SARS-Co-V-2, etc., with influenza being common in the later trimesters of pregnancy which causes more severe illness and fetal growth restriction, and preterm birth).5,6 The risk factors for maternal sepsis may be broadly categorized as obstetric-related and patient-related (Box 1).

Maternal sepsis is an important direct and indirect cause of maternal mortality that accounted for 10.7% (uncertainty interval 5.9–18.6) of global maternal deaths.7 The magnitude is highest in Southern Asia where sepsis is responsible for 13.7% of all maternal deaths.7 Sepsis is attributed as a cause for 9.7%, 11.6%, and 7.7% of maternal deaths in Africa, Asia, and Latin America/Caribbean respectively and is increasing steadily in more developed countries.8-11 The US reported an annual increase of 10% in maternal mortality between 1998 and 2008 and the UK Obstetric Surveillance System reported an incidence of severe sepsis of 4.7 out of 10,000 maternities in 2014.8-11

• • • • • • • • • •

Operative interventions Cervical cerclage Prolonged rupture of the membranes Pelvic infection Group A or B streptococcal infection in close contacts or family members Vaginal discharge Multiple pregnancies Retained products of conception Preterm prelabor rupture of membranes (PPROM) Amniocentesis or other invasive procedures

Patient-related risk factors for sepsis are as follows: ■ Primiparity ■ Congestive cardiac failure ■ Chronic renal or liver failure ■ Infection by the human immunodeficiency virus ■ Systemic lupus erythematosus ■ Diabetes mellitus ■ Obesity ■ Poor nutrition ■ Febrile illness or antibiotic use in the 2 weeks prior to presentation.

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Section 19:  Present and Future Challenges in ICU Organization and Management The risk of infectious morbidity is 5–20% higher in a cesarean section (CS) compared to a vaginal delivery with the highest risk for a CS after the onset of labor, lower for an elective CS, and least for an operative or instrumental vaginal delivery.11

CHALLENGES The management strategies of sepsis in nonpregnant patients are standardized. However, managing sepsis in pregnancy is very challenging as mostly all studies in sepsis exclude pregnant women resulting in a lack of a standardized management approach. Challenges faced by clinicians are as follows: ■ The hemodynamic and biochemical changes in pregnancy, increased physiological reserve, immune adaptive state, and late presentation during the course of disease. Importantly, it affects two or multiple lives. ■ The clinical signs and symptoms of several pregnancyassociated conditions mimics sepsis and septic shock, e.g., hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome, acute fatty liver of pregnancy (AFLP), eclampsia, cardiomyopathy, embolic disorders, etc. Further, these disorders can be complicated by concomitant sepsis during the course of the disease. ■ Only a few sepsis scoring systems are available for these patients, as Surviving Sepsis Campaign (SSC) guidelines and protocolized sepsis bundles for management of sepsis are there for the general population. ■ The blood gases and many laboratory values are altered in pregnancy. ■ The gravid uterus may impede ultrasound-guided fluid status assessment and response.

DIAGNOSIS OF MATERNAL SEPSIS The diagnosis of maternal sepsis is not straightforward. Hyperdynamic circulatory state in pregnancy and vasodilatation due to progesterone can lead to a fall in blood pressure and consequent compensatory sinus tachycardia that can mask the cardiovascular symptoms associated with sepsis and are detectable only when shock becomes severe or uncompensated. 12 Maternal quick SOFA (qSOFA) is suggested for assessment of early signs of organ dysfunction as depicted in Table 1.13 TABLE 1: Obstetrically modified qSOFA score. Score Parameter

0

1

Systolic blood pressure (mm Hg)

≥90

1 mg·L−1) were strongly associated with in-hospital death (OR 18.4 95% CI 2.6–128.6, p = 0.003).1 So various studies have taken several cut-off values such as 1, 2.205, 2.4, 4.6, and 10.36 µg mL−1 to indicate severity of illness. We are yet to have a consensus on value of D-dimer which can be correlated with mortality. So therefore unless we have larger studies and guidelines, there will always be dilemma regarding cut-off value suggesting severity.

D-dimer levels. In a study by Tang N et al., a comparison was done between heparin users and nonusers; 28 day-mortality was lower among nonusers in patients with sepsis-induced coagulopathy (SIC) score ≥ 4 or D-dimer > 3.0 μg/mL.15 In this study, heparin was used as a standard prophylactic dose. Yin et al. in their study took 449 severe COVID-19 and 104 severe non-COVID-19 pneumonia patients and found overall no difference in the 28-day mortality between COVID19 heparin users and nonusers; but in a subset of patients where D-dimer was >3.0 µg·mL−1, mortality was significantly lower in COVID-19 heparin users compared to COVID-19 heparin nonusers (32.8% versus 52.4%; p = 0.017), while no mortality difference was detected between non-COVID-19 heparin users and nonusers.16 There are several studies based on protocol-based increase in anticoagulation on the basis of D-dimer levels resulted in mortality benefit. One such study done by Apostolos KT et al. showed a protocol driven anticoagulation led to better results than “off protocol” driven physician’s discretion.17 Overall cumulative mortality (with a minimum of 4 months of follow up for all the patients) for ICU patients with severe COVID-19 was 44% (86/195). It also demonstrated that “off protocol” group patients had significantly lower mortality rates compared to the “on-protocol” group (27.47 vs. 58.6%, p < 0.001) (Box 1). Even many guidelines such as Massachusetts General Hospital Version (9.0 12.12.20) strongly discourage escalating from prophylactic dose of anticoagulation basing on D-dimer values. Most often the risk of bleeding outweighs the benefit in this scenario. Thus there will always be a dilemma to escalate or deescalate anticoagulation basing on the D-dimer values. As per the evidence available thus far one would stick to prophylactic dose of anticoagulation.

Dilemma 4: D-Dimer Guiding Anticoagulation

Dilemma 5: D-dimer in Predicting Occurrence of Deep Vein Thrombosis) and Pulmonary Embolism

Early anticoagulation decreases mortality in severe COVID-19 patients. It has also been corroborated that the benefit of anticoagulation is more with patients with high

D-dimer has been of significant clinical value in predicting deep vein thrombosis (DVT) and pulmonary embolism (PE). Several studies have shown that the D-dimer test is highly

Chapter 135:  Dilemma of D-Dimer in COVID-19 sensitive (>95%) in acute deep venous thrombosis or PE, usually with a cut-off value of 500 μg FEU/L.  In patients with low clinical probability (WELLS Score or Revised Geneva Score), higher value mandates aggressive investigation to rule out thromboembolic disorders. In a meta-analysis involving 31 studies by Stein et al., it was concluded that in patients with suspected venous thromboembolism (VTE), prevalence ranged from 20 to 78% (average 36%). In this study, patients with low clinical probability score had a false-positive D-dimer levels ranging from 40 to 60%. This study further demonstrated that D-dimer was 100% sensitive and had 100% negative predictive values in ruling out VTE in patients of low clinical probability.18 Patients with high clinical probability score should not undergo D-dimer testing because it is rare to get a level 500 μg FEU/L has a poor positive predictive value for VTE. It has a very low specificity in ruling out DVT/PE.A study by Bosson et al. suggested that a D-dimer level above 2000 μg FEU/L can predict the presence of PE, with an odds ratio of 6.9, irrespective of clinical probability.19 There was a positive correlation between the prevalence of PE and the D-dimer levels in a study done by Hochuli M et al. in patients of high clinical probability (7% at D-dimer levels of 500–1,000 μg FEU/L and 90% at 9,000 μg FEU/L).20 So therefore predicting PE in a high clinical probability case like COVID-19 patient is difficult. A decision to start, stop, or escalate treatment for thromboembolic disorder in a severe COVID-19 patient may not be correct. Postmortem studies have proven that severe COVID-19 patients are associated with immune thrombosis leading to microthrombotic complications. Most of the patients of severe COVID-19 infection have raised D-dimer due to this. This increase level of D-dimer may hinder assessment of patients with DVT or PE. One cannot conclusively decide regarding increasing the dose of anticoagulant based on raised D-dimer as it could be secondary to cytokine storm which is not so uncommon during second week of the disease. There will always be dilemma of diagnosing as well as ruling out DVT and PE in COVID-19 patients based on D-dimer values. Till we have more answers, a bed side venous Doppler and CT pulmonary angiogram (CTPA) should always be done to aid diagnosis.

Dilemma 6: D-Dimer in Patients with COVID-19 and Secondary Sepsis with DIC A large subset of patients of severe COVID-19 goes into secondary sepsis. If not treated appropriately, it may lead to severe sepsis with shock and subsequently DIC. These patients with sepsis and DIC will be having very high D-dimer levels. This high D-dimer value secondary to sepsis will confound clinician’s decision as to whether there is new DVT or PE.

Clinical assessment along with markers of infection would help make a differentiation in such dilemmas.

Dilemma 7: D-Dimer in Bleeding Disorder It is not very uncommon to see several occult bleeding complications in patients on anticoagulation. There are small case series and multiple case reports describing gastrointestinal bleeding, retroperitoneal bleeding, chest wall, and muscle bleed. In these situations, D-dimer remains high. So there will always be dilemma in interpreting D-dimer in presence of occult bleeding. One needs to quickly rule out these occult causes before starting anticoagulation.

CONCLUSION The role of D-dimer in guiding treatment in COVID-19 could be misleading. Clinicians should be aware of the details of their local D-dimer test method and cut-offs values which of course are not determined as yet in COVID-19. There are several pitfalls in assessing and interpreting the results of D-dimer in clinical scenario of moderate to severe COVID-19. One should use clinical judgment and take into account other markers to avoid/minimize any dilemma in interpreting D-dimer. The present almost universal practice of linking dose and duration of anticoagulation and severity of disease with D-dimer levels in COVID-19 is risky and could be fraught with danger.

REFERENCES 1. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62. 2. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thrombosis Haemost. 2020:18; 844-7. 3. Hadid T, Kafri Z, Al-Katib A. Coagulation and anticoagulation in COVID-19. Blood Reviews. 2021;47;100761. 4. Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, et al. Extrapulmonary manifestations of COVID19. Nat Med. 2020;26(7):1017-32. 5. Hardy M, Lecompte T, Douxfils J, Lessire S, Dogné JM, Chatelain B, et al. Management of the thrombotic risk associated with COVID-19: guidance for the hemostasis laboratory. Thrombo J. 2020;18:17 6. Tian, S, Hu W, Niu N, Liu H, Xu H, Xiao SY. Pulmonary pathology of early-phase 2019 novel coronavirus (COVID19) pneumonia in two patients with lung cancer. J Thoracic Oncol. 2020;15:700-4. 7. Pugh CW, Ratcliffe PJ. New horizons in hypoxia signaling pathways. Exp Cell Res. 2017;356:116-21. 8. Iba T, Levy JH, Warkentin TE, Thachil J, van der Poll T, Levi M, et al. Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation. J Thromb Haemost. 2019;17:1989-94.

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Section 23:  COVID-19 Related Issues 9. Cervellin  G; Bonfanti  L; Picanza  A; Lippi  G. Relation of D-dimer and troponin I in patients with new-onset atrial fibrillation. Am J Cardiol.  2014;114(7):1129-30.  10. Schutgens, Roger E. D-dimer in COVID-19: A guide with pitfalls. Hema Sphere. 2020;4(4):e422. 11. Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020;368:m1091. 12. Guan WJ, Ni ZY, Hu Y. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708-20. 13. Han H, Yang L, Liu R, Liu F, Wu KL, Li J, et al. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection. Clin Chem Lab Med. 2020;25:1116-20. 14. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497-506. 15. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18:1094-9.

16. Yin S, Huang M, Li D, Tang N. Difference of coagulation features between severe pneumonia induced by SARS-CoV2 and nonSARS-CoV2. J Thromb Thrombolysis. 2020;51(4):1107-10. 17. Tassiopoulos AK, Mofakham S, Rubano JA, Labropoulos N, Bannazadeh M, Drakos P, et al. D-Dimer-Driven Anticoagulation Reduces Mortality in Intubated COVID-19 Patients: A Cohort Study With a Propensity-Matched Analysis. Front Med. 2021;8:631335. 18. Stein PD, Hull RD, Patel KC, Olson RE, Ghali WA, Brant R, et al. D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: A systematic review. Ann Intern Med. 2004;140:589-602. 19. Bosson JL, Barro C, Satger B, Carpentier PH, Polack B, Pernod G, et al. Quantitative high D-dimer value is predictive of pulmonary embolism occurrence independently of clinical score in a well-defined low risk factor population. J Thromb Haemost. 2005;3(1):93-9. 20. Hochuli M, Duewell S, Frauchiger B. Quantitative d-dimer levels and the extent of venous thromboembolism in CT angiography and lower limb ultrasonography. VASA. 2007;36(4):267-74.

136

Steroid in Acute and Post-COVID-19 Pulmonary Syndrome

C H A P T E R Prachee Sathe, Tanima Baronia

INTRODUCTION During the pandemic of severe acute respiratory syndrome coronavirus-2019 (SARS-CoV-19) virus which started in 2019 at Wuhan in China and spread like wild fire all over the world, out of coronavirus disease (COVID) affected 239,113,440 patients world over, 3% were hospitalized, of which 3% were in intensive care unit (ICU), and total 4,874,764 died till date, majority died due to lung failure and/or cytokine storm causing superinflammation. Well known is a fact that the port of entry being upper respiratory tract the maximally affected organ system was respiratory. Pathophysiology of severe COVID-19, gradually revealed that dysregulated host immune response and cytokine storm producing severe inflammation are the key factors leading to widespread damage to pulmonary as well as systemic tissues. COVID-19 pneumonia is associated with both hyperinflammation and immunoparalysis in variable proportion. Pan endothelial vascular inflammation, disseminated coagulation, and acute respiratory distress syndrome (ARDS) are frequently triggered with or without shock. As much as the dysregulated immune response is responsible for acute pulmonary syndromes, it is also responsible for the extensive pulmonary damage and delayed pulmonary dysfunction. Various modalities and drug therapies came in and got discarded during the course of the pandemic, anti-inflammatory and immunomodulatory being of immense interest till date. Steroids remained an intriguing group of drugs because of its well-known antiinflammatory and immune modulatory effects.

STEROIDS: MECHANISM OF ACTION (ANTIINFLAMMATORY AND IMMUNOSUPPRESSIVE EFFECTS) Corticosteroids can help as a life-saving therapy when acute anti-inflammatory and immunosuppressive effects are needed, working at many steps in the inflammatory pathways. The steroid molecule going across the cell membrane binds to glucocorticoid receptor, causing a conformational change

in the receptor. Then this complex moves into the cell nucleus, binds to glucocorticoid response elements affecting the genes that either suppress or stimulate transcription in various pathways resulting in ribonucleic acid and protein synthesis. This affects the synthesis of proinflammatory mediators, from cells including macrophages, eosinophils, lymphocytes, mast cells, dendritic cells, and causes inhibition of phospholipase A2 to attenuate inflammatory response, suppressing mediator release. This response helps to attenuate the hyperimmune response.1 The flip side of the coin is of course the immunodepression allowing side effects like secondary infections. While understanding the behavior of a totally new virus causing devastating lung and systemic involvement, inflammatory processes and dysregulated immune response were revealed to be the pathophysiologic mechanisms, various molecules of synthetic steroids were tried in various doses at various stages of the disease with various amount of success or failure. All the steroid molecules are not the same. We will review the current evidence and guidelines.

Current Knowledge about Steroid Use in Critically Ill Comparison of Various Steroids Available for the Clinical Use Although synthetic steroids as a group, share a marked antiinflammatory action and poor mineralocorticoid effects they have different bioequivalence and pharmacokinetics (Table 1). Multiple studies also have shown varied “stressed” situations to have relative deficiency of these stress hormones. Available evidence shows that hydrocortisone is indicated in septic shock at a daily dose of 200–400 mg, divided every 8 hours due to its short half-life to avoid critical illness-related corticosteroid insufficiency (CIRCI); here not for anti-inflammatory action.2 Methylprednisolone with its prolonged half-life once a day dose, can be indicated in severe ARDS at a dose of 0.5–2 mg/kg/day, due to its

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Section 23:  COVID-19 Related Issues TABLE 1: Corticosteroid comparison chart. Potency relative to hydrocortisone

Half-life

Equivalent glucocorticoid dose (mg)

Anti-inflammatory

Mineral-corticoid

Plasma (minutes)

Duration of action (hours)

Hydrocortisone

20

1

1

90

8–12

Cortisone acetate

25

0.8

0.8

30

8–12

Prednisone

5

4

0.8

60

12–36

Prednisolone

5

4

0.8

200

12–36

Triamcinolone

4

5

0

300

12–36

Methylprednisolone

4

5

0.5

180

12–36

Dexamethasone

0.75

30

0

200

36–54

Betamethasone

0.6

30

0

300

36–54

Fludrocortisone

0

15

150

240

24–36

Aldosterone

0

0

400+

20

_

Short acting

Intermediate acting

Long acting

Mineralocorticoid

Note: Commonly prescribed replacement steroids equivalents Prednisone (5 mg) = Cortisone (25 mg) = Dexamethasone (0.75 mg) = Hydrocortisone (20 mg) Source: Adrenal Cortical Steroids in drug facts and comparison, 5th edition. St. Louis: Facts and Comparisons, Inc.; 1997. pp. 122-8.

good penetration into lung tissue. Dexamethasone is the most powerful synthetic steroid, with marked antiedema properties, a large randomized controlled trial (RCT) suggested its efficacy in moderate to severe ARDS patients.2,3 It is extremely important to note that these “life-saving” drugs can have short-term or long-term side effects/ complications, hence they have to be used very wisely, with continuous monitoring. Steroid-induced suppression of hypothalamic–pituitary–adrenal (HPA) axis and adrenal insufficiency can cause a significant reduction in the natural killer cell function. Natural killer cells are needed for the recognition and elimination of virally infected cells. This can act as a boomerang. Based on the current body of evidence, steroids were tried with a great hope at various stages of COVID and its severity. While many teams were confused, RECOVERY trial did come up with a definitive observation. In RECOVERY collaborative group trial,4 which was a controlled, open-label trial in hospitalized COVID-19 patients, comparing a range of possible treatments, patients were randomly assigned to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome studied was 28-day mortality. Comparative mortality was (22.9%) out of 482 patients in the dexamethasone group and (25.7%) out of 1,110 patients in the usual care group which the group reports as a significant reduction (p < 0.001) in subgroup of patients who were on oxygen support or needing ventilator. It did not show any

advantage in hospitalized patient not needing O2 support. There was a better chance of weaning the patients off ventilator in dexamethasone group. If we read carefully, it would be noticed that still there was variability such that, in the dexamethasone group, 95% of the patients received at least one dose of a glucocorticoid. The median duration of treatment was 7 days (interquartile range, 3–10). In the usual care group, 8% of the patients received a glucocorticoid as part of their clinical care.4 Another interesting observation in the results of RECOVERY trial is that, in this trial of dexamethasone in hospitalized COVID acute lung injury (ALI) patients, the incidence of continuous renal replacement therapy (CRRT) was also less in the dexamethasone receiving group.4 Serious adverse events as steroid side effects also were noticed and described in RECOVERY trial.

Meta-analysis of Steroid Trials in COVID Pulmonary Syndromes The largest meta-analysis5 included forty-four studies, covering 20,197 patients. Obviously encountered was the heterogenicity of the studies. In twenty-two studies which included observational/RCT studies, with endpoint as mortality, tried to quantify the effect of corticosteroid. The overall pooled estimate (observational studies and RCTs) showed a significantly reduced mortality in the corticosteroid group (OR 0.72 (95% CI 0.57–0.87).

Chapter 136:  Steroid in Acute and Post-COVID-19 Pulmonary Syndrome Point of concern was delayed viral clearance time, which ranged from 10 to 29 days in the corticosteroid group and from 8 to 24 days in the standard of care group. Fourteen studies looked at the need for mechanical ventilation and its duration as an endpoint. These studies reported a positive effect of corticosteroids on both. A trend toward more infections and antibiotic use was present, more so if used with other immunomodulators like tocilizumab. The authors concluded based on the findings from both observational studies and RCTs, a beneficial effect of corticosteroids on short-term mortality and a reduction in need for mechanical ventilation, but with a rising trend of delayed viral clearance and an increase in secondary infections.

Alternative Routes: Inhaled Corticosteroids Budesonide was considered as a molecule of interest because it was observed that patients with airway diseases who were already on inhaled steroids were doing better than those who were not on it. Budesonide is a synthetic, inhaled potent glucocorticosteroid with broad anti-inflammatory properties. It is regularly used in chronic bronchitis and asthma by such route. Certain inhaled corticosteroids have been shown to impair viral replication of SARS-CoV2 and reduce cell entry, creating the interest in potential of inhaled corticosteroids as therapeutic agents for COVID-19. However, observational studies of individuals who were chronic inhaled corticosteroid users have found that its use either had no effect on COVID-19 outcomes or increased risk of hospitalization.6 Hence, there is insufficient evidence for or against the use of inhaled budesonide for the treatment of COVID-19.

Special Subgroups Needing Mention: Considerations in Pregnancy It is well-known fact that a short course of betamethasone and dexamethasone which cross the placenta, is routinely used to decrease neonatal complications of prematurity in women with threatened preterm delivery. As steroids can help potentially to reduce mortality in a COVID positive pregnant women, with low-risk of fetal adverse effects for a short course of dexamethasone therapy, it is recommended to use dexamethasone in hospitalized pregnant patients with COVID-19 who are mechanically ventilated or who require supplemental oxygen.

Complications While known complications include acute psychosis, glucose intolerance, gastrointestinal (GI) hemorrhage, and secondary infections, the delayed ones can be more dangerous such as avascular necrosis, diabetes mellitus, HPA axis suppression, etc.

In addition to known side effects and complications of systemic corticosteroids, there was a humongous rise in rhinocerebellar mucormycosis, 80% cases coming from India. In a study reporting 101 cases of mucormycosis in people with COVID-19, 82 cases were from India and 19 from the rest of the world. Mucormycosis was predominantly seen in males (78.9%), in patients having active COVID disease or post-COVID. Risk factors identified were pre-existing diabetes mellitus in 80% of cases and associated diabetic ketoacidosis (DKA) in 14.9%. Notably, corticosteroid intake for the treatment of COVID-19 was recorded in 76.3% of cases. Mucormycosis involving nose and sinuses (88.9%) was most common followed by rhino-orbital (56.7%) with mortality of 30.7% of the cases.7 A cumulative prednisone dose of >600 mg or a total methylprednisone dose of 2–7 g given during the month before predisposes immunocompromised people to mucormycosis. Nonetheless, there are a few case reports of mucormycosis resulting from even a short course (5–14 days) of steroid therapy, especially in diabetics.7 COVID-19 disease and rampant use of corticosteroids in unregulated dose/duration raises a red flag for treating physicians.

Current World Health Organization and Centers for Disease Control and Prevention Guidelines and Recommendations (Reference quoted verbatim guidelines for the benefit of readers) Recommendation 1: We recommend systemic corticosteroids rather than no systemic corticosteroids for the treatment of patients with severe and critical COVID-19 (strong recommendation, based on moderate certainty evidence).8 Recommendation 2: We suggest not to use corticosteroids in the treatment of patients with nonsevere COVID-19 (conditional recommendation, based on low certainty evidence) (Table 2).8

POST-COVID-19 SYNDROME Post-COVID-19 syndrome is a condition seen in patients with history of SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that cannot be explained by an alternative diagnosis, lasting for at least 2 months. Symptoms commonly seen are easy fatiguability, cough, shortness of breath, chest pain, intermittent fever, cognitive dysfunction, anxiety disorders, depression, memory issues, neuralgias, muscle pain or spasms, postexertion malaise, and sleep disorders among others. Most of these symptoms have a significant impact on day-to-day functioning, but the most incapacitating are the respiratory symptoms, so much so that the term “pulmonary long COVID (LC)” was coined.9

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Section 23:  COVID-19 Related Issues TABLE 2: Management of COVID-19 patients based on disease severity. Disease severity

Treatment options

Patient hospitalized No role of steroids (AIII) but no supplemental oxygen needed Requiring supplemental oxygen

• Remdesivir if minimal supplemental oxygen needed (BIIa) • Dexamethasone + remdesivir where supplemental oxygen requirement steadily increases (BIII) • Dexamethasone alone if remdesivir not available or contraindicated

Requiring HFNC or NIV

• Dexamethasone (AI) • Dexamethasone + remdesivir (BIII) • If rapidly increasing oxygen requirement and systemic inflammation • Consider baricitinib (BIIa) or IV tocilizumab (BIIa)

Requiring IMV or ECMO

• Dexamethasone (AI) • If within 24 hours of admission to ICU • Dexamethasone + IV tocilizumab (BIIa)

Fig. 1: CT scan of chest showing post-COVID fibrosis. (COVID: coronavirus disease; CT: computed tomography)

Rating of recommendation: A = strong, B = moderate, and C = optional Rating of evidence: I = 1 or more randomized controlled trials (RCTs), IIa = Other RCTs or subgroup analyses of randomized trials, IIb = nonrandomized trials or observational cohort studies, and III = expert opinion. (COVID-19: coronavirus disease-2019; ECMO: extracorporeal membrane oxygenation; HFNC: high flow nasal cannula; IMV: intermittent mandatory ventilation; NIV: noninvasive ventilation) Source: https://www.covid19treatmentguidelines.nih.gov/management/ clinical-management/hospitalized-adults--therapeutic-management/

Need and Timing for Pulmonary Follow-up It is being strongly recommended that all symptomatic COVID-19 affected individuals including those with mild disease must undergo a pulmonary follow-up within 3 months after the infection. Follow up may include plethysmography, exercise testing with 6-minute walk test or its equivalent, blood gas analysis, pulmonary function tests (PFTs), diffusion capacity measurements (TLCO), and chest computed tomography (CT) scans depending upon the severity of persisting symptoms.9 High-resolution CT (HRCT) findings may range from interstitial opacities, consolidations, pneumatoceles, persistent groundglass opacities to traction bronchiectasis, and fibrotic changes (Figs. 1 to 3). Reduced diffusion capacity may be the result of alveolar surface loss, interstitial fibrosis or vascular impairment. Though the 6-minute walk test is not validated in post-COVID 19-associated pulmonary impairment, it may help the diagnosis of exerciserelated hypoxia and decreased exercise capacity.9 These pulmonary follow ups have brought to light with increasing frequency the occurrence of lung fibrosis in those who suffered from moderate-to-severe COVID-19. 10,11 It has

Fig. 2: CT scan of chest showing organizing pneumonia in postCOVID patient. (COVID: coronavirus disease; CT: computed tomography)

Fig. 3: CT scan of chest showing post-COVID pneumatocele. (COVID: coronavirus disease; CT: computed tomography)

Chapter 136:  Steroid in Acute and Post-COVID-19 Pulmonary Syndrome been described in literature by various terms such as organizing pneumonia, pulmonary fibrosis, fibrotic lung disease, or interstitial lung disease (ILD). The sustained inflammation with release of inflammatory mediators causes progressive destruction of lung parenchyma and persistence of fibroblasts, leading to deposition of collagen and extracellular matrix components, ultimately resulting in fibrous remodeling.12 The role of reactive oxygen species, barotrauma, and microthrombi has also been suggested.10

Use of Steroids and Antifibrotics: What is the Current Evidence? Many pharmaceutical measures have been tried in the prevention and/or treatment of this condition, including steroids and antifibrotic agents such as, nintedanib, pirfenidone, treamid to name a few, with varying results and no conclusive evidence of benefit. 13 The role of dexamethasone in acute COVID-19 for up to 10 days is now considered based on the RECOVERY trial. 14 But its use beyond this short time frame for prevention of fibrosis remains a matter of uncertainty. Steroids are considered first-line treatment in conditions like organizing pneumonia, which is part of the spectrum of post-COVID lung sequelae. There is paucity of long-term studies and evidence in the treatment of this disabling and increasingly common condition. There is some evidence that steroids can slow down the progression of pulmonary fibrosis in rat idiopathic pulmonary fibrosis (IPF) models, and its mechanism may be related to the reduction of tumor necrosis factor-alpha (TNF-α), transforming growth factor beta-1 (TGF-β1) and PDGF levels, and the elevation of caveolin-1 levels.13 Inhaled corticosteroids may improve COVID-19related bronchial syndromes as is seen with other viral exacerbations in asthma or COPD.14 In post-COVID-19 patients with persistent cough, inhaled corticosteroids may suppress mucosal inflammation in airways with a clinically relevant reduction in bronchial hyperreactivity, though its role in other causes of cough remains controversial. 14 There have been reports of reduced lung remodeling in these patients with the use of methylprednisolone. Some have reported improved functional states after 1 month of treatment with steroids.15 Oral prednisone 0.5 mg/kg with a dose reduction scheme over 6 weeks was shown to be associated with significant symptomatic, spirometric, and radiological improvement in patients with post-COVID-19 persistent inflammatory ILD seen 6 weeks after discharge.16 An ongoing trial with comparison of two corticosteroid regimen for post-COVID-19 diffuse lung disease (COLDSTER), compares an oral prednisolone regimen with 40 mg/day given for 1 week, 30 mg/day for 1 week, 20 mg/ day for 2 weeks, and 10 mg/day for 2 weeks (medium dose)

with 10 mg/day for 6 weeks (low dose). The investigators hypothesize that in post-COVID diffuse lung disease, the medium dose of glucocorticoid will be more effective than the low dose in causing a radiological resolution, however the actual results are awaited on completion of the study in December 2021.17 Despite numerous case reports and emerging studies optimal dose and duration of systemic steroids is as yet, uncertain. A variety of regimens have been tried with varying degrees of benefit. There is also the concern that the steroids may worsen the hypercoagulability 18 seen in these patients. Additionally, they may contribute further to increased incidence of intercurrent infections and psychological problems, fatigue,19 etc. that is seen in long COVID. There is concern that these drugs may in fact increase the mortality.

Uncertain Points Needing Future Research Long-term effect of systemic corticosteroids on mortality, development of long-term diabetes mellitus, and functional outcomes in COVID-19 survivors are still unknown. As novel immune modulator therapies may emerge, their interaction will have to be studied with systemic corticosteroids. Comparison will have to be ongoing for new investigational therapies for severe and critical COVID-19 in combination with systemic corticosteroids or systemic corticosteroids alone. Incidence of mucormycosis, especially after the second wave of COVID-19 in India, has highlighted the impact of systemic corticosteroids on immunity with the risk of a subsequent infection and the risk of death after 28 days. Hence, further trials need to be planned to study steroid preparation, dosing, and optimal timing of drug initiation. Different study populations that were under-represented in the trials (e.g., children, immunocompromised patients, and patients with tuberculosis) need to be studied. Effect of steroids on viral replication needs to be studied as well. Vaccination on one side and the COVID-19 variants of concern on the other side will keep making the changes in clinical scenarios in coming times.

CONCLUSION Corticosteroids are double-edged sword because “appropriate” immunity is needed to recover from a disease. The use of such potent immune modulators with potential life-threatening side effects has to be made judiciously, keeping in mind drug/dose/duration/de-escalation and taking into account newly emerging evidence. In the face of a tidal wave of patients with crippling pulmonary compromise, despite the various concerns and awaiting further robust evidence from randomized trials, steroids, systemic or inhaled, along with pulmonary rehabilitation, remain a viable and economical treatment option for postCOVID fibrosis.

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REFERENCES 1. Shang L, Zhao J, HU Y, Du R, Cao B, et al. On the use of corticosteroids for 2019-nCoV pneumonia. Lancet. 2020;395(10225):683-4. 2. Berton AM, Prencipe N, Giordano R, Ghigo E, Grottoli S. Systemic steroids in patients with COVID19: pros and contras, an endocrinological point of view. J Endocrinol Invest. 2020;44(4):873-5. 3. Villar J, Ferrando C, Martinez D, Ambrós A, Muñoz T, Soler JA, et al. Dexamethsone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020;8(3):267-76. 4. The RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with COVID19-preliminary report. N Engl J Med. 2021;384:693-704. 5. van Paassen J, Vos JS, Hoekstra EM, Neumann KMI, Boot PC, Arbous SM. Corticosteroid use in COVID-19 patients: a systematic review and meta-analysis on clinical outcomes. Crit Care. 2020;24(1):696. 6. Yu LM, Bafadhel M, Dorward J, Hayward G, Saville BR, Gbinigie O, et al. Inhaled Budesonide for COVID19 in people at high risk of complicaions in the community in UK (PRINCIPLE): a randomised , controlled, open-label, adaptive platform trial. Lancet. 2021;398(10303):843-55. 7. Singh AK, Singh R, Joshi SR, Misra A. Mucormycosis in COVID-19: A systematic review of cases reported worldwide and in India. Diabetes Metab Syndr. 2021;15(4):102146. 8. WHO. (2020). Corticosteroids for COVID-19. [online] Available from WHO/2019-nCoV/Corticosteroids/2020 [Last accessed March, 2022]. 9. Funke-Chambour M, Bridevaux PO, Clarenbach CF, Soccal PM, Nicod LP, von Garnier C. Swiss Recommendations for the follow-up and Treatment of Pulmonary Long COVID. Respiration. 2021;100(8):826-41.

10. Scelfo C, Fontana M, Casalini E, Menzella F, Piro R, Zerbini A, et al. A Dangerous consequence of the recent pandemic: early lung fibrosis following COVID-19 pneumonia. Ther Clin Risk Manag. 2020;16:1039-46. 11. Tale S, Ghosh S, Meitei SP, Kolli M, Garbhapu AK, Pudi S. Post-COVID-19 pneumonia pulmonary fibrosis. QJM. 2020;113(11):837-8. 12. Sime PJ, O’Reilly KM. Fibrosis of the lung and other tissues: new concepts in pathogenesis and treatment. Clin Immunol. 2001;99(3):308-19. 13. Bazdyrev E, Rusina P, Panova M, Novikov F, Grishagin I, Nebolsin V. Lung Fibrosis after COVID-19: Treatment Prospects. Pharmaceuticals. 2021;14(8):807. 14. Lipworth B, Chan R, Kuo CR. Use of inhaled corticosteroids in asthma and coronavirus disease 2019: Keep calm and carry on. Ann Allergy Asthma Immunol. 2020;125(5):503-4. 15. Cano EJ, Fonseca Fuentes X, Corsini Campioli C, O’Horo JC, Abu Saleh O, Odeyemi Y, et al. Impact of corticosteroids in COVID-19 outcomes: systematic review and meta-analysis. Chest 2021;159(3):1019-40. 16. Myall KJ, Mukherjee B, Castanheira AM, Lam JL, Benedetti G, Mak SM, et al. Persistent post COVID19 Interstitial lung disease.An observational study of corticosteroid treatment. Ann Am Thorac Soc. 2021;18(5):799-806. 17. NIH. Comparision of Two Corticosteroid Regimens for Post COVID-19 Diffuse Lung Disease (COLDSTER). [online] Available from ClinicalTrials.gov Identifier: NCT04657484 [Last accessed March, 2022]. 18. Brotman DJ, Girod JP, Posch A, Jani JT, Patel JV, Gupta M, et al. Effects of short-term glucocorticoids on hemostatic factors in healthy volunteers. Thromb Res. 2006;118(2):247-52. 19. Warrington TP, Bostwick JM. Psychiatric adverse effects of corticosteroids. Mayo Clin Proc. 2006;81(10):1361-7.

137

Fluid Management in COVID-19: Principles and Practice

C H A P T E R Roop Kishen, Saurabh Taneja Primum non nocere (First, do no harm)

INTRODUCTION Fluids are drugs and like drugs, they have their beneficial and adverse effects. Fluid administration is fundamental to the clinical care of the hospitalized patients, especially critically ill, making fluids the most common drugs prescribed in these patients. Although about 80% of patients infected with severe acute respiratory syndrome coronavirus 2019 disease (SARS COVID-19, henceforth referred to as COVID19) are asymptomatic or exhibit only mild symptoms, about 20% require hospitalization, some becoming seriously ill.1 Most centers report that about 25% of hospitalized patient require intensive care unit (ICU) admission.1 Besides lungs, COVID-19 infections involve many other systems such as cardiovascular, renal, and coagulation systems. Although the pandemic has been present for just 2 years, much has been learned about the pathophysiology of the disease; however, much more still needs to be learned. Accepted basic principles of ICU care are advocated for clinical management of critically ill patients with COVID-19 infection. Specifically, there is lack of substantial data on optimal fluid management in these patients, making this aspect of their care difficult. However, principles of resuscitation and fluid therapy in non-COVID-19 infected have been applied to these patients; but some differences exist, partly because of the pandemic proportion of the infection as well as some therapeutic maneuvers that might be required (e.g., lung recruitment maneuvers and prone position ventilation). This chapter addresses the principles of fluid management in the critically ill adult COVID-19 patients but not in the pediatric patients.

WHY ARE FLUIDS NEEDED? Water is the essence of life and about 60% of our bodies (80% in infants and 60% in adults) is composed of water. Water is present in all cells of the body and is the medium in which all the reactions of the living cells, essential for life, take place. In health, we fulfil the need for water and electrolytes by voluntary intake of fluids and food. An average adult, under nonextreme weather conditions, ingests ≈2,200 mL of fluids a

day (as water, beverages, and food), whereas a small amount, ≈300 mL, is generated by aerobic metabolism, a total normal intake of 2,500 mL/day.2 An equal amount of fluid is lost from the body in a day (≈1,500 mL as urine; ≈900 mL in exhaled air and sweat, and ≈100 mL in feces).2 Body homeostasis is maintained by precise regulation mechanisms which keep the quantity of fluids and electrolytes constant. In disease, intake of fluids may be compromised due to the very nature of illness (e.g., loss of appetite and altered level of consciousness). There may also be excessive losses due to vomiting, diarrhea, and excessive sweating in febrile illness. Fluids are needed for cardiovascular resuscitation in trauma, sepsis, and septic (distributive) shock. Once the resuscitation phase is over, fluids are required for maintenance of vascular volume where oral intake is not possible or compromised, for drug carriage and as enteral or parenteral nutrition. It is important to take into account all these fluids or accumulation can easily occur.

FLUID REQUIREMENT IN COVID-19 PATIENTS Patients infected with COVID-19 present with a variety of clinical syndromes. Majority of the infected people (≈80%) are either asymptomatic or exhibit mild symptoms such as fever, dry cough, fatigue, and myalgia1,3; these patients are cared for at home with self-isolation and supportive care. About 14–15% of the total infected population develop severe symptoms and require hospitalization.3 A small proportion of patients (≈5%) become critically ill and require ICU admission and care, depending on local medical services and available infrastructure3,4—a substantial burden on critical care services, given the sheer volume of the pandemic.3 Severe form of disease usually presents with acute respiratory failure with respiratory rates of ≥30 breaths/minute, oxygen saturation ≤93%, and lung infiltrates of >50%.1,3,4 Many of the COVID-19 patients may develop septic shock requiring fluids for hemodynamic resuscitation. Some patients may present with gastrointestinal symptoms (vomiting and diarrhea), causing further fluid loss. Some may present late to the hospital and in hot and humid weather, the fluid loss may be

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Section 23:  COVID-19 Related Issues enhanced. As exhaled air contains sizeable quantities of water vapor, tachypneic respiratory failure will exacerbate fluid loss further, sometimes amounting to 2–4 L/day. Moreover, these patients usually do not receive much fluid in prehospital setting during retrieval and transport to hospital.

COVID-19 AND FLUIDS MANAGEMENT: WHAT SHOULD WE BE SPECIFICALLY AWARE OF? Fluid requirements in COVID-19 patients are dynamic, complex, and can be difficult to optimize. There are no “COVID-19 specific” guidelines for fluid management simply because data from randomized controlled trials are lacking. Published “guidelines” for COVID-19 patients from learned professional organizations are extrapolated from those for managing sepsis and septic shock in non-COVID-19 patients; all these guidelines draw upon Surviving Sepsis Campaign Guidelines – Updated for COVID-19 (SSCG-Cov-19).5 Majority of the hospitalized COVID-19 patients present with respiratory failure due to pulmonary infiltrates causing lung inflammation, often with additional secondary bacterial pneumonia. This complex clinical syndrome can lead to acute respiratory distress syndrome (ARDS) in a significant subset of patients. 3 Many patients may also suffer from sepsis and septic shock.3,4 Moreover, angiotensin-converting enzyme II (ACE-II), which is the primary receptor of COVID-19 virus in the host cells and is widely distributed in the body, allows this virus to affect a variety of cells and cause multiple organ dysfunction syndrome besides pulmonary dysfunction, with evidence of cardiac, hepatic, and renal dysfunction, altered consciousness, and clotting disturbances. 6 Fever, possible starvation in prehospital phase, tachypnea (causing increased water loss from lungs), vomiting, diarrhea, and hot and humid weather in many parts of the world can cause significant fluid losses, serious hypovolemia, and hypoperfusion; which, if not addressed promptly and effectively, can cause nonpulmonary organ damage [viz., acute kidney injury (AKI)], which considerably increases mortality and morbidity. Conversely, patients may have been transferred to a secondary or tertiary hospital from a primary healthcare facility, where they may have received fluids as part of their clinical management. This may not be apparent initially and must be carefully enquired into, as excess fluid has adverse consequences for the patient.7 Development of ARDS complicates fluid management in these severely ill patients, who may still be hypovolemic. Although distributive shock is the most common form of shock in these patients, myocardial injury (≈23%) as well as cardiac morbidity (≈40%) in the critically ill have also been reported.8 Autopsy examinations in these patients have shown cardiomegaly and left ventricular dilatation which may have been part of the clinical syndrome or caused by excessive fluid administration.8 Thus, most of these critically ill patients

will require fluid infusion as part of their initial resuscitation and ongoing care, some may have had adequate or excess fluid and this must be looked for, documented, and taken into account when planning fluid management. Besides, in a sizeable majority, because of ARDS and/or concomitant myocardial problems, caution is advised to avoid fluid overload.8 Thus, the clinicians need to be aware that fluid requirements in patients with this novel disease can change several times in the course of disease. Careful consideration needs to be given to this dynamic fluid requirement in order to avoid untoward clinical consequences.9

ASSESSMENT OF FLUID REQUIREMENT As the fluid requirements change overtime and both too little or too much fluid is undesirable in any, especially critically ill COVID-19 patients, judicious fluid infusions, where fluids are cautiously administered after assessment of preload responsiveness is the way forward.10 This assessment is dependent upon available resources, medical infrastructure, cost, and experience of the medical staff. Fluid responsiveness in a patient can be assessed by static and dynamic parameters. Static markers such as central venous pressure (CVP) are still commonly used as a measure of fluid responsiveness,11 despite poor relationship between CVP and blood volume or its predictability of hemodynamic response to fluid infusion.12 Clinical parameters such as capillary refill time (CRT), skin temperature, measured hourly urine output as well as the laboratory parameters such as base deficit and serum lactate are used to guide fluid resuscitation. Although a recent study did not find any difference in mortality between CRT targeted resuscitation strategy versus reduction in serum lactate amongst septic shock patients, the former group had less incidence of organ failures.13 It has been suggested that dynamic measures such as pulse pressure variation (PPV) and stroke volume variation (SVV) are better as against static measures in assessing volume requirements. But these too are considered unreliable in many common conditions in critically ill patients, namely spontaneously breathing patients, ARDS patients with low tidal volume ventilation, and patients having cardiac arrhythmias or intraabdominal hypertension.14 A method to assess fluid responsiveness without any external fluid infusion is passive leg raising (PLR) test. This equates to giving a reversible fluid challenge (FC) of about 300 mL fluid. PLR has the advantage that it can be repeated without causing excessive fluid accumulation. The effect of this and/or FC test on preload can be assessed by various noninvasive and invasive techniques. Echocardiography can be used to detect changes in cardiac output within 1–2 minutes of PLR.15 In a single center study, Trendelenburg maneuver has been found useful to assess fluid responsiveness in mechanically ventilated ARDS patients in prone position.16 In patients on controlled mechanical

Chapter 137:  Fluid Management in COVID-19: Principles and Practice ventilation, intrathoracic pressure swings lead to changes in inferior vena cava (IVC) diameter. This variation in IVC diameter (maximum–minimum/average) can be used to assess responsiveness to fluids.17 The methods of assessing fluid responsiveness are continuously evolving with improving area under the receiver operator characteristic curve as we move from static pressure and volume parameters [receiver operating characteristic (ROC) ~0.5–0.6] to dynamic techniques based on heart–lung interactions during mechanical ventilation (ROC ~0.7–0.8) to techniques based on real or virtual fluid challenge (ROC ~0.9) like PLR.18

WHAT GUIDELINES ARE AVAILABLE TO US? Surviving Sepsis Campaign provided their guidelines (SSCGCov-19) in 2020.5 Other professional bodies followed and also produced guidelines mainly based on SSCG-Cov-19.5 Guidelines published by National Institute of Health (NIH)19 and World Health Organization (WHO)20 endorsed SSCGCov-19 recommendations. Anaesthesia and Intensive Care Medicine in the UK also published guidelines, which were recently updated.21 Besides these guidelines, some “thoughts” and recommendations were also made by the International Fluid Academy (IFA).10 All these guidelines are based on sound intensive care principles and their recommendations are for conservative fluid management in these patients. National Institute of Care and Excellence (NICE) in the UK published guidelines on management of AKI in COVID-19 patients recommending conservative fluid management as well.22 SSCG-Cov-19 5 and NIH guidelines 19 recommend assessing fluid responsiveness with the aid of dynamic parameters and using conservative fluid administration strategy. WHO guidelines20 also recommend conservative fluid management in patents without evidence of hypoperfusion. For resuscitation in septic shock, they advocate a fluid bolus of 250–500 mL over 15–30 minutes (much like SSCG-Cov-19) and suggest using dynamic parameters to assess fluid responsiveness. UK’s Joint Anaesthesia and Intensive Care Medicine guidelines21 also advocate conservative fluid management in ARDS patients but also caution about “running patients too dry” in order to avoid AKI. IFA’s recommendations10 for fluid management in COVID-19 patients are similar to others; however, IFA suggests smaller quantities of fluids (4 mL/kg) as initial bolus and de-escalating fluids sooner than later.10 They also advocate using 20% albumin to bring up the serum albumin level and strongly advocate “Fluid Stewardship” in our ICUs. NICE guidelines follow the same pattern and advocate conservative fluid management in COVID-19 patients. 22 Thus, clinicians should always strive for conservative fluid management but maintaining euvolemia; however, this is easier said than done!

WHAT KIND OF FLUIDS ARE APPROPRIATE IN THESE PATIENTS? All guidelines agree on using crystalloids as resuscitation as well as maintenance fluids in these patients. Balanced salt solutions are recommended against 0.9% saline. Colloids are not recommended at all and there is strict caution about using starches in these patients. Rather than continue with fluid infusion, all guidelines recommend early use of vasoactive drugs to maintain mean arterial pressure ≥65 mm Hg to maintain organ perfusion. Albumin as a resuscitation fluid is not recommended, at least in initial phases of resuscitation. It may have a place in later stages if large fluid infusions are required.

HOW AND WHEN TO STOP FLUID RESUSCITATION? A NOTE ON DE-ESCALATE? Fluid resuscitation can be divided into four stages, namely, rescue, optimization, stabilization, and de-escalation.23 Rescue phase or the initial phase comprises of active fluid resuscitation of a patient in shock. This is followed by optimization phase where fluids are given in titrated manner where the patient is in a stage of compensated shock. Stabilization phase follows this where fluids are given for maintenance and there is no imminent threat or presence of shock. De-escalation phase is the last stage of resuscitation, the aim at this stage is to remove any accumulated fluids, this phase is achieved over days to weeks. Most patients with good renal function undergo spontaneous diuresis in this recovery phase. However, some may require a diuretic or ultrafiltration to remove excess fluids.24

PRACTICE POINTS ■ Ideal fluid strategy in COVID-19 patients is not known.

Guidelines and recommendations that are currently available, are extrapolated from non-COVID-19 patients and are based on poor quality of evidence. ■ Fluids are drugs and must be prescribed with all due caution and care used for drug prescribing. Like drugs, fluids have beneficial as well as harmful effects depending both on their quantity as well as the quality (contents). ■ Know when to prescribe fluids. Fluid requirements are never static but change overtime, sometimes from hour to hour. Individual requirements also vary depending on patients’ clinical presentation, nature, and severity of presenting condition, concomitant illnesses, etc. ■ Assess fluid requirements and fluid responsiveness. It is not always easy to determine fluid requirements in an individual patient from routine clinical examination. Parameters such as CRT, skin temperature, and PLR tests are noninvasive and cheap. Invasive as well as ultrasound-guided (USG) parameters are gaining popularity and acceptability, are cost-effective, and easy to carry out even in low- to middle-income countries.

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Section 23:  COVID-19 Related Issues ■ All dynamic fluid responsive tests have their limitations;

they are complementary to simultaneous clinical assessment and should help in deciding how much, when, and when not to give fluids to a patient. ■ Decide how much fluid to give and for how long. Too little or too much fluid is harmful. Thus, there must be at least a daily calculation of fluid intake/output. Weighing patients is a very good way of keeping track of this “fluid creep” but not always easy in the critically ill. ■ Know when to stop fluid resuscitation, give fluids for maintenance only, and/or de-escalate fluids. ■ There is an urgent need for “fluid stewardship” much like the antibiotic stewardship. ■ Fluid management must be individualized as “one size does not fit all!” ■ Clinicians must always treat the patient and NOT the number. ■ And finally, always remember—Primum non nocere.

CONCLUSION Fluid management in critically ill patients is challenging. A balance has to be maintained between aggressive resuscitation strategy and keeping patients “too dry.” Fluid management in the critically ill is aided by bedside clinical parameters, point-of-care laboratory parameters, and invasive and noninvasive techniques. This fluid stewardship is made more difficult in COVID-19 patients presenting with sepsis, ARDS, and respiratory failure. Due to lack of data on fluid management strategies in COVID-19 patients, available guidelines and strategies need to be followed along with meticulous monitoring.

REFERENCES 1. Guan W-J, Ni Z-Y, Hu Y, Liang WH, Ou CQ, He J, et al. Clinical characteristics of coronavirus disease 2019 in China. N Eng J Med. 2020;382:1708-20. 2. Lobo DN, Lewington AJP, Alliosn SP. 2013. Basic concepts of fluid and electrolyte therapy. [online] Available from: https:// www.researchgate.net/publication/249625074_Basic_ Concepts_of_Fluid_and_Electrolyte_Balance. [Last accessed March 2022]. 3. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72,314 cases from the Chinese Centre for Disease Control and Prevention. JAMA. 2020;323(13):1239-42. 4. Hajjar LA, da Silva Costa IBS, Rizk SI, Biselli B, Gomes BR, Bittar CS, et al. Intensive care management of patients with COVID-19: a practical approach. Ann Intensive Care. 2021;11(1):36. 5. Alhazzani W, Møller HM, Arabis YM, Loeb M, Gong MN, Fan E, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID‑19). Intensive Care Med. 2020;46(5):854-87. 6. Kazory A, Ronco C, McCullough PA. SARS-Cov-2 (COVID-19) and intravascular volume management strategies in the critically ill. Proc Baylor Univ Med Cent. 2020;33(3):370-75.

7. Jaffee W, Hodgins S, McGee WT. Tissue oedema, fluid balance, and patient outcomes in severe sepsis: an organ systems review. J Intensive Care Med. 2018;33(9):502-9. 8. Koratal A, Ronco C, Kazory A. Need for objective assessment of volume status in critically ill with COVID-19: The TriPOCUS approach. Cardiorenal Med. 2020;10:209-16. 9. Hasanni A, Mostafa M. Evaluation of fluid responsiveness during COVID-19 pandemic: What are the remaining choices? J Anaesth. 2020;34(5):758-64. 10. Malbrain MLNG, Ho S, Wong A. Thoughts on COVID-19 from the International Fluid Academy. ICU Management Pract. 2020;20(1):80-5. 11. Cecconi M, Hofer C, Teboul JL, Pettila V, Wilkman E, Molnar Z, et al. Fluid challenges in intensive care: the FENICE study: A global inception cohort study. Intensive Care Med. 2015;41(9):1529-37. 12. Marik PE, Cavallazzi R. Does central venous pressure predict fluid responsiveness? An updated meta-analysis and a plea for some common sense. Crit Care Med. 2013;41(7):1774-81. 13. Hernández G, Ospina-Tascón GA, Damiani LP, Estenssoro E, Dubin A, Hurtado J, et al. Effect of a resuscitation strategy targeting peripheral perfusion status vs serum lactate levels on 28-day mortality among patients with septic shock:  The ANDROMEDA-SHOCK Randomised Clinical Trial. JAMA. 2019;321(7):654-64. 14. Monnet X, Marik PE, Teboul JL. Prediction of fluid responsiveness: an update. Ann. Intensive Care. 2016;6(1):111. 15. Maizel J, Airapetian N, Lorne E, Tribouilloy C, Massy Z, Slama M. Diagnosis of central hypovolemia by using passive leg raising. Intensive Care Med. 2007;33(7):1133-8. 16. Yonis H, Bitker L, Aublanc M, Perinel Ragey S, Riad Z, Lissonde F, et al. Change in cardiac output during Trendelenburg manoeuvre is a reliable predictor of fluid responsiveness in patients with acute respiratory distress syndrome in the prone position under protective ventilation. Crit Care. 2017;21(1):295. 17. Feissel M, Michard F, Faller JP, Teboul JL. The respiratory variation in inferior vena cava diameter as a guide to fluid therapy. Intensive Care Med. 2004;30(9):1834-7. 18. Marik PE, Lemson J. Fluid responsiveness: an evolution of our understanding. Br J Anaesth. 2014;112(4):617-20. 19. National Institute of Health. (2021). Hemodynamics. [online] Available from: https://www.covid19treatmentguidelines. nih.gov/management/critical-care/hemodynamics/.[Last accessed March 2022]. 20. World Health Organisation. COVID-19 Clinical Management: Living Guidance 2021. [online] Available from: https:// www.who.int/publications/i/item/WHO-2019-nCoVclinical-2021-1. [Last accessed March 2022]. 21. Joint AAGBI, ROC, ICS and FICM guidelines on COVID-19 patients. [online] Available from: https://icmanaesthesiacovid-19. org/clinical-guide-for-the-management-of-critical-care-foradults-with-covid-19-during-the-coronavirus-pandemic. [Last accessed March 2022]. 22. Selby NM, Forni LG, Laing CM, Horne KL, Evans RD, Lucas BJ, et al. COVID-19 and acute kidney injury in hospital: Summary of NICE guidelines. BMJ. 2020;369:m1963. 23. Hoste EA, Maitland K, Brudney CS, Mehta R, Vincent JL, Yates D, et al. Four phases of intravenous fluid therapy: a conceptual model. Br J Anaesth. 2014;113(5):740-7. 24. Finfer S, Myburgh J. Bellomo R. Intravenous fluid therapy in critically ill adults. Nat Rev Nephrol. 2018;14(9):541-57.

138

Cytokine Removal in COVID-19related Sepsis/Cytokine Storm

C H A P T E R Vivek Nangia, Amina Mobashir, Sidhaant Nangia

INTRODUCTION While the concept of cytokine storm syndrome (CSS) was first proposed over a century ago, by Sir William Osler, the father of Modern Medicine in his descriptive work, “The Evolution of Modern Medicine”, however, most understanding about this complex syndrome has evolved over the last three decades. It is now well-known that sepsis is an umbrella term that includes various aspects of CSS which in turn is nothing but an uncontrolled hyperimmune response caused by an excess of proinflammatory cytokines and may lead to multiorgan failure and even death. It includes formerly used terms such as hemophagocytic lymphohistiocytosis (HLH), malignancy-associated hemophagocytic syndrome (MAHS), macrophage activation syndrome (MAS), cytokine storm (CS), infection-associated hemophagocytic syndrome (IAHS), and can occur in various conditions including infections, malignancies, and rheumatological conditions. A large number of viruses, bacteria, protozoa, and fungi have been found to cause CSS. Many viruses such as Corona SARS-CoV-1, which resulted in severe acute respiratory syndrome (SARS) outbreak in 2002, influenza H5N1 in 2006, influenza H7N9 in 2013, Corona Middle Eastern respiratory syndrome (MERS), Ebola, and now SARS-CoV-2, which has resulted in the current pandemic are known to cause CSS.1 Cytokine storm syndrome occurs following a complex interplay of various cells, signaling pathways, and cytokines following the entry of the pathogenic microbe. The key cytokines that play a pivotal role in the immunopathogenesis are interferon-γ (IFN- γ), interleukin-1 (IL-1), IL-6, tumor necrosis factor (TNF), and IL-18.2 Various therapeutic options have been trialed, but none has proven to be the gold standard yet.

IMMUNOPATHOGENESIS OF CYTOKINE STORM SYNDROME Over 200 cytokines have been discovered and based on their structure and function, they can be classified into six

major classes, namely ILs, colony-stimulating factors (CSFs), IFNs, TNF, growth factors (GF), and chemokines (CHs). Cytokines are small proteins which may exhibit their effect through different mechanisms. They act on neighboring cells via paracrine signaling or on the cytokine-secreting cells through autocrine signaling. Some cytokines act by intracrine signaling after binding to intracellular receptors, while membrane bound cytokines interact with neighboring cells via juxtacrine signaling. Usually cytokines are only locally acting, near the site of its secretion, but in certain pathological conditions, they may act on distant sites, in an endocrine manner, resulting in systemic effects.1 The entry of an invasive pathogenic organism is neutralized first by an innate immune response and later by an adaptive immune response. The immune response should ideally be appropriate to the pathogenic microbe, with a balance between the proinflammatory and the antiinflammatory mediators and then return to homeostasis. While IL-1β, IL-2, IL-6, IL-7, IL-12, IL-18, TNF-α, IFN-γ, and granulocyte colony-stimulating factor (GCSF) serve as proinflammatory mediators, regulatory T cells, cytokines such as IL-10, transforming growth factor (TGF)-β, and IL-1ra serve as anti-inflammatory mediators. However, in some patients, an exaggerated response results in an overabundance of proinflammatory mediators leading to significant collateral damage. 3 Cytokines are crucial in controlling this interplay by coordinating antimicrobial effector cells and providing regulatory signals that direct, amplify, and resolve the immune response.4

THERAPEUTIC STRATEGIES The main goal of treating the CSS is to control the overexaggerated immune response and limit the collateral damage. While there is no standard treatment currently, but the general strategies include elimination of the trigger, targeted immunomodulation, or nonspecific immunosuppression and supportive care to the organs affected.4

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Section 23:  COVID-19 Related Issues The specific pharmacological options during the COVID-19 pandemic, which have been evaluated so far, include inhibitors of IL-1a receptor (anakinra and canakinumab), inhibitors of IL-6 receptors (tocilizumab, sarilumab, and siltuximab), TNF-α blocker (etanercept), IFN-γ blocker (emapalumab), and cytokine signal transducers such as Janus Kinases (JAKs) inhibitors (baricitinib). The nonspecific pharmacological options include glucocorticoids, intravenous immunoglobulin (IVIg), and convalescent plasma.5

BLOOD PURIFICATION TECHNIQUES A potential nonpharmacological therapeutic option for CSS is blood purification techniques. The biggest advantage of these techniques is that they are able to target and clear a much wider panel of inflammatory mediators as compared to all the specific pharmacological options.

Continuous Renal Replacement Therapy The experience of continuous renal replacement therapy (CRRT) in patients with severe MERS has shown that besides removing fluid from the body, it also has the potential to remove inflammatory mediators.6 As per a study conducted, use of high cut-off (HCO) membrane during CRRT was able to remove macromolecules such as IL-6 but its ability to clear TNF-α was limited,7 and its usage in patients with septic shock did not result in any significant survival benefit.8 However, in a study involving 38 patients of septic shock and acute renal injury, using continuous venovenous hemodialysis (CVVHD) with HCO for 72 hours, resulted in significant reduction in cytokine levels. In this study, 30 patients survived while 8 died.9

Cytokine Adsorption Column or Immunoadsorption Immunoadsorption involves removal of cytokines, CHs, and antibodies using extracorporeal devices and thus purifying the blood.10 The commonly used devices for the purpose are mentioned below.

CytoSorb (Cytosorbents, Monmouth, NJ, USA) CytoSorb is one such hemoadsorption device which has been used to capture and reduce inflammatory mediators. It can be applied during standard hemodialysis, hemofiltration, and extracorporeal membrane oxygenation (ECMO). It has the ability to filter out molecules 5–60 kDa in size, has CE mark, and has been granted Emergency Use Authorization by the US Food and Drug Administration (FDA) for use in COVID-19 patients. Several retrospective studies and case reports of patients with severe sepsis and septic shock, acute respiratory distress

syndrome (ARDS) have proven its role in effectively reducing the blood levels of inflammatory factors thereby significantly improving the outcomes. In a case series of three severely ill adult patients with COVID-19 disease, published from India, single use of CytoSorb was associated with significant improvement in biochemical parameters and clinical outcomes. All three patients survived. C-reactive protein (CRP) levels decreased by 91.5, 97.4, and 55.75%, and mean arterial pressure improved by 18, 23, and 17% in patient 1, 2, and 3, respectively, on day 7 post-therapy.11 In a larger retrospective study from Iran, of 26 patients of COVID-19 illness with ARDS, treated with CytoSorb filter in addition to the routine therapy, 21 patients survived and a significant reduction in vasopressor requirements and plasma levels of inflammatory markers along with improvement in PaO2/FiO2 ratios and in Sequential Organ Failure Assessment (SOFA) score has been reported.12 In another similar case series of 15 patients of COVID-19 with ARDS requiring intubation and mechanical ventilation and renal replacement therapy, from Britain, 10 received CytoSorb and 5 HA 330 cartridge. Out of these, 11 patients were on ECMO, 8 expired and 7 survived. However, a significant reduction in various parameters such as ferritin (3,622 ng/mL vs. 1,682 ng/mL p = 0.022), CRP [222 mg/ mL vs. 103 mg/mL, p = 0.008, 95% confidence interval (CI) 22.4–126.5], lactate (2 mmol/L vs. 1.3 mmol/L, p = 0.017), and procalcitonin (15.3 ng/mL vs. 4.2 ng/mL, p = 0.023) have been reported, while there was no difference reported in IL-6, IL-1, IL-10, and TNF-α levels.13 Other similar studies have also reported a significant reduction in the levels of inflammatory markers, vasopressors, and improved oxygenation. Currently two trials employing hemoadsorption therapy for infection-related CS (NCT04195126, NCT03685383) and one employing Continuous venovenous hemofiltration and adsorption for severe septic shock (NCT03974386) are ongoing.14

AN69 Membrane (Oxiris) This is a high throughput membrane with highly hydrophilic hydrogel structure which is able to remove medium and high molecular weight mediators using ionic charge interactions. With slight modification of the surface with a multilayer linear structure of polyethylenimine cationic polymer, it can also remove negatively charged endotoxins.15 Experience in the past from Hong Kong16 and France17 in patients with severe sepsis showed significant improvement in SOFA score and reduction in in-hospital mortality by about 30% respectively. A major advantage of oxiris is that it has a heparin coating and hence in patients with increased risk of bleeding, it can be used without anticoagulation.18

Chapter 138:  Cytokine Removal in COVID-19-related Sepsis/Cytokine Storm In a case reported from India, its use in a COVID-19 patient with multiorgan involvement, during CRRT, led to reduction in IL-6 levels, improvement in respiratory status and survival.19 In a small case series of five patients of severe COVID-19 with ARDS and septic shock, from China, use of oxiris was associated with a significant reduction in the inflammatory mediators such as IL-6, IL-8, and IL-10 (p < 0.05), improvement in organ dysfunction, hemodynamics and oxygenation, and no adverse event to report.20 In a pilot study from Italy, 37 patients of COVID-19 with multiorgan involvement, were subjected to oxiris as an extracorporeal blood purification therapy. During the first 72 hours of instituting the therapy, median IL-6 levels (baseline level—1,230 pg/mL) decreased with the most significant reduction happening in the first 24 hours (p = 0.001) and so did the SOFA score from a median baseline score of 13 with the most significant reduction happening in the first 48 hours (p = 0.001). 8.3% reduction in mortality was observed in the oxiris group as compared to the expected mortality rates. The best results were observed in patients in whom it was administered early in the course of their intensive care unit (ICU) stay. The only technical complication experienced was premature clotting in about 18.9% patients, that too was similar to CRRT performed in other critically ill patients.21 In a larger prospective cohort study from Macedonia, of 44 COVID-19 patients, use of oxiris was associated with a reduction in the levels of acute phase proteins such as ferritin, CRP, fibrinogen, several inflammatory markers such as IL-6, and a resolution of numerous cytopenias such as lymphocytes, basophils, eosinophils, and platelets.22

Other Filters Some other filters which have been used for the purpose include polymethyl methacrylate membrane, Biosky offering different filter sizes from 150 to 350 mL, Jaffron HA 330, a

synthetic resin hemofilter, and AN69ST, an acrylonitrile/ methallyl sulfonate copolymer membrane. Overall, there is very limited experience of their usage and none in COVID-19 available. Some of the technical features of these devices have been compared in Table 1.

Timing of the Therapy Although no study has addressed this issue specifically, but considering that the inflammatory mediators have a very short half-life, it may be worthwhile to administer these therapies early on in the course of the CSS. Once the cascade has started, then the benefit from the removal of cytokines may be very limited.23

Disadvantages No study has reported any significant adverse event or technical difficulty and hence labeled it as a safe, feasible, and simple modality. Apart from the usual catheter-related complications such as infection, dislodgement, bleeding, and pneumothorax, the major disadvantage of all these therapies is that its nonselective and adsorbs a wide range of cytokines including the anti-inflammatory ones and can even result in loss of nutrients, electrolytes, and drugs including antibiotics, thus requiring monitoring of drug levels. Another disadvantage is that patients can vary in their levels of cytokines in the blood, hence these therapies may not be beneficial to all. And above all, there are no large scale randomized controlled trials to support their use.24

Coupled Plasma Filtration Adsorption This is another extracorporeal technique in which plasma is extracted from the blood, passed through a nonspecific sorbent, which removes the inflammatory mediators and then returned back into the blood. There is very limited data available to support its use.25

TABLE 1: Commonly used devices for the cytokine adsorption column. Device

Surface area 2

Blood flow rate

Integration

Material

Shelf life

Crosslinked Divinylbenzene

3 years

CytoSorb

45,000 m (more than 4 European football fields)

100–700 mL/min HP/HD/CRRT/ECMO/CPB

Biosky

Biosky Brochure: “… 5 European football fields to bind uremic toxins” (more than 50,000 m2)

100 mL/min at start, 180–400 mL/min once stabilized

HP/HD/CRRT/CPB

Medical neutral macropore synthetic resin

2 years

HA-380

100,000 m2

100–700 mL/min HP/HD/CRRT/CPB

Neutral macroporous resin

2 years

Oxiris

1.5 m2

100–450 mL/min SCUF/CVVH/CVVHD/CVVHDF

AN69 HF hollow fiber

2 years

(CPB: cardiopulmonary bypass; CRRT: continuous renal replacement therapy; CVVG: continuous venovenous hemofiltration; CVVHD: continuous venovenous hemodialysis; CVVHDF: continuous venovenous hemodiafiltration; ECMO: extracorporeal membrane oxygenation; HP: hemoperfusion; HD: hemodialysis; SCUF: slow continuous ultrafiltration)

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Therapeutic Plasma Exchange This technique is superior to CRRT for the removal of molecules from the plasma. It has often been used successfully for the treatment of antibody-mediated severe diseases such as thrombotic microangiopathies, glomerulonephritis forms, Guillain-Barré syndrome, and primary and secondary HLH.26 Some small studies support its use in sepsis also. In a systemic review published, therapeutic plasma exchange (TPE) was shown to reduce the mortality in adult patients with sepsis.27 Use of TPE has successfully led to rapid reduction in the dosage of vasopressors in patients with septic shock,27 reduced proinflammatory cytokines (IL-6, IL-1ß, and angiopoietin-2), 28 and partially reversed coagulation disorders.29 Use of TPE in COVID-19 patients with CSS has shown definite benefit. In a case report of a COVID-19 patient with respiratory failure and antiphospholipid syndrome, three sessions of TPE led to significant clinical improvement resulting in decreased titers of antiphospholipid antibodies and inflammatory markers, including IL-6.30 In a small case series reported from Turkey, of six patients suffering from COVID-19-related autoimmune meningoencephalitis with ARDS requiring mechanical ventilation, four patients recovered well and were discharged. One patient exited from the study, and one was still hospitalized at the time of publication. All these patients had high levels of inflammatory markers such as ferritin, fibrinogen, CRP, IL-6 in sera, and bilateral cerebral inflammation compatible with meningoencephalitis on magnetic resonance imaging (MRI) and were given three to nine sessions of TPE before they recovered.31 In a case series of eight patients from Iran, of COVID‐19 with septic shock and ARDS, subjected to TPE when they were continuing to be hypoxic despite steroids, only one patient died, that too, attributable to poor general condition and delay in initiation of TPE, while rest all recovered. The survivors received four to five sessions of TPE and were hospitalized between 8 and 22 days after the onset of symptoms.32 A few other case studies have indicated that use of TPE in patients of COVID-19 with ARDS and shock resulted in dramatic improvement. In a somewhat larger case series, of 31 patients from Oman, the TPE group was associated with higher extubation rates (73% vs. 20%; p = 0.018), improvement in laboratory and ventilatory parameters and a lower 14 days (0  vs. 35%; p = 0.033) and 28 days (0 vs. 35%; p = 0.033) postplasma exchange mortality compared to patients not on TPE. However, all-cause mortality was only marginally lower in the TPE group.33

Therapeutic plasma exchange has its own share of disadvantages also. It could result in higher risk of bleeding, catheter-related infections, electrolyte imbalances such as hypocalcemia and hypokalemia, and anaphylactic shock. The major limitation is the lack of expertise and infrastructure available to carry out TPE across all centers. The timing of initiation of TPE is very important. It has been recommended to be started early in patients with respiratory failure requiring mechanical ventilation particularly those with elevated inflammatory biomarkers. TPE may be instituted every day, or on alternate days and may be continued till clinical improvement. In a few studies, on an average, 2–14 daily sessions, were required before recovery. As for the choice of method, centrifugal one might be preferable, as randomized controlled trials (RCTs) on TPE in septic shock have showed positive results with using centrifugation, although filtration types are also considered useful.6

CONCLUSION Cytokine storm syndrome results from a complex interplay of the various proinflammatory and anti-inflammatory mediators. It is a life-threatening condition, for which no gold standard specific therapy is available yet. Among the various potential modalities, cytokine removal is a promising strategy. Though large scale studies are lacking, yet it could be employed in patients with high cytokine levels, high SOFA score, respiratory failure, and hemodynamic instability. Like most other interventions, early institution of therapy may improve the outcomes further.

REFERENCES 1. Xi Y. COVID-19-associated cytokine storm syndrome and diagnostic principles: an old and new Issue. Emerg Microbes Infect. 2021;10(1):266-76. 2. Kaiafa G, Veneti S, Polychronopoulos G, Pilalas D, Daios S, Kanellos I, et al. Is HbA1c an ideal biomarker of wellcontrolled diabetes? Postgrad Med J. 2021;97(1148):391-8. 3. Canna SW, Behrens EM. Making sense of the cytokine storm: a conceptual framework for understanding, diagnosing, and treating hemophagocytic syndromes. Pediatr Clin North Am. 2012;59(2):329-44. 4. Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med. 2020;383(23):2255-73. 5. Kim JS, Lee JY, Yang JW Immunopathogenesis and treatment of cytokine storm in COVID-19. Theranostics. 2021;11(1):316-29. 6. Silvester W. Mediator removal with CRRT: complement and cytokines. Am J Kidney Dis. 1997;30(5 Suppl 4):S38-43. 7. Morgera S, Rocktaschel J, Haase M, Lehmann C, von Heymann C, Ziemer S, et al. Intermittent high permeability hemofiltration in septic patients with acute renal failure. Intensive Care Med. 2003;29(11):1989-95. 8. Atan R, Peck L, Prowle J, Licari E, Eastwood GM, Storr M, et al. A double-blind randomized controlled trial of high cutoff

Chapter 138:  Cytokine Removal in COVID-19-related Sepsis/Cytokine Storm versus standard hemofiltration in critically ill patients with acute kidney injury. Crit Care Med. 2018;46(10):e988-94. 9. Villa G, Chelazzi C, Morettini E, Zamidei L, Valente S, Caldini AL, et al. Organ dysfunc- tion during continuous venovenous high cut-off hemodialysis in patients with septic acute kidney injury: a prospective observational study. PLoS One. 2017;12(2):e0172039. 10. Alkattan A, OH Hashi K, Kendeel M. Treatment options during cytokine storm. Dr. Sulaiman Al Habib Med J. 2021;3(2):48-52. 11. Mehta Y, Mehta C, Nanda S, Kochar G, George JV, Singh MK, et al. Use of CytoSorb therapy to treat critically ill coronavirus disease 2019 patients: a case series. J Med Case Reports. 2021;15(1):476. 12. Nassiri AA, Hakemi MS, Miri MM. Blood purification with CytoSorb in critically ill COVID-19 patients: A case series of 26 patients. Artif Organs. 2021;45(11):1338-47. 13. Paisey C, Patvardhan C, Mackay M, Vuylsteke A, Bhagra SK. Continuous hemadsorption with cytokine adsorber for severe COVID-19: A case series of 15 patients. Int J Artif Organs. 2021;44(10):664-74. 14. Tang Y, Liu J, Zhang D, Xu Z, Ji J, Wen C. Cytokine storm in COVID-19: The current evidence and treatment strategies. Front Immunol. 2020;11:1708. 15. Malard B, Lambert C, Kellum JA. In vitro comparison of the adsorption of inflammatory mediators by blood puri- fication devices. Intensive Care Med Exp. 2018;6(1):12. 16. Shum HP, Chan KC, Kwan MC, Yan WW. Application of endotoxin and cytokine adsorption haemofilter in sep- tic acute kidney injury due to Gram-negative bacterial infection. Hong Kong Med J. 2013;19(6):491-7. 17. Schwindenhammer V, Girardot T, Chaulier K, Grégoire A, Monard C, Huriaux L, et al. oXiris(R) use in septic shock: experience of two french centres. Blood Purif. 2019;47(3):1-7. 18. Zhang L, Yan Tang GK, Liu S, Cai J, Chan WM, Yang Y, et al. Hemofilter with adsorptive capacities: case report series. Blood Purif. 2019;47(3):1-6. 19. Lobo VA, Lokhande A, Chakurkar V, D’Costa PM. Continuous hemodiafiltration with the oxiris filter ameliorates cytokine storm and induces rapid clinical improvement in COVID-19 – A case report. Indian J Nephrol. 2021;31(6):555-8. 20. Zhang H, Zhu G, Lee Y, Lu Y, Fang Q, Shao F. The absorbing filter Oxiris in severe coronavirus disease 2019 patients: A case series. Artif Organs. 2020;44(12):1296-1302. 21. Villa G, Romagnoli S, Rosa SD, Greco M, Resta M, Pomarè Montin D, et al. Blood purification therapy with a hemodiafilter featuring enhanced adsorptive properties for cytokine removal in patients presenting COVID-19: a pilot study. Crit Care. 2020;24(1):605.

22. MedRxiv. (2020). Rosalia RA, Ugurov P, Neziri D, Despotovska S, Kostoska E, Veljanovska-Kiridjievska L, et al. Extracorporeal blood purification in moderate and severe COVID-19 patients: a prospective cohort study. [online] Availble from: https:// www.medrxiv.org/content/10.1101/2020.10.10.20210096v1. [Last accessed March, 2022]. 23. Quenot JP, Binquet C, Vinsonneau C, Barbar SD, Vinault S, Deckert V, et al. Very high volume hemofiltration with the Cascade system in septic shock patients. Intens Care Med. 2015;41(12):2111-20. 24. Ronco C, Bagshaw SM, Bellomo R, Clark WR, Husain-Syed F, Kellum JA, et al. Extracorporeal blood purification and organ support in the critically ill patient during COVID-19 pandemic: Expert review and recommendation. Blood Purif. 2021;50(1):17-27. 25. AL Shareef K, Bakouri M. Cytokine blood filtration responses in COVID-19. Blood Purif. 2021;50(2):141-9. 26. Clark WF, Huang SS, Walsh MW, Farah M, Hildebrand AM, Sontrop JM. Plasmapheresis for the treatment of kidney diseases. Kidney Int. 2016;90(5):974-84. 27. Rimmer E, Houston BL, Kumar A, Abou-Setta AM, Friesen C, Marshall JC, et al. The efficacy and safety of plasma exchange in patients with sepsis and septic shock: a systematic review and meta-analysis. Crit Care. 2014;18(6):699. 28. Knaup H, Stahl K, Schmidt BMW, Idowu TO, Busch M, Wiesner O, et al. Early therapeutic plasma exchange in septic shock: a prospective open-label nonrandomized pilot study focusing on safety, hemodynamics, vascular barrier function, and biologic markers. Crit Care. 2018;22(1):285. 29. Stahl K, Schmidt JJ, Seeliger B, Schmidt BMW, Welte T, Haller H, et al. Effect of therapeutic plasma exchange on endothelial activation and coagulation-related parameters in septic shock. Crit Care. 2020;24(1):71. 30. Ma J, Xia P, Zhou Y, Liu Z, Zhou X, Wang J, et al. Potential effect of blood purification therapy in reducing cytokine storm as a late complication of critically ill COVID-19. Clin Immunol. 2020; 214:108408. 31. Dogan L, Kaya D, Sarikaya T, Zengin R, Dincer A, Akinci IO, et al. Plasmapheresis treatment in COVID-19-related autoimmune meningoencephalitis: Case series. Brain Behav Immun. 2020;87:155-8. 32. Adeli SH, Asghari A, Tabarraii R, Shajari R, Afshari S, Kalhor N, et al. Therapeutic plasma exchange as a rescue therapy in patients with coronavirus disease 2019: a case series. Pol Arch Intern Med. 2020; 130(5):455-8. 33. Khamis F, Al-Zakwani I, Hashmi SA, Dowaiki SA, Bahrani MA, Pandak N, et al. Therapeutic plasma exchange in adults with severe COVID-19 infection. Int J Infect Dis. 2020;99:214-8.

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Cough Management in COVID Patients

C H A P T E R Vinay Singhal, Amit Gupta, Kunal Sahai

INTRODUCTION A novel virus SARS-CoV-2 was first detected in Wuhan, China, in December 2019 and from there it spread to rest of the world. It had varied presentation, from asymptomatic cases to patients’ mild, moderate, or severe illness. The common symptoms of COVID-19 are fever, dry cough, fatigue, and breathing difficulties. Cough can be most common symptom and it can be distressing to the patient and to the people around. It can increase the transmission by respiratory droplets.1 Identifying ways to control COVID19-associated cough would not only relieve the patient but also help to prevent community transmission and disease spread.

HOW TO DEFINE COUGH? Cough is a natural protective mechanism that allows clearing of the airways of irritants, particles, and microbes by an air expulsion from the lungs with fast speed. Although all coughs are acute at onset, they can be classified according to the duration as acute (8 weeks) categories. The most common causes of acute cough are respiratory infections (most likely of viral cause), followed by as asthma, chronic obstructive pulmonary disease (COPD), and pneumonia. For subacute cough, they were postinfectious cough and exacerbation of asthma, COPD, and upper airway cough syndrome (UACS). The most common causes for the chronic cough were UACS from rhino sinus conditions, asthma, gastroesophageal reflux disease (GERD), and nonasthmatic eosinophilic bronchitis.2

ACUTE COUGH IN COVID-19 Dry cough is a very common initial symptom in 60–70% of COVID-19 symptomatic patients in the acute phase like any other flu infection.3,4 Cough was reported in 50% of 370,000 confirmed COVID-19 cases with known symptom status reported to the Centers for Disease Control and Prevention (CDC).5 Cough carries the risk of droplet infection in the

community, apart from being distressing and leading to social isolation due to stigmatization in the pandemic. The median time of onset of cough was 1 day from the start of illness and it lasted for an average of 19 days and in 5% of cases persisted >4 weeks.6 A complex reflex arc is responsible for cough and this arc is initiated by the trigger of cough receptors existing mainly in the epithelium of the upper and lower respiratory tracts along within the pericardium, esophagus, diaphragm, and stomach by various chemical and mechanical irritants via activation of ion channels.7 Cough reflex traverse as an afferent pathway via the vagus nerve to the “cough center” in the medulla and then the cough center generates an efferent signal via vagus, phrenic, and spinal motor nerves to expiratory musculature. Initiation of cough may be associated with neuroinflammation due to interaction of virus with airway vagus nerve, this can initiate cough, along with ageusia and anosmia.8 The cough during the COVID period can be due to preexisting conditions or comorbidity having cough as the feature or it can be of COVID itself.

COUGH IN POST-COVID SYNDROME Cough can persists for long time for weeks to months, referred as post-COVID syndrome or long-COVID. PostCOVID syndrome is there when the COVID symptoms persists for >3 months.9 Sudre et al.10 studied two groups of symptoms in people with long COVID, one is fatigue, headache, and upper respiratory complaints (dyspnea, sore throat, persistent cough, and loss of smell) and the other is a multi­system complaints including ongoing fever and gastroenterological symptoms. Cough was present in 16–18% post-COVID patients 60 days after infection8,11 to 12% patients after 90 days of start of symptoms and 2.5% of patients after 1 year of infection.12 Lung fibrosis is the feared complication of respiratory infections. Myall et al. report a 4% incidence of post-COVID-19 inflammatory interstitial lung disease (ILD) among a large cohort of patients that

Chapter 139:  Cough Management in COVID Patients required hospitalization.13 The presence of fibrotic band-like radiographic abnormalities correlates with decrements in lung function, cough, and frailty. The persistence of cough was associated with other postCOVID-19 symptoms such as fatigue, dyspnea, and chest pain. These symptoms along with cognitive impairment, including confusion and memory loss (brain fog), are associated with a deleterious effect on activities of daily living. The post-COVID syndrome is pathophysiologically conglomeration of multiple symptoms and signs involving multiple organ systems and occurs due to dysregulated immune response leading to endothelial damage, thrombosis, and organ damage.14

Causes of Cough with Post-COVID Syndrome Cause of cough in post-COVID-19 patient and why it develops in some and not in others is largely unknown. Post-COVID syndrome may be associated with female sex or certain chronic condition such as respiratory comorbidities and severity of acute COVID-19 presentation. However, the persistence of cough was not associated with other post-COVID symptoms such as fatigue, dyspnea, and chest pain. It was also not associated with age, obesity, woman gender, height, weight, being active smoker, or cough as onset symptom of COVID, number of pre-existing medical comorbidities, or with hospitalization variables like the number of symptoms at hospital admission, number of days at hospital, and intensive care unit (ICU) admission.12 It is usually accompanied by multisystem involvement indicating varying underlying mechanism.

Persistence of Pre-existent or Co-existing Diseases Cough can present in post-COVID/long COVID syndrome as part of pre-existing comorbidities such as asthma, COPD, ILD, GERD, sinusitis, oral candidiasis, or drug uses such as angiotensin-converting enzyme inhibitors (ACEi). During the management of cough, here we will consider the management of the specific condition by careful history and relevant examination because during COVID-19 management, the necessary treatment of such conditions can be suboptimal.

Persistence of Respiratory Symptoms and Cough Post-COVID-19 COVID-19 illness can cause fibrotic damage to lung parenchyma or damage to the airways. This lung fibrosis or airway damage could increase sensitivity due to any mechanical stimulation for cough as seen in with idiopathic pulmonary fibrosis. In long COVID, the presence of cough with other symptoms of fatigue, dyspnea, chest pain, altered taste, and smell suggests derangement of central nervous system. Song et al.8 postulated the possibility

that SARS-CoV-2 infection leading to neuroinflammation and neuroimmune interactions as mechanisms of cough hypersensitivity by infecting the sensory nerves mediating cough. They also examined whether the neurotropism of SARS-CoV-2 could explain the other symptoms of COVID19 and post-COVID syndrome. Brain magnetic resonance imaging (MRI) imaging of patients with neurological complications of COVID-19 infection have shown cortical signal abnormalities and neuroinflammatory features with post-COVID syndrome,15 and positron emission tomography (PET) imaging of brain suggests hypometabolism in the olfactory gyrus and connected limbic-paralimbic regions, extending to the brainstem and the cerebellum in patients with long COVID.16 Neurotropism associated with COVID-19, activation of vagal sensory neurons with neuroinflammation needs to be studied for better understanding of central cause of COVID-related cough. This may also help us in managing the cough with appropriate use of antiviral, antiinflammatory, or neuromodulator drugs (e.g., gabapentin and pregabalin) for the treatment of acute or chronic cough associated with COVID-19.

Cough due to Complications of COVID-19 or Pre-existing/Co-existing Illness Cough can appear or worsen in patients with COVID-19 during treatment. There are instances when worsening occurs as patient acquires secondary bacterial infections. This may be associated with the development of pleuritis and subsequently pleural effusion. Among the nonpulmonary causes of cough, myocardial injury and heart failure are common. The specific condition must be managed as per with relevant investigations including blood tests, imaging, electrocardiogram, and echocardiography. Tuberculosis should be considered in differential diagnosis in patients with persistent respiratory symptoms in post–COVID-19 as it can occur due to reactivation of latent tuberculosis or new infection secondary to use of immunosuppressive medication or postviral immune function abnormalities. Barotrauma/air leak syndrome is also seen very often with COVID pneumonia. Forceful coughing with sudden alveolar overdistension can increase intra-alveolar pressure and rupture the alveoli. Air leak syndrome includes pneumomediastinum, pneumopericardium, pneumothorax, or subcutaneous emphysema and has considerable prevalence. It is primarily caused by chest trauma, cardiothoracic surgery, esophageal perforation, and mechanical ventilation. However, spontaneous alveolar air leakage is a rare phenomenon especially following viral pneumonia. Although an incidence of 11.6% previously had been reported concerning the severe acute respiratory syndrome (SARS) outbreak, a much lower incidence (0.72%) has been reported in patients with COVID-19.17

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Section 23:  COVID-19 Related Issues

MANAGEMENT OF COUGH IN COVID-19 Although it is the assessment of disease severity that becomes very important while managing a case of COVID-19, but at the same time, symptoms of cough, fever, and breathlessness can be highly distressing even in those who do not have severe disease. Treatment of cough in COVID depends upon the patient’s presentation (acute or chronic) and availability of the treatment options. Management includes detailed evaluation of clinical findings to find out the acute cause as well as pre-existing or coexisting diseases behind the cough. The examination should mainly emphasize general examination for pallor, nails for clubbing, cyanosis, lymph nodes swelling, and chest auscultation that can find crepts and rhonchi as well as decreased/altered air entry. The examination of nose should be especially helpful in finding polyps or reddish nasal mucosa (allergic), cobblestone appearance, and secretions in nasopharyngeal mucosa (postnasal drip). Systemic examination should also be done to rule out diseases such as lymphoma, vasculitis, sarcoidosis, and lung cancer.

Investigations The chest X-ray (CXR) is an integral part to clinch the dia­ gnosis of COVID and non-COVID diseases. Chronic cough with normal CXR is found most commonly in GERD, asthma, postnasal discharge (PND), and drugs such as ACEi. Sputum examination is must in cases of nonresponding cough to find out the cause of secondary infections, especially Grams stain/acid fast bacilli (AFB) stain/KOH mount, and culture. CXR and sputum examination for AFB will determine the diagnosis of tuberculosis. The computed tomography (CT) scan is also useful when the cause of cough remains undiagnosed. Reverse transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2 is obviously required to establish the diagnosis of COVID-19.

General Measures Communication with the patient and family is important. They should be told about the risks, benefits, and possible outcomes of the treatment options. They should also be aware of escalation plans in case of any worsening of symptoms. Treatment plan need to be modified for the patients with older age, pre-existing/co-existing comorbidities, impaired immunity, or the patients who have weak or reduced cough ability. Although many over-the-counter drugs are available for the relief of cough, but none seems to be effective for the treatment for the cough associated with viral pneumonias. In the UK National Institute for Health and Care Excellence guidelines for managing acute symptoms of COVID-19, only taking honey or opioid-derived antitussives are recommended for cough.18 Opiates could exert antitussive effects by acting on the cough reflex network in the

brainstem, and might have some effects in suppressing cough, particularly in the early stages. However, opiates are not universally effective and have associated risks of dependence, abuse, or central side effects.

Management of Cough with Pre-existing Diseases Treatment of pre-existing reasons in non-COVID cough obviously starts after a correct diagnosis with the help of examination and investigations. Antihistamines, decongestants, and nasal sprays will relieve allergic and postnasal drip cough. Bronchodilators and steroids are to be given for patients with asthma/cough variant asthma. The infective causes are treated with appropriate antibiotics/ antitubercular (ATT) after stain/cultures. Proton pump inhibitors (PPIs) and diet management along with propped up position, while reclining will help majority of GERD patients. The postinfectious cough resolves spontaneously in most of the cases. Switching from ACEi and beta-blockers to other antihypertensives such as calcium channel blockers (CCBs) or angiotensin receptor blockers (ARBs) will help in relieving drug-induced cough. Lifestyle modification such as cessation of smoking and environmental modifications such as good ventilation that improves air quality along with avoidance of exposure to fumes and smoke from kitchen and fuels are helpful in many patients. The avoidance of triggers and allergens will help in asthma/cough variant asthma.

Management of Cough with Post-COVID Syndrome/Long COVID Oral corticosteroids are often used for the lower respiratory tract infections other than COVID-19. But their use to treat cough in nonasthmatic patients with lower respiratory tract infection was usually not as effective. Use of corticosteroids for hypoxia with COVID-19 cases can also deal with the pathophysiology for the cough (early inflammatory response and neuroimmune pathology). Though use of dexamethasone decreases the mortality in the hospital treated patients with COVID-19, its effect on the cough was never assessed. 19 Gabapentin and pregabalin, the neuromodulator drugs, had been shown to be effective in chronic cough with long COVID. These drugs can be useful to relieve the other symptom of post-COVID syndrome, such as pain. Antimuscarinic drugs could be used to control COVID-19 cough, because they can decrease cough sensitivity in acute viral upper respiratory tract infection. According to Swiss Recommendations, there is moderate recommendation for inhaled steroids in persistent cough post-COVID. Recommendation for systemic steroids for interstitial abnormalities post-COVID if there is no active infection is only moderate.

Chapter 139:  Cough Management in COVID Patients However, there is no recommendation for antifibrotic therapy in signs of pulmonary fibrosis post-COVID.20 Investigation of novel therapeutic interventions that interferes with the neuroinflammatory pathways could be advantageous, such as inhibitors of TRP channels, ATPgated P2X3 receptors, neurokinin-1 receptors (NK1Rs), or sodium channels. Substance P and NK1R might also be a potential target for intervention, because NK1R antagonists such as aprepitant or orvepitant have shown antitussive potential in patients with lung cancer-associated cough or chronic refractory cough, possibly through blocking of central NK1Rs.21

CONCLUSION Cough can be a highly distressing symptom as we manage the case of COVID-19 irrespective of the severity of disease. Though frequency and prevalence of cough are very well studied, but effect of various treatment modalities such as corticosteroids and antivirals (remdesivir) on COVID-19 related cough was not assessed in trials. We need to have better understanding of activation of vagal sensory neurons, neuroinflammation, neuroimmunity, and peripheral and central sensitization for the pathophysiology of acute and chronic cough or cough associated with post-COVID syndrome. Chronic cough should be considered as syndrome and should be considered for the management with other symptoms of post-COVID syndrome.

REFERENCES 1. Dhand R, Li J. Coughs and sneezes: their role in transmission of respiratory viral infections, including SARS-CoV-2. Am J Respir Crit Care Med. 2020;202(5):651-9. 2. Irwin RS, French CL, Chang AB, Altman KW; CHEST Expert Cough Panel*. Classification of cough as a symptom in adults and management algorithms: CHEST Guideline and Expert Panel Report. Chest. 2018;153(1):196-209.  3. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. 4. Grant MC, Geoghegan L, Arbyn M, Mohammed Z, McGuinness L, Clarke EL, et al. The prevalence of symptoms in 24,410 adults infected by the novel coronavirus (SARSCoV-2; COVID-19): A systematic review and meta-analysis of 148 studies from 9 countries. PLoS One. 2020;15(6): e0234765. 5. Stokes EK, Zambrano LD, Anderson KN, Marder EP, Raz KM, El Burai Felix S, et al. Coronavirus Disease 2019 Case Surveillance - United States, January 22-May 30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(24):759-65. 6. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62.

7. Belvisi MG, Dubuis E, Birrell MA. Transient receptor potential A1 channels: insights into cough and airway inflammatory disease. Chest. 2011;140(4):1040-7. 8. Song WJ, Hui CKM, Hull JH, Birring SS, McGarvey L, Mazzone SB, et al. Confronting COVID-19-associated cough and the post-COVID syndrome: role of viral neurotropism, neuroinflammation, and neuroimmune responses. Lancet Respir Med. 2021;9(5):533-44. 9. Raveendran AV, Jayadevan R, Sashidharan S. Long COVID: An overview. Diabetes Metab Syndr. 2021;15(3):869-75. 10. Sudre CH, Murray B, Varsavsky T, Graham MS, Penfold RS, Bowyer RC, et al. Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App. medRxiv. 2020. 11. Carfi A, Bernabei R, Landi F; Gemelli Against COVID-19 PostAcute Care Study Group. Persistent symptoms in patients after acute COVID-19. JAMA. 2020;324(6):603-5. 12. Fernández-de-las-Peñas C, Guijarro C, Plaza-Canteli S, Hernández-Barrera V, Torres-Macho J. Prevalence of PostCOVID-19. Cough one year after SARS-CoV-2 infection: A Multicenter Study. Lung. 2021;199(3):249-53. 13. Myall KJ, Mukherjee B,  Castanheira AM, Lam JL, Benedetti G, Mak SM, et al. Persistent post-COVID-19 interstitial lung disease. An observational study of corticosteroid treatment. Ann Am Thorac Soc. 2021;18(5):799-806. 14. Østergaard L. SARS CoV-2 related microvascular damage and symptoms during and after COVID-19: consequences of capillary transit-time changes, tissue hypoxia and inflammation. Phys Rep. 2021;9(3):e14726. 15. Katal S, Gholamrezanezhad A. Neuroimaging findings in COVID-19: a narrative review. Neurosci Lett. 2021;742:135529. 16. Guedj E, Campion J, Dudouet P, Kaphan E, Bregeon F, TissotDupont H, et al. 18 F-FDG brain PET hypometabolism in patients with long COVID. Eur J Nucl Med Mol Imaging. 2021;48(9):2823-33. 17. Eperjesiova B, Hart E, Shokr M, Sinha P, Ferguson GT. Spontaneous pneumomediastinum/pneumothorax in patients with COVID-19. Cureus. 2020;12(7):e8996. 18. National Institute for Health and Care Excellence in collaboration with NHS England and NHS Improvement. Managing COVID-19 symptoms (including at the end of life) in the community: summary of NICE guidelines. BMJ. 2020;369:m1461. 19. Tomazini BM, Maia IS, Cavalcanti AB, Berwanger O, Rosa RG, Veiga VC, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA. 2020;324(13):1307-16. 20. Funke-Chambour M, Bridevaux PO, Christian F, Soccal PM, Nicod LP, von Garnier C, et al. Swiss Recommendations for the Follow-Up and Treatment of Pulmonary Long COVID. Respiration. 2021;100(8):826-41. 21. Smith J, Allman D, Badri H, Miller R, Morris J, Satia I, et al. The neurokinin-1 receptor antagonist orvepitant is a novel antitussive therapy for chronic refractory cough: results from a phase 2 pilot study (VOLCANO-1). Chest. 2020;157(1):111-18.

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140

Post-COVID Neuropsychiatric Complications

C H A P T E R Anand Sanghi, Chirag Matravadia, Rajesh Maniar

INTRODUCTION Viral infections of the respiratory tract affect all the systems of the body including the central nervous system (CNS). This affection gives rise to many of the psychiatric and neurological problems.1 Long- and short-term complications of CNS abnormalities have been reported in some of the patients affected with COVID-19 infection, such as stroke and isolated psychiatric syndromes.2 There was no single wave of COVID-19 infection, but more than one waves are seen. And as the world is going through its second/third wave (varying from country to country), this is a good time to understand about the effects of COVID-19 infection on the acute and chronic neuropsychiatric sequelae and to know its mechanism. Anxiety, stress, and depression are some of the acute psychiatric manifestations seen in patients with COVID-19 infection.3 It has been seen that the long-term effects are alone not related to the illness itself, but are also related to stigma or memories and amnesia-associated with the critical care that these patients receive while undergoing treatment.4 Nearly one-third of the hospitalized patients have reported acute neurological conditions such as headache, sensorium changes, acute cerebrovascular accidents, convulsions, and ataxia. 5 There are also reports of acute cognitive problems such as attention and dysexecutive symptoms. 6 Nevertheless, we can only estimate about COVID-19 infection’s long-term neuropsychiatric and cognitive effects.

PATHOPHYSIOLOGY OF NEUROPSYCHIATRIC CONSEQUENCES OF COVID-19 ■ Neuropsychiatric symptoms of COVID-19 infection

are seen due to factors such as electrolyte imbalance, inflammation of the liver, impaired renal function, problems with oxygenation, hyperinflammation,7 and isolation of the patients due to concerns of spread of the disease to others and these lead to the multifactorial delirium.

■ A secondary mode of infection by which COVID-19

infection affects the CNS function is the viral-induced immune reaction and immune response of the body. This can occur both during and after the spell of acute infection. Though the virus is not commonly seen in the cerebrospinal fluid (CSF), but a viral-induced inflammatory response can lead to blood–brain barrier (BBB) dysfunction, resulting in immune cell infiltration and CNS tissue damage.7 ■ COVID-19 infection (SARS-CoV-2) induces coagulo­ pathy, which results in the damage or failure of various organ systems. The viral invasion of vascular endothelium leads to activated thrombotic and inflammatory cascades during the hypercoagulable state, which can lead to cerebrovascular events.7 Among the hospitalized patients due to COVID-19 infection, the most common neurological finding is that of stroke.8 ■ Apart from the three modes of action mentioned above, another direct mode of action on the CNS was also proposed though less common. Due to high prevalence of loss of taste and smell in these patients, it was thought that the COVID-19 infection directly affects CNS using the olfactory axonal migration. But later studies have confirmed that metabolic support to the olfactory sensory neurons was provided by the olfactory epithelial cells and these neurons were not directly involved in this mechanism.9 Therefore, it is the BBB where the direct invasion of COVID-19 infection occurs, through (1) transcellular migration (host endothelial cells); (2) paracellular migration (through tight junctions); and (3) an immune system “Trojan Horse” cell passing through the BBB.8

NEUROPSYCHIATRIC COMPLICATIONS: ROLE OF ANGIOTENSIN-CONVERTING ENZYME 2 RECEPTORS Cytokine storm builds up when the coronaviruses attach themselves to the angiotensin-converting enzyme 2 (ACE-2) receptors that are present in the respiratory epithelial

Chapter 140:  Post-COVID Neuropsychiatric Complications cells causing inflammation and this leads to multiple organ damage and immune-mediated encephalopathies such as delirium and convulsions. These ACE-2 enzymes are present in oronasal, respiratory, cardiovascular, and cerebrovascular and immune systems. SARS-CoV-2 can remain dormant in the neurons of patients recovering from COVID-19’s acute effects, raising the likelihood of long-term repercussions by causing demyelination and neurodegeneration.10

CYTOKINE STORM AND ITS ROLE IN NEUROPATHOPHYSIOLOGY The dysregulation of the cytokine network is linked to another pathogenic mechanism. It has been demonstrated that during cytokine storm, there is upregulation of proinflammation cytokines, such as interleukin 10 (IL-10), tumor necrosis factor α (TNF-α), IL-6, IL-2R, and CCL2 (C–C motif chemokine ligand 2).11 Due to this, the organs already damaged by the COVID-19 infection continue to produce endogenous substances that are capable to generating chronic and systemic inflammation. Furthermore, the “cytokine storm” raises crucial questions concerning the degenerative chronicity of the CNS in particular, given that other neurodegenerative pathologies, such as Parkinson, Alzheimer, Huntington disease, and amyotrophic lateral sclerosis, are caused by a similar process. Since SARS-CoV-1 and MERS-CoV offer descriptions related with autoimmune neurodegenerative disorders,11 highlight the heightened inflammatory reaction and its relationship with autoimmune mechanisms by COVID-19.

NEUROPSYCHIATRIC EFFECTS OF CORONAVIRUS INFECTION Nonspecific Neurological Symptoms Patients with COVID-19 may experience nonspecific neurological symptoms such as disorientation and headache.12 Headache, myalgia, dizziness, and exhaustion are the most commonly reported nonspecific symptoms13 found that 36.4% of COVID-19 patients admitted at the Hospital of Huazhong University of Science and Technology in Wuhan, China, showed neurological symptoms.

Delirium Delirium, along with agitation and altered awareness, is the most common neuropsychiatric presentation in patients with COVID-19, with clinical expression in 65% of patients in the critical care unit.6 With the growth in delirium rates as a sign of COVID-19, it is time to consider if mental status changes should be included in the test criteria. The pathophysiology of this mechanism is unknown; however, it could be a primary symptom induced by the virus infecting the nervous system, or a secondary manifestation caused by encephalopathy caused by inflammation or other virusrelated systemic consequences.

Depression COVID-19 infection results in a hyperinflammatory state marked by an elevation in C-reactive protein, ferritin, and IL-6 levels, which, despite being a transient state, is likely to be linked to psychiatric issues.6 C-reactive protein, a peripheral inflammatory marker, was found to be linked with depressive symptoms in patients. Thus, it is discovered that COVID-19 patients suffer from psychological distress, and that inflammatory indicators are linked to the degree of depressive symptoms in these individuals.14 Post-COVID depressive symptoms are more likely seen in females,15 postinfection physical discomfort, severe infection,15 elevated inflammatory markers,14 and prior psychiatric illness.

Anxiety Studies show that as dangerous infectious disease spreads, social levels of anxiety symptoms rise, such as the psychological load produced by SARS-CoV-1, in which a significant portion of the sample had anxiety problems. Hypochondriac fears and anxieties could be a contributing factor.16 Fear and confusion regarding COVID-19 are among the many effects of the virus, and they can lead to diseases like anxiety. It has been observed that the pandemic has a greater impact on people who have previously experienced psychiatric illnesses, which could be linked to proinflammatory cytokines in these patients.

Post-traumatic Stress Disorder With a prevalence of over 40% (postdischarge period of 1–6 months) prior coronavirus epidemics,17 post-traumatic stress disorder (PTSD) was one of the most prevalent psychiatric illnesses diagnosed among SARS and MERS survivors. To date, the prevalence of PTSD in COVID-19 patients appears to range between 20 and 30%, while the prevalence of less precisely defined post-traumatic stress symptoms (PTSS) varies substantially.18 Younger age, female gender,18 requirement for intensive care unit (ICU)-level care,18 and having a previous psychiatric history are the most common risk factors for PTSD/PTSS following SARS-CoV-2 infection found so far. Many risk variables for COVID-19 are also risk factors for PTSD, which is interesting. Patients with PTSD have higher incidence of obesity, diabetes, metabolic syndrome, cardiovascular illness, and autoimmune disease. Delirium and ICU-level treatment, which are both typical COVID-19 sequelae,19 also are the risk factors for PTSD/ PTSS, with >20% of critical care survivors reporting PTSS 12 months after discharge.

Psychosis Higher incidences of psychosis have been recorded during many pandemics or epidemics since the 1918 Spanish influenza pandemic. An observational study from China found a 25% increase in psychotic illnesses early in the COVID-19 pandemic. 20 This link has been

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Section 23:  COVID-19 Related Issues linked to the pandemic’s significant mental stress, but, as previously mentioned, more direct processes have also been suspected. 21 Although there is not enough information to define a typical COVID-19 psychotic presentation, considerable disorganization and confusional signs have been described. 22 COVID-19 therapy has been linked to the onset of psychosis. Chloroquine and hydroxychloroquine, which were once the cornerstones of COVID-19 treatment, have been linked to hallucinations and other psychotic symptoms.22 Due to CYP3A4 suppression, this risk is increased in patients receiving lopinavir/ritonavir combination therapy.23 High-dose corticosteroids, which are still one of the only effective therapies for severe COVID-19 infection, can elicit psychotic symptoms, which have also been reported in the context of viral disease therapy.

NEUROPSYCHIATRIC INTERVENTIONS Unspecific Neurological Complications Because several medications utilized as a therapeutic resource in normal settings can aggravate the acute respiratory crisis associated with COVID-19, treating individuals with neurological issues caused by SARS-CoV-2 necessitates extra vigilance. Immunosuppressive treatments for autoimmune neurological disorders and corticosteroid medications stand out among them.

Delirium The majority of cases of delirium caused by the COVID-19 infection have been hyperactive or mixed variations with high levels of anxiety, which makes treatment more difficult. Low-potency antipsychotics, especially second-generation antipsychotics such as olanzapine and quetiapine, should be preferred in such circumstances. Furthermore, despite the lack of evidence to support the use of any therapies in COVID-19-related hyperactive delirium, most psychiatrists believe haloperidol to be the best agent for managing agitation in delusional patients.24 Melatonin or melatonin receptor agonists (ARM) treatment has also been linked to a lower occurrence of delirium in studies. Melatonin, in this sense, should be considered a first-line medication for treating sleep-wake rhythm and awareness abnormalities, as well as reducing the usage of chemicals that can cause central respiratory depression, such as benzodiazepines.25 As a result, health workers must adhere to local rules and regulations for the monitoring and management of delirium. It is also vital to implement simple delirium screening procedures, especially given the high workload during the COVID-19 crisis.

Depression COVID-19 clinical management should always be careful, and this is the key. Immune modulation medicines, such as IL-6 inhibitors and melatonin, are being studied for the treatment of depression caused by infection-induced

hyperinflammation, and other therapy, such as cytokine blocking medications and Janus kinase inhibitors (JAK), have also been suggested.26

Anxiety COVID-19 patients with anxiety or panic symptoms, as well as breathing problems, may be evaluated and managed by a psychiatrist. Although the use of lower dosages of benzodiazepines may be suitable in some circumstances, it is crucial to note the risk of respiratory depression. As a result, clinicians must weigh the disadvantages and advantages of prescribing benzodiazepines to patients who have severe respiratory symptoms. Depending on the conditions and symptoms of each patient, other medications such as gabapentin, buspirone, hydroxyzine, or a low dose of selective serotonin reuptake inhibitors (SSRIs) may be used. Other nonpharmacological and psychological therapies, such as psychotherapy, should also be investigated.24

Post-traumatic Stress Disorder While there is evidence to support the use of the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine and selective serotonin reuptake inhibitors (SSRIs) for PTSD in medically sick patients, possible dangers should be carefully considered on a case-by-case basis. The α-1 receptor blocker prazosin has been demonstrated in several studies to reduce nightmare frequency and intensity, as well as improve other PTSD symptoms in patients.27 Although limited Internet connection and poor health state in many afflicted patients make in-person psychological interventions preferable when available, there is some evidence that psychoeducational services delivered online to COVID-19 survivors with PTSS have been effective. Supportive counselling, resilience training, and psychological first aid have some evidence in treating PTSD. Exposure-based cognitive behavioral treatment (CBT) has the highest level of evidence in persons with PTSD.

Psychosis Patients hospitalized for severe COVID-19 may present to primary care settings on antipsychotics that were started during the acute period,21 and patients hospitalized for severe COVID-19 may present to primary care settings on antipsychotics that were started during the acute period.22 It is crucial to remember that antipsychotics can cause QT prolongation and Torsades de Pointes, especially when used with other QT prolonging drugs (e.g., azithromycin). Furthermore, COVID-19 infection is proarrhythmogenic in and of itself.

CONCLUSION The severe acute respiratory syndrome is primarily responsible for the clinical deterioration of COVID-19 infection;

Chapter 140:  Post-COVID Neuropsychiatric Complications nevertheless, understanding the atypical consequences, particularly psychiatric and neuropsychiatric ones, is critical for mitigating the direct and indirect effects of this pandemic event. Depression, anxiety, post-traumatic stress disorder, psychosis, nonspecific neurological symptoms, delirium, and cerebrovascular problems, were the most common mental and neuropsychiatric consequences. Acute respiratory disorders can cause mental and neuropsychiatric symptoms during or after the infectious period. As a result, therapeutic intervention, both pharmacological and nonpharmacological, is required in the treatment of such illnesses; nonetheless, it is still vital to monitor the psychological effects of the medications used to treat COVID-19. Healthcare practitioners will be able to plan proper healthcare delivery and allocate resources with the use of robust neuropsychiatric and cognitive monitoring. For many COVID-19 survivors, early intervention for emergent cognitive deficits will be important for independent functioning and enhanced quality of life.

REFERENCES 1. Kępińska AP, Iyegbe CO, Vernon AC, Yolken R, Murray RM, Pollak TA. Schizophrenia and influenza at the centenary of the 1918-1919 Spanish influenza pandemic: mechanisms of psychosis risk. Front Psychiatry. 2020;11:72. 2. Butler M, Watson C, Rooney A, Badenoch J, Cross B, Butler M, et al. The neurology and neuropsychiatry of covid-19. BMJ Opinion. 2020;92(9). 3. Asmundson GJG, Taylor S. Coronaphobia: Fear and the 2019nCoV outbreak. J Anxiety Disord. 2020;70:102196. 4. Jones C, Humphris GM, Griffiths RD. Psychological morbidity following critical illness-the rationale for care after intensive care. Clinical Intensive Care. 1998;9(5):199-205. 5. Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683-90. 6. Rogers JP, Chesney E, Oliver D, Pollak TA, McGuire P, FusarPoli P, et al. Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic. Lancet Psychiatry. 2020;7(7):611-27. 7. Achar A, Ghosh C. COVID-19-Associated neurological disorders: the potential route of CNS invasion and bloodbrain barrier relevance. Cells. 2020;9(11):2360. 8. Jain R, Young M, Dogra S, Kennedy H, Nguyen V, Jones S, et al. COVID-19 related neuroimaging findings: a signal of thromboembolic complications and a strong prognostic marker of poor patient outcome. J Neurol Sci. 2020;414:116923. 9. Gupta K, Mohanty SK, Mittal A, Kalra S, Kumar S, Mishra T, et al. The Cellular basis of loss of smell in 2019-nCoV-infected individuals. Briefings in bioinformatics. 2021;22(2):873-81. 10. Lippi A, Domingues R, Setz C, Outeiro TF, Krisko A. SARS‐ CoV‐2: at the crossroad between aging and neurodegeneration. Mov Disord. 2020;35(5):716. 11. Troyer EA, Kohn JN, Hong S. Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric

symptoms and potential immunologic mechanisms. Brain Behav Immun. 2020;87:34-9. 12. Asadi-Pooya AA, Simani L. Central nervous system manifestations of COVID-19: a systematic review. J Neurol Sci. 2020;413:116832. 13. Carod-Artal FJ. Complicaciones neurológicas por coronavirus y COVID-19. Rev Neurol. 2020;70(9):311-22. 14. Guo Q, Zheng Y, Shi J, Wang J, Li G, Li C, et al. Immediate psychological distress in quarantined patients with COVID19 and its association with peripheral inflammation: a mixedmethod study. Brain Behav Immun. 2020;88:17-27. 15. Ma Y-F, Li W, Deng H-B, Wang L, Wang Y, Wang P-H, et al. Prevalence of depression and its association with quality of life in clinically stable patients with COVID-19. J Affect Disord Elsevier. 2020;275:145-8. 16. Furer P, Walker JR, Chartier MJ, Stein MB. Hypochondriacal concerns and somatization in panic disorder. Depress Anxiety. 1997;6(2):78-85. 17. Han RH, Schmidt MN, Waits WM, Bell AK, Miller TL. Planning for mental health needs during COVID-19. Curr Psychiatry Rep. 2020;22(12):1-0. 18. Halpin SJ, McIvor C, Whyatt G, Adams A, Harvey O, McLean L, et al. Postdischarge symptoms and rehabilitation needs in survivors of COVID‐19 infection: A cross‐sectional evaluation. J Med Virol. 2021;93(2):1013-22. 19. Garcez FB, Aliberti MJ, Poco PC, Hiratsuka M, Takahashi SF, Coelho VA, et al. Delirium and adverse outcomes in hospitalized patients with COVID‐19. J Am Geriatr Soc. 2020;68(11):2440-6. 20. Hu W, Su L, Qiao J, Zhu J, Zhou Y. COVID-19 outbreak increased risk of schizophrenia in aged adults. Chinaxiv. [online] Available from: https://www.clinicaltmssociety. org/system/files/2020.02.29-chinaxiv-covid-19-outbreakincreased-risk-of-schizophrenia-in-aged-adults.pdf. [Last accessed March 2022]. 21. Brown E, Gray R, Monaco SL, O’Donoghue B, Nelson B, Thompson A, et al. The potential impact of COVID-19 on psychosis: a rapid review of contemporary epidemic and pandemic research. Schizophr Res. 2020;222:79-87. 22. Parra A, Juanes A, Losada CP, Álvarez-Sesmero S, Santana VD, Martí I, et al. Psychotic symptoms in COVID-19 patients. A retrospective descriptive study. Psychiatry Res. 2020;291:113254. 23. Mascolo A, Berrino PM, Gareri P, Castagna A, Capuano A, Manzo C, et al. Neuropsychiatric clinical manifestations in elderly patients treated with hydroxychloroquine: a review article. Inflammopharmacology. 2018;26(5):1141-9. 24. Bilbul M, Paparone P, Kim AM, Mutalik S, Ernst CL. Psychopharmacology of COVID-19. Psychosomatics. 2020;61(5):411-27. 25. Zambrelli E, Canevini M, Gambini O, D’Agostino A. Delirium and sleep disturbances in COVID-19: a possible role for melatonin in hospitalized patients? Sleep Med. 2020;70:111. 26. Ferrando SJ, Klepacz L, Lynch S, Tavakkoli M, Dornbush R, Baharani R, et al. COVID-19 psychosis: A potential new neuropsychiatric condition triggered by novel coronavirus infection and the inflammatory response? Psychosomatics. 2020;61(5):551-5. 27. Raskind MA, Peskind ER, Chow B, Harris C, Davis-Karim A, Holmes HA, et al. Trial of prazosin for post-traumatic stress disorder in military veterans. N Engl J Med 2018;378(6): 507-17.

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Constipation and Diarrhea in COVID Patients: Management

C H A P T E R Mansi Dandnaik, Ripal Patel Shah, Tejash Parikh

INTRODUCTION Constipation is a major problem among bedridden patients. The prevalence of constipation in severe COVID-19 patients is estimated to be at least one in three patients. Immobility and medications are more important risk factors than COVID-19 itself. It becomes very important to identify and address this issue not only for patient comfort but for patient safety. Constipated patient can never be happy and concentrate on breathing. Further uncorrected constipation leads to respiratory distress. Similarly, diarrhea is also seen in as much as 30% of the patients of COVID-19 as it is seen in other viral illnesses. It is usually self-limiting but antiviral helps in early resolution. Diarrhea is also disastrous for a breathless patient and it adds to overall morbidity. Overuse of laxatives, antibiotic-associated diarrhea (Clostridioides difficile), and cytomegalovirus (CMV) colitis are not unusual causes of diarrhea in patients who are sick enough to require either mechanical ventilation or extracorporeal membrane oxygenator.

CONSTIPATION IN COVID PATIENTS The routine definition of constipation includes objective parameters such as less than three stool frequency per week, requires manual maneuvers to clear bowel, and subjective like straining while passing, hard stools, or incomplete bowel movement, etc. In critically ill individuals, subjective symptoms are difficult to assess so have to decide on the absence of defecation, the described time duration differs among studies. In view of inconclusive definition, European Intensive Care Medicine Society recommends to use the term “paralysis of the lower gastrointestinal tract” instead of “constipation.” They defined this as “the inability of the bowel to pass stool due to impaired peristalsis” and suggested that clinically absence of stool for 3 or more days in the absence of mechanical obstruction irrespective of bowel sounds.1 Incidence of constipation in critically ill varies from 5 to 90% in various studies depending on study population and

criteria used for defining constipation. More sick patients those requiring mechanical ventilation has higher incidence. Underlying etiology responsible for intensive care admission also impacts the incidence. Similar experiences related to bowel hypomotility are being reported from COVID care centers. Nearly half of the COVID-19 patients had gastrointestinal (GI) symptoms on hospital presentation which includes diarrhea, vomiting, abdominal pain, etc. Among all hospita­ lized individuals with COVID-19, nearly 74% had at least one GI complication which includes hepatobiliary, hypomotility, bowel ischemia, and others. Hypomotility of the gut is seen more commonly with severe COVID-related illness. Gastric feeding intolerance for >24 hours, clinical and/or radiological ileus was seen in 46.2 and 55.8% patients, respectively. Various hypotheses proposed for hypomotility issues related to COVID-19 which includes: ■ Pharmacological adverse events, e.g., opioids as cough suppressant and sedation, and neuromuscular blocking agents ■ Metabolic and electrolyte disorders, e.g., hyperglycemia, hypokalemia, and hypoxia ■ Corona virus-induced small vessel thrombosis ■ Viral enter neuropathy ■ Critical illness, e.g., sepsis, use of vasopressor agents.

Clinical Impact Impact from constipation varies from mild abdominal distention to increasing mortality and ventilator days (Box 1). There are various studies suggesting days from early first passage of stool early (250 (>13.8) 

>250 (>13.8) 

>600 (>33.3) 

>600 (>33.3) 

pH 

7.25–7.30 

7.00–7.24 

7.30 

 

HCO2 (mmol/L) 

15–18 

10–14 

18 

 

Urine/serum ketones 

+ 

+ 

± 

± 

+ 

Serum osmolality (Osmeff ) 

 

 

 

320 

320 

Anion gap  

Elevated 

Elevated 

Elevated 

Elevated 

Elevated 

Mental status 

Alert 

Alert/drowsy 

Stupor/coma 

Stupor/coma 

Stupor/coma 

Insulin therapy 

SC/IV 

SC/IV 

IV 

IV 

IV 

Frequency of glucose monitoring 

every 1–2 hours 

every 1–2 hours 

every 1 hour 

every 1 hour 

every 1 hour 

Location of care 

Intermediate care unit 

Intermediate care unit/ICU 

ICU 

ICU 

ICU 

(DKA: diabetic ketoacidosis; HCO2: bicarbonate; ICU: intensive care unit; IV: intravenous; Na+, sodium; SC: subcutaneous ; HHS: hyperglycemic hyperosmolar syndrome; HONK: hyperosmolar nonketotic coma)

Role of Subcutaneous Insulin Use in Diabetic Ketoacidosis In context of pandemic along with available evidence, SC insulin therapy proves to be useful for mild/moderate uncomplicated DKA. From the Cochrane review (2016) assessing IV insulin versus SC rapid-acting insulin protocol found that the effects of SC versus IV insulin (rapid-acting insulin analogues) are comparable for treating mild or moderate DKA.34 Summary of SC insulin randomized controlled trials (RCTs) in DKA and potential strategies in COVID-19 is given in Table 2. One study was assessing the impact of adding early basal insulin within the first 12 hours at the dose of 0.25 unit/kg. The authors observed reduction in rebound hyperglycemia [33.3% in the intervention group versus 93.5% in the control (P 12 weeks, respectively, after acute phase.5,6 The content of the chapter is based on position statements from Indian Society of Anaesthesiologists6 and Indian Society of Critical Care Medicine,7 WHO8 guidelines for the prevention

and treatment of COVID-19, and a comprehensive review of updated literature on the perioperative management of infectious patients.9-12

PERIOPERATIVE CONCERNS FOR PATIENTS WITH ACTIVE COVID-19 The causative organism for COVID-19, i.e., severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be transmitted to HCWs involved in their care mainly during aerosol-generating procedures (laryngoscopy, endotracheal intubation, extubation, and bronchoscopy). Therefore, infection control measures to limit spread of the virus are essential component of the perioperative care of these patients.

Infection Control Based on the experience from other infectious agents (Ebola, SARS-CoV, etc.) and guidance from the Centers for Disease Control and Prevention (CDC), various other societies have published recommendations for infection control during anesthesia for patients with COVID-19.6,13,14 Goals are to prevent infection transmission to HCWs and to prevent contamination of the anesthesia machine and other anesthesia equipment. Similar infection control measures should be employed while caring for both suspected or confirmed COVID-19 cases and include handwashing with soap or hand hygiene with chlorhexidine, universal precaution including use of personal protective equipment (PPE), standard handling of medical waste disposal, and environment and equipment disinfection. Although the available literatures on the use of PPE during aerosol generating procedures and risk of infection transmission showed conflicting results, it is prudent to use the PPE while caring for all COVID-19 suspected or confirmed cases.15-17 The extended or level III PPE which include reinforced fluid-resistant long-sleeved surgical gown with attached hood, full length disposable plastic apron, filtering face piece 3 (FFP3) respirator or powered

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Section 23:  COVID-19 Related Issues hood respirator, disposable full face visor, pair of disposable gloves, and dedicated shoes with shoe covers should be worn for all aerosol-generating procedures. Level 2 airborne precaution which include disposable apron, disposable gloves, FFP3 respirator, and eye protection should be used by all other HCWs while caring for the patients who do not undergo aerosol-generating procedures. Another area which need distinct consideration is donning (putting on) and doffing (putting off ) of PPE. It is suggested that donning and doffing should be monitored by a trained observer as error during these are common which may lead to contamination of HCWs with pathogens.18,19 Used PPE must be removed slowly and deliberately in the correct sequence to reduce the possibility of selfcontamination. After removing gloves and other PPE, a thorough hand hygiene should be performed before touching any body parts.

Preoperative Evaluation and Preparation There is increased risk of perioperative morbidity (pul­m onary complications) and mortality in patients with COVID-19, therefore the preoperative evaluation should focus on risk assessment.20,21 This risk should be balanced against the risks of delaying or avoiding the planned procedure before deciding to perform surgery. The reported odds for 30-day mortality after surgery is >5.22 The overall mortality with emergency surgery was reported to be higher compared with elective surgery (26 vs. 19%).20 There is consensus that in confirmed or suspected COVID19 patients, elective procedures should be postponed till 8 weeks after symptom resolution.23 During the transport within a medical facility, a surgical mask should be used by the patient and they should be directly transported to dedicated OR without holding in the preoperative area. A protective barrier with slits for easy patient access may be fitted on the transport trolley (Fig. 1). If possible portable tent system with high-efficiency particulate air (HEPA) filtration should be used during transport for patients with COVID-19.24 A high-quality heat and moisture exchanging (HME) filter should be used

between patient and breathing circuit while transporting the intubated patient. Similarly, during recovery patients should be transported directly to an airborne infection isolation room without keeping them in the postanesthesia care unit (PACU).

Avoiding Contamination of Anesthesia Equipment A dedicated OR with appropriate operation of laminar flow and the functional HEPA filter with limited entry (only personnel involved in direct care of the patient) should be used for COVID-19 patients undergoing surgery. For preventing contamination and need for disinfection of the anesthesia equipment, only necessary equipment should be kept in the OR particularly during aerosol-generating procedures. Other equipment should be kept ready outside the OR and brought in when required. Preventing contamination of all the component of anesthesia workstation is critical.25 The surface contamination of the outer parts of the anesthesia workstation and other reusable equipment (multipara monitor, ultrasound machine, etc.) can be prevented by covering it with plastic covers. During removal of these covers after use, similar care should be taken as during doffing of PPE. The contamination of internal components of the anesthesia workstation can be prevented by putting HME filters rated for viral filtration efficiency between both limbs of breathing circuit and anesthesia workstation as well as between patient’s airway interface and breathing circuit. These filters should be replaced between two cases. For decontamination of the anesthesia workstation and reusable equipment, cleaning should be performed according to manufacturer’s recommendations while disposables items should be bagged for disposal as contaminated waste.26 When the HME filters are placed as recommended, there is no need to replace the water trap that receives the gas sampling line and the carbon dioxide absorber, however, the gas sampling tubing should be replaced between two cases. Similarly, the internal components of the anesthesia workstation and breathing system do not need cleaning or decontamination when HME filters are used as recommended. Between the two cases, the OR should remain closed to allow adequate air exchanges for removing aerosolized pathogens and then the OR should undergo a thorough deep terminal cleaning using guidelines from CDC. Enhanced environmental cleaning and disinfection of the OR using ultraviolet C (UV-C) light and/or hydrogen peroxide vapor is encouraged.26

Anesthesia Management

Fig. 1: A dedicate transport trolley fitted with protective barrier.

Selection of anesthetic technique (general vs. regional) for confirmed or suspected COVID-19 patients should take into consideration both the patient factors as well

Chapter 145:  Perioperative Concerns in COVID as the procedure. As there are risk and benefit to both the techniques, selection of one technique over the other has no advantage when either would be appropriate. The general principles to be followed for both the techniques are as mentioned below.

General Anesthesia Induction of general anesthesia should be performed using rapid sequence induction and intubation. The selection of induction agent should take in to consideration the patient factor. Adequate preoxygenation should be performed and volume status should be optimized (intravenous fluids or vasopressor) particularly in critically ill patients as they may become even more hypoxemic and hypotensive after induction and during intubation. Consideration should be given for using ketamine, etomidate, or a combination of ketamine and propofol rather than propofol alone.27 If bag mask ventilation is required, low pressure small volume breath should be delivered maintaining a tight seal between face and mask. For securing the airway, the endotracheal intubation should be preferred over a supraglottic airway to prevent leak around the airway device and to prevent viral spread. The airway must be secured rapidly and repeated attempts at intubation must be avoided to reduce aerosolization of respiratory secretions. 28-30 Videolaryngoscopy has distinct advantage as it may increase the first attempt success rate and also allows the clinician to remain at distance from the patient’s airway during the procedure.31 Further it also ensures adequate depth under direct vision eliminating chest auscultation to confirm the equal air entry on both sides of the chest. The other aerosol-generating procedures during anesthesia care include bag mask ventilation, jet ventilation with an open airway, open suctioning of airways, airway endoscopy/bronchoscopy, noninvasive ventilation, highflow oxygen, nebulized medications, tracheostomy, and transesophageal echocardiography. During the intubation, attention should be paid to reduce coughing and/or bucking. It was suggested that intubation should be performed in a negative pressure room outside the OR as most ORs use positive pressure air flow; however, recent simulation-based studies suggest that air exchange rate and other factors may affect aerosol distribution.32 Double gloves should be used during intubation and outer gloves should be removed immediately after securing the airway. After the successful intubation, the cuff should be inflated before connecting the breathing circuit. Disconnection should be avoided as much as possible and if required the viral filters should be left on the endotracheal tube (ETT). Alternatively, a clamp can be placed on the ETT with the ventilator on standby if viral filters are not on place. A closed suction system can be placed for tracheal suctioning before extubation and when required.

Fig. 2: A protective barrier provided with arm sheaths or slits to allow access to the patient airway during intubation and extubation.

Variety of protective barrier devices have been developed to protect the anesthesiologist from droplet or aerosol contamination during intubation and extubation. 33,34 These devices are provided with arm sheaths or slits to allow access to the patient airway during intubation and extubation (Fig. 2) and may have incorporated continuous suction to vent aerosols.35,36 The concerns with these devices are that these have not been critically evaluated in humans, they may prolong the intubation and adequate view of the patient’s airway may be compromised. Because of the concern that these devices may increase exposure of healthcare providers, the Food and Drug Administration (FDA) has issued an alert recommending against the use of passive protective barriers (those without negative pressure) for use when caring for patients with known or suspected COVID-19.37 Similar to the endotracheal intubation, the tracheal extubation is also considered as a high-risk procedure for aerosolization of respiratory secretions, therefore all the precautions should be followed. Care must be taken to avoid coughing to prevent spread of secretions during extubation. A surgical mask, wet gauze, or clear plastic drape may be placed over the patient’s mouth and nose while the ETT is still in place just prior to extubation. For management of the difficult airway, the basic principles for management of the difficult airway also apply to patients with COVID-19. In general, awake fiberoptic intubation should be avoided and if it is required, the airway should be anesthetized using topical local anesthetic ointment or gel, and/or nerve blocks. Nebulized and transtracheal injection of local anesthetic should be avoided.

Regional Anesthesia The advantage of regional anesthesia over general anesthesia in COVID-19 patients is that risk of aerosolization of respiratory secretions can be avoided and it should be used for lower extremity and lower abdominal surgery if not contraindicated. A few small randomized controlled studies suggest better outcome with neuraxial technique

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Section 23:  COVID-19 Related Issues compared to general anesthesia.38 Many COVID-19 patients are receiving anticoagulants which affect the timing of or decision to use neuraxial anesthesia or deep peripheral nerve blocks. If the procedure is decided to be performed under regional anesthesia alone, a surgical mask should be placed on patient’s mouth and nose at all times. For the patients requiring oxygen supplementation, minimal possible flow to maintain the oxygen saturation of around 94% should be used. The oxygen face mask should be placed over the surgical mask, while the nasal prongs under a surgical mask.

PERIOPERATIVE CONCERNS FOR PATIENTS WITH LONG COVID AND POST-COVID As the wrath of the pandemic is on the declining phase, lots of population is waiting for the elective surgeries. But, these patients who were tested positive for COVID-19 previously need to be evaluated thoroughly before taking the patient under anesthesia. Various anesthesia societies have sug­ gested thorough preanesthetic check-up for ruling out all the risks associated with respiratory, cardiac, renal, and neurological complications in the perioperative period. Clinical systemic manifestations in post-COVID phase are as follows: ■ Pulmonary: After recovery from the acute phase, the degree of lung involvement varies from minimal lung involvement to restrictive lung disease. The degree of lung involvement depends on the age of the patient, severity of illness, duration of ICU stay, and mechanical ventilation.22,39 Airway hyper-reactivity may persist for 2–6 weeks following acute infection. Therefore, pulse oximetry, 6-minute walk test, and screening pulmonary function tests should be done prior to taking patients for surgery under anesthesia. High-resolution computed tomography (HRCT) of the thorax and pulmonary angiography may be warranted in some patients to see whether lungs have progressive disease or recovered from the insult. ■ Cardiac: Direct damage to myocardium has been reported during the acute phase which may have prolonged effects in few patients. This may present with varied symptoms such as chest pain, palpitations owing to dysrhythmia, and cardiomyopathy. Decreased perfusion may be evident on cardiac magnetic resonance imaging (MRI). Routine electrocardiography (ECG) and transthoracic echocardiography are advisable in patients presented for surgery 2–6 months after acute phase.40,41 ECG may reveal ST-T changes, inversions of T wave, and abnormalities in PR intervals. Echocardiography will help differentiate myocarditis from myocardial infarctions and regional wall motion abnormalities. N-terminal pro-brain natriuretic peptide (NT-pro-BNP) was considered mandatory for all minor and major surgeries in a few studies.42

■ Renal: The kidney insult due to the virus may be due

to direct inflammation and injury and due to direct viral injury through angiotensin-converting enzyme 2 (ACE-2) receptors. Preoperative evaluation of kidney functions such as serum creatinine and blood urea nitrogen is advised to rule out the degree of kidney damage.40 ■ Neurological: Due to direct damage to the olfactory nerves, the patients might have persistent loss of smell (11–13%) and taste (7–9%).3 Patient may present with other neurological clinical manifestations such as encephalitis, convulsions, stroke, and demyelinating neuropathy. Patients who present with demyelinating neuropathy requiring anesthesia are tough to manage. Optimal use of opioids and neuromuscular blockers is needed. Quantitative neuromuscular monitoring should be done intraoperatively to guide about the appropriate timing of administering neuromuscular blockers and reversal of neuromuscular blockade. Regional anesthesia is well avoided in these subsets of patients.40 ■ Hematological system: COVID-19 infection is a prothrombotic state. These patients are prone to develop thrombosis due to the ongoing inflammation and immobility associated with the disease state. They may present with ischemic strokes and limb ischemia. Thromboprophylaxis should be taken into considera­ tion if started, both mechanical and pharmacological. Early mobilization should be encouraged as per enhanced recovery after surgery (ERAS) protocol.40 Coagulation profile should be assessed preoperatively. ■ Decreased functional status: 59–81% patients showed weakness, fatigue, and decreased mobility even after 6 months of acute infection.3,4 They may also present with psychological distress symptoms such as anxiety and depression. Professional rehabilitation programs are being planned for these patients, but due to lack of awareness, less of the people can take its advantage.4 A new health hazard has been reported in postCOVID phase as large number of patients are presenting with rhinocerebral mucormycosis. Those patients having a history of reverse transcription polymerase chain reaction (RT-PCR) tested positive for COVID-19, immunocompromised, or raised sugar levels are prone to it. It was declared as epidemic and a notifiable disease in many states of India. Its management became more com­plicated due to scarcity of relevant antifungal drugs and their side effects. 43 They are being regularly posted for debridement of the affected area and the surgery is quite debilitating. Besides, other complica­tions which are common to other type of surgeries post-COVID, the anesthesiologists may face an additional chal­lenge of difficult airway.43 There is high likelihood of these patients going for postoperative mechanical ventilation.

Chapter 145:  Perioperative Concerns in COVID TABLE 1: Suggested timing for elective surgeries after diagnosis of COVID. Patients condition during acute S. No. phase

Suggested wait time from the date of COVID diagnosis and surgery

1.

Asymptomatic or mild nonrespiratory symptoms

4 weeks

2.

Symptomatic but did not require 6 weeks hospitalization (mild COVID illness)

3.

8–10 weeks Symptomatic who require hospitalization (moderate COVID illness)

4.

Patient who require ICU admission 12 weeks (severe COVID illness)

(ICU: intensive care unit) Adapted from: American Society of Anesthesiologists and Anesthesia Patient Safety Foundation joint statement on elective surgery and anesthesia for patients with COVID-19

Recommendations44 ■ The timing for elective surgery in post and long-COVID is

summarized in Table 1. ■ There should be a multidisciplinary discussion and

decision regarding taking up the patient for elective surgery at 7 weeks post-COVID. All the factors regarding clinical status, symptoms, degree of systemic involve­ ment, and urgency of surgery depending on the disease progression should be taken under consideration. ■ Elective surgery done within 7 weeks of contracting the disease has high mortality rates. It should only be done in cases of disease progression with calculated risk. ■ Those patients who are symptomatic need special consideration after 7 weeks. ■ The patients who are symptomatic even till 7 weeks have high mortality rate, so they should be taken for surgery only if necessary. ■ Vaccinations given to patients a few weeks before planned surgery might be protective for the patient and limit spread of nosocomial infection to other people. Hence, patients with COVID-positive status (present or past) and scheduled for surgery (elective or emergency) pose challenge to the anesthesiologists. A thorough under­standing of the associated pathophysiology of the disease process and infection control practices are of utmost importance while caring for these patients. A multidisciplinary team approach is required for adequate perioperative management of these patients.

REFERENCES 1. WHO Coronavirus (COVID-19) Dashboard | WHO Coronavirus (COVID-19) Dashboard with Vaccination Data. [online] Available from: https://www.who.int/ [Last accessed March, 2022].

2. Ministry of Health and Family Welfare, Government of India. Homepage. [online] Available from: https://www.mohfw.gov. in/ [Last accessed March, 2022] 3. Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet. 2021;397(10270):220-32. 4. The Lancet. Understanding long COVID: a modern medical challenge. Lancet. 2021;398(10302):725. 5. Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27(4):601-15. 6. Malhotra N, Bajwa SJ, Joshi M, Mehdiratta L, Hemantkumar I, Rani RA, et al. Perioperative management of post‑COVID‑19 surgical patients: Indian Society of Anaesthesiologists (ISA National) Advisory and Position Statement. Indian J Anaesth. 2021;65(7):499-507. 7. Mehta Y, Chaudhry D, Abraham OC, Chacko J, Divatia J, Jagiasi B, et al. Critical care for COVID-19 affected patients: Position statement of the Indian Society of Critical Care Medicine. Indian J Crit Care Med. 2020;24(4):222-41. 8. WHO. Infection prevention and control during health care when novel coronavirus disease (COVID-19) is suspected or confirmed. [online] Available from: https://www.who. int/publications/i/item/WHO-2019-nCoV-IPC-2021.1 [Last Accessed March, 2022]. 9. Wax RS, Christian MD. Practical recommendations for critical care and anesthesiology teams caring for novel Coronavirus (2019-nCoV) patients. Can J Anesth. 2020;67(5):568-76. 10. Park J, Yoo SY, Ko JH, Lee SM, Chung YJ, Lee JH, et al. Infection prevention measures for surgical procedures during a Middle East Respiratory Syndrome outbreak in a tertiary care hospital in South Korea. Sci Rep. 2020;10:325. 11. Missair A, Marino MJ, Vu CN, Gutierre J, Missair A, Osman B, et al. Anesthetic implications of Ebola patient management: A review of the literature and policies. Anesth Analg. 2015;121(3):810-21. 12. Chen Y, Liu Q, Guo D. Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol. 2020;92(4):418-23. 13. Perioperative considerations for the 2019 Novel Coronavirus (Covid-19). Anesthesia Patients Safety Foundation Newsletter; February 2020. [online] Available from: https:// www.apsf.org/news-updates/perioperative-considerationsfor-the-2019-novel-coronavirus-covid-19/ [Last accessed March, 2022]. 14. American Society of Anesthesiologists Committee on Occupational Health: Coronavirus Information for Health Care Professionals (Clinical FAQs). [online] Available from: https://www.asahq.org/about-asa/governance-andcommittees/asa-committees/committee-on-occupationalhealth/coronavirus/clinical-faqs [Last accessed March, 2022]. 15. El-Boghdadly K, Wong DJN, Owen R, Neuman MD, Pocock S, Carlisle JB, et  al. Risks to healthcare workers following tracheal intubation of patients with COVID-19: a prospective international multicentre cohort study. Anaesthesia. 2020; 75(11):1437-47. 16. Liu M, Cheng SZ, Xu KW, Yang Y, Zhu Q, Zhang H, et al. Use of personal protective equipment against coronavirus disease 2019 by healthcare professionals in Wuhan, China: cross sectional study. BMJ. 2020;369:m2195.

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Section 23:  COVID-19 Related Issues 17. Cook TM, Lennane S. Occupational COVID-19 risk for anaesthesia and intensive care staff - low-risk specialties in a highrisk setting. Anaesthesia. 2021;76(3):295-300. 18. Okamoto K, Rhee Y, Schoeny M, Lolans K, Cheng J, Reddy S, et  al. Impact of doffing errors on healthcare worker selfcontamination when caring for patients on contact precautions. Infect Control Hosp Epidemiol. 2019;40(5): 559-65. 19. Tomas ME, Kundrapu S, Thota P, Sunkesula VC, Cadnum JL, Mana TS, et al. Contamination of health care personnel during removal of personal protective equipment. JAMA Intern Med. 2015;175(12):1904-10. 20. COVIDSurg Collaborative. Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study. Lancet. 2020;396(10243):27-38. 21. Doglietto F, Vezzoli M, Gheza F, Lussardi GL, Domenicucci M, Vecchiarelli L, et al. Factors associated with surgical mortality and complications among patients with and without coronavirus disease 2019 (COVID-19) in Italy. JAMA Surg. 2020;155(8):691-702. 22. COVIDSurg Collaborative, GlobalSurg Collaborative. Timing of surgery following SARS-CoV-2 infection: an international prospective cohort study. Anaesthesia. 2021;76(6):748-58. 23. American Society of Anesthesiologists. COVID-19 and Elective Surgery. [online] Available from: https://www.asahq. org/in-the-spotlight/coronavirus-covid-19-information/ elective-surgery [Last accessed March, 2022]. 24. United States Food and Drug Administration. Letter. [online] Available from: https://www.fda.gov/media/137856/ download. [Last accessed March, 2022]. 25. FAQ on Anesthesia Machine Use, Protection, and Decontamination during the COVID-19 Pandemic. American Society of Anesthesiologists Committee on Occupational Health: Coronavirus. Information for Health Care Professionals (Clinical FAQs). [online] Available form: https://www.apsf.org/faq-on-anesthesia-machine-use-protection-and-decontamination-during-the-covid-19-pandemic/ [Last accessed March, 2022]. 26. Dexter F, Parra MC, Brown JR, Loftus RW. Perioperative COVID-19 defense: An evidence-based approach for optimization of infection control and operating room management. Anesth Analg. 2020;131(1):37-42. 27. Yao W, Wang T, Jiang B, Gao F, Wang L, Zheng H, et  al. Emergency tracheal intubation in 202 patients with COVID19 in Wuhan, China: lessons learnt and international expert recommendations. Br J Anaesth. 2020;125(1):e28-e37. 28. Orser BA. Recommendations for endotracheal intubation of COVID-19 patients. Anesth Analg. 2020;130(5):1109-10. 29. Cook TM, El-Boghdadly K, McGuire B, McNarry AF, Patel A, Higgs A. Consensus guidelines for managing the airway in patients with COVID-19: Guidelines from the Difficult Airway Society, the Association of Anaesthetists the Intensive Care Society, the Faculty of Intensive Care Medicine and the Royal College of Anaesthetists. Anaesthesia. 2020;75(6):785-99. 30. Cook TM, McGuire B, Mushambi M, Misra U, Carey C, Lucas N, et al. Airway management guidance for the endemic phase of COVID-19. Anaesthesia. 2021;76(2):251-60.

31. Hall D, Steel A, Heij R, Eley A, Young P. Videolaryngoscopy increases 'mouth-to-mouth' distance compared with direct laryngoscopy. Anaesthesia. 2020;75(6):822-23. 32. Tsui BCH, Pan S. Are aerosol-generating procedures safer in an airborne infection isolation room or operating room? Br J Anaesth. 2020;125(6):e485-87. 33. Canelli R, Connor CW, Gonzalez M, Nozari A, Ortega R. Barrier enclosure during endotracheal intubation. N Engl J Med. 2020;382(20):1957-58. 34. Malik JS, Jenner C, Ward PA. Maximising application of the aerosol box in protecting healthcare workers during the COVID-19 pandemic. Anaesthesia. 2020;75(7):974-75. 35. Hellman S, Chen GH, Irie T. Rapid clearing of aerosol in an intubation box by vacuum filtration. Br J Anaesth. 2020;125(3): e296-e99. 36. Tsui BCH, Deng A, Lin C, Okonski F, Pane S. Droplet evacua­tion strategy for simulated coughing during aerosolgenerating procedures in COVID-19 patients. Br J Anaesth. 2020;125(3):e299-301. 37. United States Food and Drug Administration. Protective barrier enclosures without negative pressure used during the COVID-19 pandemic may increase risk to patients and health care providers - Letter to health care providers. [online] Available from: https://www.fda.gov/medical-devices/ letters-health-care-providers/protective-barrier-enclosureswithout-negative-pressure-used-during-covid-19-pandemicmay-increase [Last accessed March, 2022]. 38. Elsharydah A, Li FC, Minhajuddin A, Gabriel RA, Joshi GP. Risk score for major complications after total hip arthroplasty: the beneficial effect of neuraxial anesthesia. A retro­ spective observational study. Curr Orthop Pract. 2020;31(2): 156-61. 39. Ojo AS, Balogun SA, Williams OT, Ojo OS. Pulmonary Fibrosis in COVID-19 Survivors: Predictive Factors and Risk Reduc­ tion Strategies. Pulm Med. 2020;2020:6175964. 40. Hoyler MM, White RS, Tam CW, Thalappillil R. Anesthesia and the “post-COVID syndrome”: Perioperative considerations for patients with prior SARS-CoV-2 infection. J Clin Anesth. 2021;72:110283. 41. Davido B, Seang S, Tubiana R, de Truchis P. Post-COVID-19 chronic symptoms: a postinfectious entity? Clin Microbiol Infect. 2020;26(11):1448–9. 42. Bui N, Coetzer M, Schenning KJ, O’Glasser AY. Preparing previously COVID-19-positive patients for elective surgery: a framework for preoperative evaluation. Perioper Med. 2021;10(1):1-4. 43. Gupta KK, Singh A, Kalia A, Kandhola R. Anaesthetic considerations for post-COVID-19 mucormycosis surgery‑ A case report and review of literature. Indian J Anaesth. 2021; 65(7):545-7. 44. El-Boghdadly K, Cook TM, Goodacre T, Kua J, Blake L, Denmark S, et  al. SARS-CoV-2 infection, COVID-19 and timing of elective surgery: A multidisciplinary consensus statement on behalf of the Association of Anaesthetists, the Centre for Perioperative Care, the Federation of Surgical Specialty Associations, the Royal College of Anaesthetists and the Royal College of Surgeons of England. Anaesthesia. 2021;76(7):940-46.

146

Prolong Sedation, Analgesia, and Paralysis in COVID-19— Adverse Outcome

C H A P T E R Palepu B Gopal, VVSSD Prasanthi

INTRODUCTION Severe COVID-19 pneumonia patients with acute respira­ tory distress syndrome required prolonged period of sedation in high doses and continued paralyzing agents for endotracheal intubation and controlled ventilation.1 The clinical practice guidelines from the Society of Critical Care Medicine (SCCM) recommend a strategy of light sedation rather than deep sedation and utilization of nonbenzodiazepines for mechanical ventilation to decrease ventilator days, tracheostomy rate, and intensive care unit (ICU) length of stay.2 But deep sedation and continued paralysis were favored by ICU staff for controlled ventilation of COVID-19 patients in view of the unique pathophysiology of COVID-19 which includes high respiratory drive, impaired lung compliance, intense inflammatory response linked to tolerance to sedative agents,3 and severe ventilator dyssynchrony. Many patients required prone ventilation to improve gas exchange and the number of patients who required extracorporeal membrane oxygenation (ECMO) increased during COVID-19 pandemic. Severity of respiratory failure requiring prolonged mechanical ventilation median duration of 7–12 days, high workload on healthcare workers, reduced bedside availability of critical care staff, shortages of personal protective equipment (PPE), increased risk of accidental self-extubation, and risk of infection transmission to healthcare workers resulted in deep and prolonged sedation and paralysis. Each of these barriers, and several others, have led to increased and prolonged sedation use and requirement of combinations of multiple agents thereby increasing potential risks of side effects such as drug accumulation (midazolam), tolerance, tachyphylaxis (dexmedetomidine), hypertriglyceridemia (propofol), QT interval prolongation (haloperidol), psychotomimetic effects (ketamine), hyperalgesia, opioid dependence (fentanyl and/or hydro­ morphone), and delirium (midazolam). Prolonged and high-dose usage of sedative and paralyzing drugs gave rise to shortage of these agents, potential for increased rate of physical and psychological dependence, acute brain

dysfunction, and intensive care unit-acquired weakness (ICUAW).

SEDATION IN NONINVASIVE VENTILATION Sedation can typically decrease the respiratory drive in young COVID-19 patients who have high respiratory drive and no dyspnea when breathing spontaneously. Muriel et al. in 2015 compared three group of patients with no sedation, only analgesia, and sedation plus analgesia for outcome of noninvasive ventilation (NIV) failure and 28-day mortality rate. They found that these two outcome measures were increased with use of sedation and/or analgesia. There­fore, sedation in COVID-19 patients during NIV was not recommended. If the patient’s condition worsens, the only solution is to intubate and initiate invasive mechanical ventilation.

BRAIN AND SEDATION Acute Brain Dysfunction Delirium prevalence is reported up to 11–12% among COVID-19 hospitalized patients.4 Acute brain dysfunction in COVID-19 patients occurs due to neuroinflammation, possibly due to viral invasion through olfactory nerves, systemic brain injury related to hypoxia, endotheliitis, multiorgan involvement, procoagulant nature of the disease, and the effects of heavy sedative strategies, especially benzodiazepines. Other factors such as immobilization, prolonged mechanical ventilation, and social isolation from families4 also added to this dysfunction. In a cohort study, mechanically controlled and ventilated COVID-19 patients had a median Richmond Agitation Sedation Scale (RASS) of −4 [interquartile range (IQR), −5 to −3] and, during the 21-day study period, the median number of days alive and free of coma or delirium were only 5 days (IQR, 0.0–14.0).4 Additionally, approximately about two-third of patients received benzodiazepines for a median of 7.0 days (4.0–12.0) (Figs. 1A and B). Controlled ventilation, use of restraints, and sedatives were the factors associated with a higher risk of delirium the next day.

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Section 23:  COVID-19 Related Issues

A

B Figs. 1A and B: Level of sedation, respiratory support, mortality, and intensive care unit (ICU) discharge in COVID-19 patients. (Source: Pun BT, Badenes R, Heras La Calle G, Orun OM, Chen W, Raman R, et al. Prevalence and risk factors for delirium in critically ill patients with COVID-19 (COVID-D): A multicentre cohort study. Lancet Resp Med. 2021;9(3):239-50).

The potential significant adverse outcomes included prolonged controlled ventilation, delirium, increased morbidity and mortality, and long-term sequelae of the postintensive care syndrome (PICS), which included cognitive impairment.

Delayed Emergence of Consciousness Sustained high levels of sedation and neuromuscular paralysis facilitate lung protective ventilation and ventilator synchrony in COVID-19 patients with acute respiratory distress syndrome, but may delay recovery of consciousness and impair neurologic outcome.5 The consequences of sedatives on cognition dysfunction are well-established.5 Neurological examination alone cannot guide sedative dosing because comatose patients who are adequately sedated appear identical on examination to those who are highly sedated. This can be guided by electroence­ phalogram (EEG) examination which appear as slow delta oscillations in adequate sedation and burst suppression in high levels of sedation. Continuous EEG monitoring in COVID-19 patients is practically not possible for obvious reasons.

Iatrogenic Withdrawal Syndrome  The prolonged use of opioids and benzodiazepines during the ICU stay and pre-existing comorbidities results in iatrogenic withdrawal syndrome, which is defined as “a constellation of signs and symptoms that can be induced by abruptly stopping or reducing the dose of a sedative, reducing plasma concentration, and administering an antagonist of that drug.”6 Tolerance is defined as a decrease in the pharmaco­ logical action of a drug after its continuous use (Table 1).6 Opioid-induced hyperalgesia (OIH) is a different pheno­ menon and is defined as paradoxically exaggerated res­ ponse to pain due to continuous use of an opioid.7 Prolonged benzodiazepines use increased risk of withdrawal and prolonged mechanical ventilation, especially in elderly patients. Prolonged therapy with opioids can cause physiological and psychological dependence.

CARDIOVASCULAR COMPLICATIONS Sedatives such as dexmedetomidine cause exaggerated hemodynamic instabilities, such as hypotension,

Chapter 146:  Prolong Sedation, Analgesia, and Paralysis in COVID-19—Adverse Outcome TABLE 1: Definitions of withdrawal syndromes.6 Term

Definition

Tolerance

A decrease in response to a drug dose that occurs with continued use; increasing doses are needed to achieve the effect originally produced by regular doses

Physical dependence

A state of adaptation that manifests through a drug class-specific withdrawal syndrome

Psychological dependence

A subjective sense of need for a specific psychoactive substance, either to obtain its positive effects or to avoid negative effects associated with abstinence

brady­c ardia, and heart block in critically ill COVID patients. Propofol induces a dose-dependent decrease in the systemic vascular resistance and myocardial contractility, 8 which may worsen the pre-existing hemodynamic instability in COVID-19 patients with septic shock or cardiogenic shock. Morphine has potential of histamine release leading to hypotension. Patients with COVID-19 are known to develop myocardial injury, viral myocarditis, and stress cardiomyopathy.8 Further sedatives induced decrease in myocardial contractility, hypotension, and heart block leads to decreased endorgan perfusion which may not be well-tolerated in these patients.

PULMONARY COMPLICATIONS At high doses and rapid infusion, fentanyl is associated with chest wall rigidity, which can decrease compliance and lead to inappropriate ventilation which can be a potentially devastating complication in the critically ill patient with COVID-19.9

NEUROMUSCULAR COMPLICATIONS Critical care management grabs the attention of intensivist during the acute phase of illness and neuromuscular complications such as ICUAW and positioning-related peripheral nerve injuries are less taken care. Muscle atrophy starts within 4 hours of inactivity due to degradation and programmed myocyte death. Prolonged sedation and paralysis lead to immobility and muscle inactivity leading to disuse atrophy which is the major cause for critical illness neuromyopathy. Critical illness polyneuropathy and myopathy were predominant in severe COVID-19 who required mechanical ventilation. ICUAW is caused by either critical illness polyneuropathy or critical illness myopathy. 10 Respiratory muscles weakness can lead to difficult weaning from mechanical ventilation. ICUAW is associated with prolonged stays in the ICU and a major contributor for physical impairment and dysfunction following ICU stay. 10 ICUAW is potentiated

by the other risk factors associated with COVID-19 which include drugs such as corticosteroids and aminoglycosides, and hyperglycemia, which is an invariable consequence of steroid usage. The long-term consequences of ICUAW are indistinguishable from several features of postcritical care myoneural and pathological syndromes such as postinfective polyneuropathy. These will have significant effect on recovery and quality of life and may necessitate long-term neurorehabilitation with attendant complica­ tions (Fig. 2).

GASTROINTESTINAL EFFECTS COVID-19 patients have virus attaching to angiotensinconverting enzyme 2 (ACE-2) receptors expressed on gut causing activation of inflammation and paralytic ileus. This is aggravated by opioid sedation induced risk of hypomotility, abdominal distention, and other related complications increasing risk of pulmonary aspiration impairing ventilation. Prone ventilation further augments this risk by increasing intra-abdominal pressure due to physical compression. Hypomotility leads to intolerance to feeds and malnutrition in prolong ICU stay. Prolonged and high-dose propofol infusions can independently result in elevated levels of triglycerides, thereby increasing the risk of pancreatitis.

DRUG-RELATED ADVERSE EFFECTS Seizures Prolonged and higher doses of sedatives such as lorazepam lead to propylene glycol toxicity. Intravenous (IV) lorazepam has a solvent named propylene glycol (1,2-propanediol). Propylene glycol has been associated with toxicity in highdose and/or prolonged lorazepam therapy. This is clinically characterized by cardiac arrhythmia, seizures, lactic acidosis, hypotension, and agitation. Propylene glycol toxicity should be considered whenever a patient has an unexplained anion gap metabolic acidosis in patients receiving high doses of IV lorazepam.

Propofol-related Infusion Syndrome Propofol-related infusion syndrome is a rare condition that may occur with prolonged (>48 hours) and higher-dose (>4–5 mg kg−1 h−1) of propofol infusions.8 It is manifested with refractory bradycardia, metabolic acidosis, rhabdomyolysis, hyperlipidemia, enlarged liver, and hyperkalemia. This should be treated by stopping the infusion and providing supportive measures. Some patients may require hemodialysis, or even ECMO in severe cases. Inability to stop or lower the dose of propofol while supporting adequate sedation becomes problematic in patients presenting with COVID-19. 

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Fig. 2: Adverse events vicious cycle secondary to prolonged and high-dose sedation and paralysis. (ICU: intensive care unit; ICUAW: intensive care unit-acquired weakness)

Hypertriglyceridemia COVID-19 may increase potential risk factors for triggering hemophagocytic lymphohistiocytosis (HLH).11 Con­comitant use of sedatives such as propofol for prolonged period results in hypertriglyceridemia and cytokine storm in a subset of COVID-19 patients deviating the intensivist in the diagnosis of HLH. The HLH presenting features are fever, cytopenia, hypertriglyceridemia, elevated ferritin, elevated lactate dehydrogenase (LDH), and abnormal liver function tests. Hypertriglyceridemia, defined as a blood level >150 mg/ dL, is a major risk factor for cardiovascular events,12 leading healthcare providers to choose sedatives other than propofol for sedation.

Drug Shortages and Sustained Utilization of Intensive Care Unit Resources Drug shortages have resulted in usage of alternative sedation strategies and agents apart from regular sedation strategies thereby increasing drug interactions and associated side effects. Increased use of sedatives in pandemic has led to worsening shortages, ultimately forcing some hospitals to ration supplies and others to go without the same. Propofol has been listed as a drug in shortage since 2018, has seen an enhanced usage during the COVID-19 pandemic. Food and Drug Administration (FDA) and American Society of Health-System Pharmacists cited 10 sedative and analgesic agents shortage in their databases including propofol and dexmedetomidine.13 Ketamine has wide variety of advantages in critical illness, including in pain management, in postoperative

analgesia, in refractory status epilepticus, and as adjunctive sedation. Ketamine will have an opioid-sparing effect owing to its analgesic property. Although ketamine is associated with hypertension and tachycardia, it may also decrease cardiac function in some subsets of critically ill patients, including those with septic shock. It is also associated with psychotomimetic effects which should be addressed.

Drug Interactions Attention must be paid to the potential interaction between sedative agents and other drugs administered as part of treatment and about 300 international clinical trials are currently underway. Hydroxychloroquine and haloperidol combination can cause significant QT prolongation. Metabolism of hydroxychloroquine is increased with concomitant administration of barbiturates. In patients with high fever, dexmedetomidine may need to be stopped to understand the cause of the fever. Barbiturates may increase metabolism of other drugs as they are P450 enzyme inducers.

Drug Accumulation Polypharmacy in COVID-19 patients along with multi­ organ dysfunction leads to significant pharmacokinetic and pharmacodynamic (pK/pD) alterations. Prolonged infusions may also lead to drug accumulation which is significant in critically ill COVID-19 patients. Fentanyl undergoes CYP3A4 metabolism, the derangement of which in hepatic dysfunction can lead to its accumulation.

Chapter 146:  Prolong Sedation, Analgesia, and Paralysis in COVID-19—Adverse Outcome Morphine has active metabolites such as morphine 6 glucuronide that can accumulate in the setting of renal failure, leading to neurotoxicity. The incidence of acute kidney injury (AKI) has been reported recently to be around 25% in COVID-19 patient who are critically ill. Hence, drug accumulation and associated side effects are common with prolonged infusions of high doses of sedatives and analgesics such as 1-hydroxymidazolam, active metabolite of midazolam, which is eventually excreted by the kidneys and can accumulate during prolonged infusions in AKI.

Quality of Life

Sedation-induced Intensive Care Unit-acquired Infections

Deep and prolonged sedation associated with longer time to extubate, and prolonged ICU stay leads to higher mortality rate at 3 months after ICU discharge. Prolonged sedation and paralysis can be one of the attributable factors for increased mortality and morbidity.

Prolonged duration of therapy may also result in develop­ ment of long-term adverse effects including B and T cellmediated immune dysfunction. Prolongation sedation and paralysis in the presence of risk factors for infection, microaspiration, gastrointestinal motility disturbances, microcirculatory effects, and immunomodulatory effects increase the incidence of infection in critically ill COVID-19 patients.14

Venous Thromboembolism Neuromuscular blockade in conjunction with deep sedation presents added risk for COVID-19 patients due to its hypercoagulable state. Since patients are immobilized, there is the potential for increased rates of deep venous thromboembolism,15 primary pulmonary artery thrombosis, and arterial thrombosis. This along with a hypercoagulable state has led to various grades of pulmonary embolism with an incidence of 16.7%,16 with attendant morbidity and mortality in COVID-19 patients.

Difficult Weaning Sedatives with longer half-life cause delay in extubation especially in patients with proximal muscle weakness, diaphragmatic weakness, and decreased respiratory reserve. This is further complicated by delayed excretion of drugs depending on renal and hepatic metabolism, which is commonly deranged in these patients.

Microcirculatory Effects of Sedation Sedation may alter tissue perfusion when already compromised, as in septic patients, and contributes to the development of multiorgan failure.17 Benzodiazepines can induce an increase in cutaneous blood flow secondary to vasodilation, a decrease in reactive hyperemia, and alterations of vasomotion. It has been proved in clinical studies that alterations of normal microcirculatory control mechanisms may contribute to the development of organ failure in septic patients through compromise in the tissue nutrient blood flow.17,18

Over sedation synergistically acts with other risk factors such as pulmonary impairment, ICUAW, cognitive dysfunction, physical impairment, and psychiatric dysfunction leading to poor functional outcomes. Critically ill patients with COVID-19 will likely have delayed recovery from physical and cognitive impairment which may significantly impact the quality of life.

Increased Mortality and Morbidity

CONCLUSION Prolong sedation, analgesia, and paralysis in COVID-19 patients have been a necessary evil with inevitable attendant adverse consequences. Some of these adverse conse­quences were quite troublesome, even after successful recovery from COVID-19 and continued to haunt the patient long after necessitating prolonged rehabilitation. This phase was not without complications, some of which added to morbidity and mortality. Clear understanding of etiopathogenesis of these syndromes and strategies to mitigate the same will lessen the incidence of the syndromes and complications in these patients and reduce the burden on healthcare systems.

REFERENCES 1. Kapp CM, Zaeh S, Niedermeyer S, Punjabi NM, Siddharthan T, Damarla M. The use of analgesia and sedation in mecha­ nically ventilated patients with COVID-19 ARDS. Anesth Analg. 2020:10.1213/ANE.0000000000005131. 2. Devlin JW, Skrobik Y, Gélinas C, Needham DM, Slooter AJC, Pandharipande PP, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018;46(9):e825-73. 3. Martyn JAJ, Mao J, Bittner EA. Opioid tolerance in critical illness. N Engl J Med. 2019;380(4):365-78. 4. Pun BT, Badenes R, Heras La Calle G, Orun OM, Chen W, Raman R, et  al. Prevalence and risk factors for delirium in critically ill patients with COVID-19 (COVID-D): A multi­ centre cohort study. Lancet Respir Med. 2021;9(3):239-50. 5. Edlow BL, Claassen J, Victor JD, Brown EN, Schiff ND. Delayed reemergence of consciousness in survivors of severe COVID19. Neurocrit Care. 2020;33(3):627-9. 6. Kampman K, Jarvis M. American Society of Addiction Medicine (ASAM) national practice guideline for the use of medications in the treatment of addiction involving opioid use. J Addict Med. 2015;9(5):358-67. 7. Carullo V, Fitz-James I, Delphin E. Opioid-induced hyperalgesia: A diagnostic dilemma. J Pain Palliat Care Pharmacother. 2015;29(4):378-84.

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Section 23:  COVID-19 Related Issues 8. Karamchandani K, Dalal R, Patel J, Modgil P, Quintili A. Challenges in sedation management in critically ill patients with COVID-19: A brief review. Curr Anesthesiol Rep. 2021;1-9. 9. Roan JP, Bajaj N, Davis FA, Kandinata N. Opioids and chest wall rigidity during mechanical ventilation. Ann Intern Med. 2018;168(9):678. 10. Hermans G, Van den Berghe G. Clinical review: Intensive care unit acquired weakness. Crit Care. 2015;19(1):274. 11. Henderson LA, Canna SW, Schulert GS, Volpi S, Lee PY, Kernan KF, et al. On the alert for cytokine storm: Immuno­ pathology in COVID-19. Arthritis Rheumatol. 2020;72(7): 1059-63. 12. Thompson WG, Gau GT. Hypertriglyceridemia and its pharmacologic treatment among US adults—invited commentary. Arch Intern Med. 2009;169(6):578. 13. Hubmayr RD, Abel MD, Rehder K. Physiologic approach to mechanical ventilation. Crit Care Med. 1990;18(1):103-13.

14. Nseir S, Makris D, Mathieu D, Durocher A, Marquette CH. Intensive care unit-acquired infection as a side effect of sedation. Crit Care. 2010;14(2):R30. 15. Murray MJ, Deblock H, Erstad B, Gray A, Jacobi J, Jordan C, et al. Clinical Practice Guidelines for Sustained Neuromuscular Blockade in the Adult Critically Ill Patient. Crit Care Med. 2016;44(11):2079-103. 16. Helms J, Tacquard C, Severac F, Leonard-Lorant I, Ohana M, Delabranche X, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: A multicenter prospective cohort study. Intensive Care Med. 2020;46(6):1089-98. 17. De Backer D, Cortes DO, Donadello K, Vincent JL. Pathophysiology of microcirculatory dysfunction and the pathogenesis of septic shock. Virulence. 2014;5(1):73-9. 18. Sakr Y, Dubois MJ, De Backer D, Creteur J, Vincent JL. Persistent-microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med. 2004;32(9):1825-31.

147

Multisystem Inflammatory Syndrome in Adults

C H A P T E R Yatindra Dube, Akshaykumar Chhallani, Nirmal Jaiswal

INTRODUCTION In April 2020, few previously healthy pediatrics patients were identified suffering from clinical syndrome similar to Kawasaki disease and toxic shock syndrome.1 Shock, GI (gastrointestinal) abnormality, and cardiac dysfunction were the predominant symptoms in those patients. This was latter labeled as multisystem inflammatory syndromechildren (MIS-C). Centers for Disease Control and Prevention (CDC) reported 3,185 similar cases in April 2020.2 Similar to these cases, various case reports and case series were published in adult population and were labeled as multisystem inflammatory syndrome-adults (MIS-A).3 Unfortunately, as in pediatrics, there is lack of high-quality data to guide diagnosis and treatment of MIS-A and most of the management is guided either by experiences from case reports or small case series.

ETIOPATHOGENESIS Although pathogenesis of MIS-A is not very clear, virusinduced endothelial dysfunction and coagulopathy are the main identified pathological features. Endothelialitis and complement deposition in the vessels of affected organ have been found to be pathognomonic feature of MIS-A. This deposition causes cardiac dysfunction, skin rash, and gastrointestinal symptoms.4

DIAGNOSIS Contrary to MIS in children, diagnostic criteria in adults lack a clarity. Septic shock and flare of collagen vascular disease are very close differential diagnosis for MIS-A. The potential role of procalcitonin as a rapid diagnostic marker to differentiate between sepsis and MIS-A which have two different mechanism of systemic inflammatory response remains vital. Centers for Disease Control and Prevention has recommended following clinical criteria to diagnose MIS-A.2 ■ A severe illness requiring hospitalization—aged ≥21 years.

■ A positive test result of SARS-CoV-2 infection either by

polymerase chain reaction (PCR) or antigen or serology during admission or in the previous 12 weeks. ■ Severe dysfunction of one or more extrapulmonary organ systems (e.g., hypotension or shock, cardiac dysfunction, arterial or venous thrombosis or thromboembolism, or acute liver injury). ■ Laboratory evidence of severe inflammation as evidenced by abnormally high values of CRP [C-reactive protein, ferritin, D-dimer, interleukin (IL)-6]. ■ Absence of severe respiratory illness (to exclude patients in which inflammation and organ dysfunction might be attributable simply to tissue hypoxia). ■ There should not be alternative diagnosis and no obvious microbiological cause. In MIS-C, skin manifestations were more common in the younger cohort, while myocarditis and gastrointestinal symptoms were more frequent in older children. Similar findings were noted by Davogustto et al. who identified GI symptoms were more common in adults.4

TREATMENT High-quality evidence for an optimal treatment strategy for MIS-A is lacking. Good supportive medical management is mainstay in treating MIS-A and close monitoring of affected patients is very important.5,6 Though definitive evidence is lacking; intravenous immunoglobulins 2 g/kg and intravenous (IV) methylprednisolone 1–2 mg/kg/day can be tried. There are few case reports treated successfully with IL-1 receptor antagonist (anakinra) or high-dose methylprednisolone 10–30 mg/kg/day in refractory patients. This treatment is extrapolated from successful outcomes in MIS-C.

Vaccination following Multisystem Inflammatory Syndrome—Adults A conversation between the patient, their guardian(s), and their clinical team or a specialist (e.g., specialist in

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Section 23:  COVID-19 Related Issues infectious diseases, rheumatology, or cardiology) is strongly encouraged to assist with decisions about the use of COVID-19 vaccines as there is lack of data in this regard.7 CDC recommends vaccination in patients after MIS-A if: ■ Clinical recovery has been achieved, including return to normal cardiac function. ■ It has been ≥90 days since their diagnosis of MIS-C. ■ They are in an  area of high or substantial community transmission of SARS-CoV-2 or otherwise have an increa­ sed risk for SARS-CoV-2 exposure and transmission. ■ Onset of MIS-C occurred before any COVID-19 vaccination. Additional factors when considering individual benefits and risks may include: ■ An increased personal risk of severe COVID-19 (e.g., age and underlying conditions). ■ Timing of immunomodulatory therapies [Advisory Committee on Immunization Practices (ACIP)’s general best practice guidelines for immunization can be consulted for more information].

CONCLUSION ■ MIS-A is a potentially fatal clinical condition after SARS-

CoV-2 infection which is delayed hyperinflammatory immunological response. ■ It needs high clinical suspicion, acumen, and timely actions to diagnose and treat these patients in small window of opportunity to avoid fatalities. ■ Further research, encouragement to enroll in clinical trials, data sharing, and collaborations are needed to know utility of immunoglobulins, steroids, and other potential available treatment in the management protocol.

CONFLICT OF INTEREST The authors declare that they have no conflict of interest.

REFERENCES 1. Dufort EM, Koumans EH, Chow EJ, Rosenthal EM, Muse A, Rowlands J, et al. Multisystem inflammatory syndrome in children in New York State. N Engl J Med. 2020;383(4):347-58. 2. Centers for Disease Control and Prevention. (2020). Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19). CDC Health Alert Network. [online] Available from: https://www. mayoclinic.org/diseases-conditions/mis-c-in-kids-covid-19/ symptoms-causes/syc-20502550. [Last accessed March, 2022]. 3. Morris SB, Schwartz NG, Patel P, Abbo L, Beauchamps L, Balan S, et al. Case series of multisystem inflammatory syndrome in adults associated with SARS-CoV-2 infection— United Kingdom and United States, March–August 2020. Morb Mortal Wkly Rep. 2020;69(40):1450. 4. Davogustto GE, Clark DE, Hardison E, Yanis AH, Lowery BD, Halasa NB, et al. Characteristics associated with multisystem inflammatory syndrome among adults with SARS-CoV-2 infection. JAMA Netw Open. 2021;4(5):e2110323. 5. Chow EJ. The multisystem inflammatory syndrome in adults with SARS-CoV-2 infection—another piece of an expanding puzzle. JAMA Netw Open. 2021;4(5):e2110344. 6. Henderson LA, Canna SW, Friedman KG, Gorelik M, Lapidus SK, Bassiri H, et al. American College of Rheumatology clinical guidance for multisystem inflammatory syndrome in children associated with SARS-CoV‐2 and hyperinflammation in pediatric COVID‐19: Version 1. Arthritis Rheumatol. 2020;72(11):1791-805. 7. Centers for Disease Control and Prevention. (2021). Interim clinical considerations for use of COVID-19 vaccines currently authorized in the United States. [online] Available from: https://www.cdc.gov/vaccines/covid-19/clinicalconsiderations/covid-19-vaccines-us.html. [Last accessed March, 2022].

148

Lung Transplant Success Stories in COVID

C H A P T E R Vijil Rahulan, Unmil Shah, Sharanya Kumar

INTRODUCTION Novel coronavirus was declared a pandemic by WHO (World Health Organization) on 11 March 2020.1 At time of writing this article, WHO has recorded 240,940,937 SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) cases and 490,3911 fatalities across the globe.2 SARS-CoV-2 infection can lead to severe respiratory failure and acute respiratory distress syndrome (ARDS) requiring mechanical ventilation. The mortality of patients with critical coronavirus disease 2019 (COVID-19) is strikingly high, ranging between 15 and 74%, particularly when invasive mechanical ventilation (IMV) has been required.3 Some patients would require extracorporeal membrane oxygenation (ECMO) as a bridge to recovery (if initiated early) or as a bridge to lung transplantation. Estimated in-hospital mortality 90 days after ECMO initiation was 37.4%.4 Lung transplantation becomes the only life-saving option at that time for such post-COVID end-stage lung disease. Worldwide, lung transplantation has been performed for such severe post-COVID-19 fibrosis demonstrating irreversible lung damage, with acceptable early post-transplant outcomes. Between May 2020 and September 2021, our center has performed 25 lung transplants for post-COVID ARDS-related end-stage fibrosis who met the criteria for candidacy for transplantation. 24 were bridged with ECMO and 1 patient was a known case of interstitial lung disease who became COVID-19 positive and worsened, requiring continuous noninvasive ventilatory (NIV) support. We will briefly describe clinical summary of three such successful transplantation and discuss our standard of practice in perioperative management of these patients.

CASE #1 A 30-year-old previously healthy male was tested COVID19 positive and was admitted in a local hospital in Punjab. His computed tomography (CT) score was 22 on admission and he received steroid, tocilizumab, antibiotics, oxygen, and other supportive therapies. In view of increasing oxygen

requirement, he was intubated and ventilated 10 days later. Despite high ventilatory settings and prone position, he developed mixed respiratory failure and was put on VV-ECMO (venovenous extracorporeal membrane oxygenation) the next day. He was airlifted to our center the following day. He was admitted in our respiratory intensive care unit (ICU) and was treated as per standard protocol for COVID ECMO and ARDS ventilation and underwent tracheostomy on 5th day of admission. His respiratory compliance was poor and continued to be dependent of ECMO support. He had two episodes of gram-negative sepsis requiring low-dose pressors but responded well to appropriate antibiotics. After 4 weeks of ECMO and ventilatory assist, he could not be weaned and his CT chest displayed parenchymal damage, fibrosis, cystic changes, and traction bronchiectasis. After several rounds of discussion with team, the patient and family members, decision to proceed with lung transplantation was made. He was evaluated by multidisciplinary team and was registered at state’s cadaveric transplantation program. He received suitable organ call and successfully underwent bilateral lung transplant on 33rd day of initiation of ECMO. The intraoperative ischemia time was 390 minutes. He was weaned off ECMO in operating room and shifted to ICU with inotropes and nitric oxide. He was started on triple immunosuppression regimen and prophylactic antibiotics. He was gradually weaned of supports and tolerated increasing duration of tracheostomy mask. He developed airway anastomotic stenosis needing regular bronchoscopy and balloon dilatation. Tracheostomy was decannulated on 26th day and he was discharged on oral medications on 35th postoperative day (POD). On regular follow-up, 5 months later he was at home and did not require oxygen (Figs. 1A to D).

CASE #2 A 34-year-old male with no known comorbidities, had history of high-grade fever and was diagnosed COVID-19 positive. He was admitted with desaturation and started on

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Figs. 1A to D: Case 1# (A) Preoperative computed tomography (CT); (B) Chest X-ray (CXR) on extracorporeal membrane oxygenation (ECMO); (C) Pneumonectomy specimen showing nodular consolidation; and (D) Histopathology showing vascular thickening and thrombus.

noninvasive ventilation. In view of worsening hypoxemia, he was intubated on 6th day of admission. Respiratory failure aggravated and VV-ECMO was initiated after 3 days. Repeat reverse transcription polymerase chain reaction (RT-PCR) was negative for COVID-19. He was airlifted to our center after a week of ECMO initiation. He was in sepsis and had femoral hematoma on admission which was managed conservatively. Elective tracheostomy was done in anticipation of prolonged wean from ventilatory support. After 6 weeks, he continued to be ECMO dependent with poor respiratory compliance and gas exchange. Highresolution computed tomography of the chest (HRCT) showed diffuse fibrotic changes and the decision was made to evaluate and list for lung transplantation. He underwent bilateral lung transplantation on 52nd day of initiation of ECMO. Ischemia time was 320 minutes. On table, VV-ECMO weaned and decannulation done. On POD-3, he was tolerating intermittent bilevel positive airway pressure (BiPAP) and T-piece trial. On POD-9, he was shifted to ward with intermittent BiPAP/T-piece. On POD-14, tracheostomy decannulation was done. Gradually O2 was weaned off. In view of clinical improvement and hemodynamic stability, patient was discharged on 24th day after surgery. He recently completed 10 months of follow-up and not requiring oxygen (Figs. 2A to D).

CASE #3 A 64-year-old male, known chronic obstructive pulmonary disease (COPD) was found COVID-19 positive and was admitted with desaturation. He was started on oxygen support along with other COVID-19 treatment. He was continued with 25 L of oxygen via HFNC (high flow nasal cannula). He had low saturation even on HFNC and was put on mechanical ventilatory support. He was started on antifibrotics, antibiotics, steroids, and other supportive measures. He progressed to type II respiratory failure regardless of fully ventilatory support and multiple sessions of proning. VV-ECMO was initiated on day 9 of mechanical ventilation. With continued poor lung compliance and HRCT of the chest showing feature of end-stage lung disease, need for transplantation was explained. He was registered for lung transplantation, under supra urgent category. On waitlist, he was extubated and was supported with intermittent noninvasive ventilation. He received a transplant call on day 34 of ECMO initiation and was taken up for bilateral lung transplantation. Following transplant, he was shifted to ICU with inotropes, nitric oxide, VV-ECMO, and ventilatory support. VV-ECMO was weaned off on postoperative day 2. He was slowly weaned off ventilator and supported with intermittent NIV. Triple regimen

Chapter 148:  Lung Transplant Success Stories in COVID

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Figs. 2A to D: Case 2# (A) Computed tomography (CT) of the chest; (B) Chest X-ray (CXR) on extracorporeal membrane oxygenation (ECMO); (C) Pneumonectomy specimen showing cystic changes; and (D) Histopathology showing pneumocyte hyperplasia.

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Figs. 3A to D: Case #3 (A) Computed tomography (CT) of the chest; (B) Chest X-ray (CXR) on extracorporeal membrane oxygenation (ECMO); (C) pneumonectomy specimen showing fibrotic shrunken lung; and (D) histopathology showing interstitial fibrosis with honeycombing.

immunosuppressants were initiated. Bronchoscopy was done at periodic intervals to evaluate airway healing, anastomosis, and bronchial toileting. Patient was shifted to ward on postoperative day 14 with intermittent NIV support. Fungal culture grew Paecilomyces species and

was treated appropriately. In view of clinical improve­ ment and hemodynamic stability, patient was discharged on 28th postoperative day. On regular follow-up, 10 months later he was at home and did not require oxygen (Figs. 3A to D).

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DISCUSSION

Listing and Evaluation for Lung Transplantation

Since the beginning of pandemic our center has managed 64 COVID patients on VV-ECMO. 45 were referred from other states, among which 42 ECMOs were instituted by our mobile team comprising of cardiac surgeon, anesthetist, perfusionist, and nursing staff and the patients were airlifted to our center. The ECMO configuration in these situations was femoral vein to internal jugular vein. Referring institutional resource limitation forced our hand to carry most of the equipment necessary for ECMO initiation. This coupled with individual state enforced travel restrictions and limited connecting flights, protracted the transfer of these sick patients.

Although lung transplantation is the definitive therapy in patients with post-COVID-19 ARDS-related end-stage lung disease, its effect is miniscule in the setting of a pandemic due to such a small number of patients successfully enduring it. The median survival postbilateral lung transplant in current era is approaching 7 years. This clearly illustrates that the spontaneous recovery is the best possible outcome. Many of the patients referred to our center were elderly, had uncontrolled comorbidities, were physically deconditioned, and had sepsis with multiple organisms. Some of them developed secondary organ dysfunction such as renal failure, severe right ventricular dysfunction, gastrointestinal bleed, and cerebrovascular accidents precluding them from the consideration of a probable transplant.

Extracorporeal Membrane Oxygenation Management On receiving at our institute, they were managed in separate ICU till the laboratory report of COVID-19 turned negative. They were managed as per recommendation of national and international bodies comprising of intensive therapies such as ARDS ventilation, ECMO management, invasive monitor­ ing, nutrition, physiotherapy, and COVID-19-directed therapies such as steroid, antiviral, and immunomodulators. We observed high need of sedation, antihypertensives and high ECMO flows to maintain acceptable oxygen saturation. In spite of adequate anticoagulation, some patients developed digital gangrene. 60% of our patients required ECMO oxygenator and/or circuit exchanges for oxygenator failure and thrombosis. All of our patients received multiple blood product transfusion during ECMO bridging. Confirmed heparin-induced thrombocytopenia was observed in three of our patients and were switched to bivalirudin with activated partial thromboplastin time target above 50 seconds. Postprocedural bleeding following tracheostomy or intercostal drain insertion was less observed in bivalirudin-treated group, when compared to heparin group. Intraoperatively we used heparin or continued with bivalirudin with additional citrate anticoagulant in the cell saver. Critical illness neuropathy affecting both upper and lower limbs were often seen, demanding active physiotherapy and reconditioning. We observed high burden of sepsis with organisms such as Pseudomonas, Klebsiella, Enterococcus, Enterobacter, Stenotrophomonas, Serratia, Elizabethkingia, Chryseobacterium, and Sphingomonas. Candida auris was also seen in five cases, entailing change of invasive lines and ECMO circuit in addition to targeted antibiotics. Patients were regularly evaluated with sedation breaks and spontaneous breathing trials. Their clinical status, ventilatory parameters, and ECMO requirements were routinely assessed and sequential radiologic evaluation was done to gauge the progression of disease or signs of recovery.

Preoperative Phase After 4–6 weeks of ECMO run, the family of the patients demonstrating irreversible lung injury by clinical, ventilatory, and radiological parameters were communicated the need for evaluation for lung transplantation. After serial counseling sessions, the transplantation evaluation was started. History was carefully assessed for any pre-existing lung disease and comorbidities. Sensitization of the patients due to exposure to extracorporeal circuit and multiple product transfusions were checked with panel reactive antibody (PRA) levels. Subjects with PRA levels >30 (two in our cohort) were treated with five cycles of plasmapheresis (PLEX) and intravenous immunoglobulin and PRA levels were repeated a week later. Certain modifications in evaluation were prudent due to ECMO dependency of our cases. 6-minute walk test and right heart study were not performed and cardiac function was evaluated radiologically. We followed the standard principles for listing the patients and adhered to the guidelines laid out by our state and national cadaveric donation governing bodies. Cases were removed from active waiting list if new complications arose such as severe sepsis or organ dysfunction. On waiting list, patients were and the family were regularly counseled for the need of transplantation in the face of nonrecovery. Any signs of clinical improvements were communicated and decision to delist from active organ waitlist was considered. Emergence of any new complication was timely and appropriately dealt with. Right ventricular dysfunction necessitated inhaled nitric oxide (iNO), inotrope, focused fluid management, and pulmonary dilators. Renal dysfunction usually resolved with a few sessions of renal replacement therapy. Gastrointestinal bleed was evaluated with endoscopies and coagulopathy management. Pointof-care coagulation testing with thromboelastography was routinely used in cases of active bleeding. Our transfusion triggers were restrictive and we used leukodepleted packed red cells and group-specific platelet transfusion if needed.

Chapter 148:  Lung Transplant Success Stories in COVID Four patients who were awaiting lung transplant were delisted as three succumbed to sepsis and one developed intracranial hemorrhage. Our center performed 25 lung transplants (22 males, 3 female) for severe post-COVID ARDS between May 2020 and August 2021. The median age of the study population was 42 years [interquartile range (IQR) 31–66]. The median body mass index (BMI) was 26.7. Median pretransplant ventilatory days were 58 (IQR 22–87) and the mean duration of preoperative ECMO support was 50.9 days.

Intraoperative Phase On receiving the group matched organ donor call, the size matching was done with predicted total lung capacity formula or CT of the chest based lung volume comparison if available. The donor history, laboratory parameters, radiography, and bronchoscopy were considered before accepting the lung for transplantation. As dictated by the logistics of organ arrival to our center, the recipient was prepared and shifted to operating room. The donor and the recipient blood were cross-matched to detect the presence of any donor-specific antibodies (DSAs). After intravenous induction and relaxation, recipient lungs were isolated with double lumen tube. Bronchoscopy was utilized in cases of inadequate isolation of the lungs. The Clamshell incision was used to expose the native lungs to facilitate pneumonectomy. We observed dense adhesions, especially in patients with prior thoracic procedure such as intercostal drainage tube placement or presence of secretion or pus-filled cystic cavities. Due to this, the period of recipient pneumonectomy and hemostasis was lengthened. Peripheral VV-ECMO was converted to central venoarterial ECMO with bicaval drainage to facilitate surgery and provide hemodynamic stability. Poor lung compliance necessitated provision of intravenous anesthetics throughout the surgery. Intraoperative cell saver was routinely used during the procedure. Induction immunosuppression with basiliximab 20 mg was used 1 hour prior to beginning of anastomosis, in most of our patients. Controlled reperfusion of lungs with gradual release of cross-clamp over 10 minutes was crucial. Transesophageal echocardiogram was used to determine the adequacy of de-airing. Methylprednisolone at the dose of 500 mg and 250 mg was administered before the reperfusion of first and second lung, respectively. One patient was positive for DSA and he received intraoperative PLEX and intravenous immunoglobulin before the release of cross clamp. The mean ischemic time in our cohort was 360 ± 155 minutes. ECMO was successfully weaned off on operating table in majority of the cases (n = 1765%). Bronchoscopy to assess the status of anastomotic sites, presence of primary graft dysfunction (PGD), and for clearing of clots was done on table prior to closure of chest. ECMO configuration was

changed to peripheral venovenous for the patients with poor gas exchange or ventilatory parameters and shifted to ICU.

Postoperative Phase In ICU, patients were sedated and ventilated with low tidal volume and iNO. The patients were gradually weaned off iNO, inotropes, and ventilatory support. Triple immunosuppression with tacrolimus, mycophenolate, and steroids were started on day 1. Tacrolimus trough levels were checked and the dose adjusted to the levels of 8–10. Antibiotics were based on donor and recipient cultures. Serial bronchoscopies were done to assess the anastomotic healing and clearance of secretions. Physiotherapy and early mobilization were started. The median length of ICU stay was 15.85 days (range 9–28). Eight (34%) of patients had PGD presenting as low P/F ratio (PaO2/FiO2 ratio 50%. They advocated the usage of large multistage draining ECMO cannula in femorofemoral or femoro-internal jugular configuration. They concluded by saying that COVID-19 ARDS causes most COVID-19-related deaths and the appropriate use of ECMO in these situations improves the prognosis. Yeung et al.,7 in their case series described three patients who underwent bilateral lung transplant for COVID19 ARDS-related end-stage fibrosis. All their patients were younger than 65 years, had radiological evidence of irreversible lung damage, negative for COVID-19 RT-PCR. They stressed that as the donor lungs are scarce, a balance between the needs of this very sick group of patients and others waiting on the list needed to be reached. All three cases in their series had good short-term outcomes showing the feasibility and considerations of lung transplantation in patients following severe acute COVID-19 in Toronto. Bharat et al.,8 in their multiinstitutional case series, chronicled 12 patients with COVID-19-associated ARDS who underwent bilateral lung transplantation at six transplantation centers between May 1 and September 30, 2020. The median age of recipients was 48 years. The CT scan of all their patients exhibited severe lung fibrosis that did not recover despite of long ECMO runs. The median duration of preoperative ECMO was 55 days. They reported that pleural adhesions and hilar lymphadenopathy made lung transplantation more technically demanding with increased intraoperative transfusions. ECMO was empirically continued postoperatively in 83% of cases. Pathology of the explanted lungs showed features of extensive, acute lung injury with fibrosis. At the time of publication, 11 patients were alive and had completed 80 days of follow-up. The authors concluded that lung transplantation was the only option for survival in some patients with severe, unresolving COVID-19-associated ARDS and could be done successfully in carefully selected patients. Marcelo Cypeland and Shaf Keshavjee9 in their paper laid out 10 factors to be scrutinized for, before listing these patients for lung transplantation. For the suitability of candidacy, they recommended that the patients were younger (500 µg/L (normal range: females 10–200 µg/L; males 30–300 µg/L) have been associated with severity of disease. Existing evidence is not enough to make a clear case in favor or against the use of ferritin level for prognostic purpose.2

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Coagulation Parameters Coagulopathy in COVID-19 differs from the usual disseminated intravascular coagulation (DIC), in having a high fibrinogen, normal or mildly prolonged prothrombin time and activated partial thromboplastin time, mild thrombocytopenia (platelet count >100 × 103/mL), and no evidence of microangiopathy. Elevated D-dimer levels are a common finding in patients with COVID-19. There is enough evidence to show that D-dimer levels have prognostic value and correlate with disease severity and in-hospital mortality. A level of >1.5–2 μg/mL on admission predicts increased mortality. D-dimer levels also help to decide regarding anticoagulation.15,16

Other Biomarkers Creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), Myoglobin (Mb), and N-terminal-proB-type natriuretic peptide (NT-proBNP) are myocardial injury specific and increased to varying degrees, in severe and critical illness. Higher levels were associated with higher mortality; their routine use can be misleading and cannot be recommended. About half of patients presented with increased lactate dehydrogenase (LDH) levels which is associated with a higher risk of respiratory failure need for ICU admission and mortality.

TEMPORAL TRENDS IN BIOMARKERS Temporal variation of biomarkers provides early and important clue along the course of the illness regarding disease progression and therapeutic response. Table 2 summarizes the temporal course of various biomarkers.

ROLE OF BIOMARKERS IN VARIOUS AREAS OF PATIENT MANAGEMENT Biomarkers in COVID-19 can be useful in the following areas:2 ■ Early suspicion and diagnosis of disease (leukopenia, lymphopenia, high NLR ratio, and LDH) TABLE 2: Temporal trends: Biomarkers in COVID-19. 16 days

Increasing total leukocyte count, lymphocyte, and platelet count predict recovery while reducing counts predict mortality

(CRP: C-reactive protein; LDH: lactate dehydrogenase; IL: interleukin)

■ Confirmation and classification of disease severity

[lymphopenia, IL-6, CRP, ferritin, LDH, D-dimers, cardiac biomarkers—CK-MB, cardiac troponin T (CTnT), Mb, and NT-proBNP] ■ Response to therapy (CRP and IL-6) ■ Prognosis [IL-6, ferritin, LDH, CRP, procalcitonin (PCT), lymphocyte count, NLR, platelet count, cardiac biomarkers—CK-MB, CTnT, Myoglobin (Mb), and NT-proBNP]

CONCLUSION An understanding of immuno-thrombo-inflammatory response in host body as a response to viral antigen is essential for the initial identification of potential biomarkers. To put in simple words, an understanding of what the virus does to the body and how the body reacts to it, is central to concept of using biomarker for initial assessment, risk stratification, therapy rationalization, and prognostication. A thorough knowledge regarding temporal trends of biomarkers add meaningful insight to clinical and bedside decision-making.

REFERENCES 1. World Health Organization. Naming the Coronavirus Disease (COVID-19 and the Virus That Causes it. (2020). [online] Available from: https://www.who.int/ emergencies/diseases/ novel-coronavirus-2019/technical-guidance/namingthe coronavirus-disease-(covid-2019)-and-the-virus-that-causes it. [Last accessed March 2022]. 2. Samprathi M, Jayashree M. Biomarkers in COVID-19: an up-to-date review. Front Pediatr. 2021;8:607647. 3. Upadhyay J, Tiwari N, Ansari MN. Role of inflammatory markers in corona virus disease (COVID-19) patients: a review. Exp Biol Med. 2020;245(15):1368-75. 4. Catanzaro M, Fagiani F, Racchi M, Corsini E, Govoni S, Lanni C. Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2. Signal Transduct Target Ther. 2020;5(1):84. 5. Bellmann-Weiler R, Lanser L, Barket R, Langer L, MacMillan TE, Cavalcanti R, et al. Prevalence and predictive value of anemia and dysregulated iron homeostasis in patients with COVID-19 infection. J Clin Med. 2020;9:E2429. 6. Terpos E, Ntanasis-Stathopoulos I, Elalamy I, Kastritis E, Sergentanis TN, Politou M, et al. Hematological findings and complications of COVID-19. Amer J Hematol. 2020;95(7):834-47. 7. Huang I, Pranata R. Lymphopenia in severe coronavirus disease-2019 (COVID-19): systematic review and metaanalysis. J Intensive Care. 2020;8:36. 8. Tan L, Wang Q, Zhang D, Ding J, Huang Q, Tang YQ, et al. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Signal Transduct Target Ther. 2020;5:33. 9. Zheng Y, Zhang Y, Chi H, Chen S, Peng M, Luo L, et al. The hemocyte counts as a potential biomarker for predicting disease progression in COVID-19: a retrospective study. Clin Chem Lab Med. 2020;58(7):1106-15.

Chapter 150:  Inflammatory Markers in COVID 10. Yan X, Li F, Wang X, Yan J, Zhu F, Tang S, et al. Neutrophil to lymphocyte ratio as prognostic and predictive factor in patients with coronavirus disease 2019: a retrospective crosssectional study. J Med Virol. 2019;92(11):2573-81. 11. Ma A, Cheng J, Yang J, Dong M, Liao X, Kang Y. Neutrophilto-lymphocyte ratio as a predictive biomarker for moderatesevere ARDS in severe COVID- 19 patients. Crit Care. 2020;24:288. 12. Wang G, Wu C, Zhang Q, Wu F, Yu B, Lv J, et al. C-reactive protein level may predict the risk of COVID-19 aggravation. Open Forum Infect Dis. 2020;7:ofaa153. 13. Chen R, Sang L, Jiang M, Yang Z, Jia N, Fu W, et al. Medical treatment expert group for COVID-19. Longitudinal

hematologic and immunologic variations associated with the progression of COVID-19 patients in China. J Allergy Clin Immmunol. 2020;146(1):89-100. 14. Liu T, Zhang J, Yang Y, Ma H, Li Z, Zhang J, et al. The role of interleukin-6 in monitoring severe case of coronavirus disease 2019. EMBO Mol Med. 2020;12(7):e12421. 15. Zhang L, Yan X, Fan Q, Liu H, Liu X, Liu Z, et al. D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19. J Thromb Haemost. 2020;18(6):1324-9. 16. Yao Y, Cao J, Wang Q, Shi Q, Liu K, Luo Z, et al. D-dimer as a biomarker for disease severity and mortality in COVID-19 patients: a case control study. J Intensive Care. 2020;8:49.

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Hyperferritinemia in COVID-19 Patients

C H A P T E R Vajrapu Rajendra, K Subba Reddy, Sambit Sahu

INTRODUCTION

BASIC PATHOPHYSIOLOGY OF FERRITIN

Iron is essential for cellular respiration and oxygen transport, but free form of iron can also be potentially lethal due to its ability to catalyze redox reactions in tissues to generate highly toxic free radicals.1 Hence, iron is bound to proteins and ferritin is the major intracellular iron storage protein. The primary role of ferritin in health is iron storage, but in inflammation, it acts as an immune modulator.2 Ferritin is considered as a molecule essential for iron metabolism in the body also as acute inflammatory biomarker. There is a feedback regulation of ferritin as per proinflammatory and anti-inflammatory processes. A serum ferritin >300 μg/L for men and >200 μg/L for women is considered as hyperferritinemia.3 In COVID-19 infection, ferritin is an early elevated biomarker along with lymphopenia and is associated with “cytokine storm syndrome” (CSS).4 It appears that there is a significant association of hyperferritinemia and the severity of COVID-19 disease. Many retrospective studies from Wuhan demonstrated that admission ferritin levels were between three and four times higher in nonsurvivors compared to survivors and 5.3 and 1.5 times higher in patients in severe than in milder forms of the disease, respectively. Several studies found that mild and moderate disease [surviving and without acute respiratory distress syndrome (ARDS)] serum ferritin levels were 1,000 μg /L.5 Thus, high serum ferritin can identify a more severe COVID-19, which helps in early and aggressive inpatient management and utilizing the limited resources more judiciously.6 It is also observed that hyperferritinemia can continue for few months after the onset of COVID-19 and it may suggest a long COVID syndrome.7 Serum ferritin and CRP (C-reactive protein) seems to be better screening tools for the early diagnosis of a severe form of COVID-19 (CSS) with lesser cost and wider availability than interleukin (IL)-6.8

Toxic levels of iron injure cells by release of free radicals and cause fibrosis. Ferritin is an intracellular, nonglycosylated protein of the reticuloendothelial system and liver. Each molecule of ferritin stores iron up to 4,500 ions in Fe3+ form. It acts as a dynamic buffer of iron in maintaining constant reserve of iron. Intracellular concentrations of ferritin about 1,000 times higher than those in the serum, serum ferritin is the result of cell lysis.9 There is regulation of ferritin by cytokines in macrophages, which causes increase in ferritin values in inflammatory conditions. There is increased levels of hepcidin (a major iron regulator) causing increased ferritin. It is also found that there is a similarity in spike protein of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) virus and hepcidin, causing a hepcidin-like effect.10 Disbalance in iron metabolism and regulation leads to following effects:11 ■ Low hemoglobin levels due to low serum iron and erythropoiesis ■ Toxic-free circulating heme causing lipid peroxidation and free radical release ■ Hyperferritinemia ■ Limits the availability of essential iron to microbes ■ Reduced nitric oxide synthesis ■ Coagulation activation ■ Mitochondrial degeneration and ferroptosis ■ Enhanced inflammatory activity [IL-1β, inhaled nitric oxide (iNO)] ■ Immunosuppression [by inhibiting T-cell proliferation, or immunoglobulin G (IgG) production] ■ Hemochromatosis type hepatic injury ■ Hyperferritinemia syndromes. As per Shoenfeld et al., the heavy chain of ferritin may have a role in macrophage activation by increased secretion of inflammatory cytokines.12 Hyperferritinemic syndromes include catastrophic antiphospholipid

Chapter 151:  Hyperferritinemia in COVID-19 Patients syndrome (CAPS), adult-onset Stills disease (AOSD), macrophage activation syndrome (MAS), secondary hemophagocytic lymphohistiocytosis (HLH), septic shock, and COVID-19 CSS. It is still under research whether ferritin is a marker of disease severity, or a modulator in disease pathogenesis.13

COVID-19 AND HYPERFERRITINEMIA14

There are many hypotheses that reducing the ferritin levels may result in a better outcome in this set of patients. Several iron-chelating agents such as deferoxamine, deferasirox, and deferiprone are under scrutiny. Some anecdotal evidence also suggests recombinant human erythropoietin (rhEPO) may have also a role to play.15 Hyperferritinemia is seen in COVID-19, Ebola, and dengue fever but not in other coronavirus epidemics such as MERS (Middle East respiratory syndrome), SARS, and influenza B infection. This knowledge could be useful during flu season to differentiate among different pathologies.16

CONCLUSION Many disease processes cause hyperferritinemia, hence a systematic diagnostic protocol is needed to differentiate the pathogenesis. In COVID-19, ferritin appears to be both the cause and the result of the disease evolution. Early identification of hyperferritinemia can help to give intensive therapies to reduce mortality and morbidity.

REFERENCES 1. Su LJ, Zhang JH, Gomez H, Murugan R, Hong X, Xu D, et al. Reactive oxygen species-induced lipid peroxidation in apoptosis, autophagy, and ferroptosis. Oxid Med Cell Longev. 2019;2019(30):1-13. 2. Kuhn LC. Iron regulatory proteins and their role in controlling iron metabolism. Metallomics. 2015;7(2):232-43. 3. Cullis JO, Fitzsimons EJ, Griffiths WJ, Tsochatzis E, Thomas DW; British Society for Haematology. Investigation and management of a raised serum ferritin. Br J Haematol. 2018;181(3):331-40. 4. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62. 5. Kappert K, Jahić A, Tauber R. Assessment of serum ferritin as a biomarker in COVID-19: bystander or participant? Insights by comparison with other infectious and non-infectious diseases. Biomarkers. 2020;25(8):616-25. 6. Ruscitti P, Berardicurti O, Di Benedetto P, Cipriani P, Iagnocco A, Shoenfeld Y, et al. Severe COVID-19, another piece in the puzzle of the hyperferritinemic syndrome. An immunomodulatory perspective to alleviate the storm. Front Immunol. 2020;11:1130. 7. Sonnweber T, Boehm A, Sahanic S, Pizzini A, Aichner M, Sonnweber B, et al. Persisting alterations of iron homeostasis in COVID‑19 are associated with non‑resolving lung pathologies and poor patients’ performance: a prospective observational cohort study. Respir Res. 2020;21:276. 8. Melo AKG, Milby KM, Caparroz ALMA, Pinto ACPN, Santos RRP, Rocha AP, et al. Biomarkers of cytokine storm as red flags for severe and fatal COVID-19 cases: A living systematic review and meta-analysis. PLoS One. 2021;16(6):e0253894. 9. Kell B, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics. 2014;6:748-73. 10. Čepelak I, Dodig S, Vučenik I. Hyperferritinemia and COVID-19? RAD CASA - Medical Sciences. [online] Available from: file:///C:/ Users/91966/Downloads/1100524.2020_hyperferritinemia_ and_COVID.pdf. [Last accessed March, 2022]. 11. Nairz M, Weiss G. Iron in infection and immunity. Mol Aspects Med. 2020;75:100864. 12. Rosario C, Zandman-Goddard G, Shoenfeld Y, MeyronHoltz EG, D’Cruz DP, et al. The hyperferritinemic syndrome: macrophage activation syndrome, Still’s disease, septic shock and catastrophic antiphospholipid syndrome. BMC Med. 2013;11:185. 13. Colafrancesco S, Alessandri C, Conti F, Priori R. COVID-19 gone bad: A new character in the spectrum of the hyperferritinemic syndrome? Autoimm Rev. 2020;19(7):102573. 14. Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysio­ logy: A review. Clin Immuno. 2020;215:108427. 15. Vlahakos VD, Marathias KP, Arkadopoulos N, Vlahakos DV. Hyperferritinemia in patients with COVID-19: An opportunity for iron chelation? Artif Organs. 2021;45(2):163-7. 16. Jusufovic V, Umihanic S, Stratton R, Alibegovic E, Piljic D, Mujkanovic A, et al. Ferritin and LDH as predictors of mortality in COVID-19 infection, bosnia and herzegovina single center study. DOI: https://doi.org/10.21203/rs.3.rs-143696/v1.

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Extracorporeal Membrane Oxygenation in COVID-19: Is it Different?

C H A P T E R Dipanjan Chatterjee, Arpan Chakraborty

INTRODUCTION Since the end of 2019, global pandemic caused by novel coronavirus SARS-CoV-2 (severe acute respiratory syn­ drome coronavirus 2) has resulted in death of millions of people. India has witnesses >5.15 lac deaths due to corona­ virus disease 2019 (COVID-19). Severe COVID-19 is a multi­systemic disease, with lungs being the most common organ affected, leading to acute respiratory failure and acute respiratory distress syndrome (ARDS). These patients have high risk of mortality in spite of best critical care practices. Clinicopathophysiological features of COVID-19associated ARDS (CARDS) are different from the ARDS due to other infective etiologies. Two phenotypes have been described. Type L (atypical ARDS) has low elastance, high compliance and low recruitability. Type H (typical ARDS) has high elastance, low compliance and high recruitability.1 CARDS may not conform to the Berlin criteria in truest sense, since the time of onset is usually 8–12 days, and the type L has high compliance as well as lack the typical picture of dependent lung consolidation of ARDS. The severe hypoxia disproportionate to the extent of radiological extent of lung consolidation has been postulated due to pulmonary vascular endothelial dysfunction with loss of hypoxic pulmonary vasoconstriction (HPV) function, cytokine storm-induced pulmonary vasodilatation, formation of microthrombi due to loss of endothelial barrier, and reninangiotensin system dysregulation all leading to severe V/Q mismatch.2 In addition, severe COVID-19 also may result in acute myocarditis and acute coronary syndrome, acute right heart dysfunction due to severe ARDS, acute kidney injury (AKI), acute hepatic dysfunction, ischemic stroke, coagulation abnormalities with pulmonary embolism, and dysregulated immune response (cytokine storm). Due to the above features the natural course of disease in CARDS differs from typical ARDS due to other etiologies. Extracorporeal membrane oxygenation (ECMO) has been used to support patients with severe ARDS due to COVID-19. ECMO during global pandemic is fraught with various issues

regarding logistics and ethics. ELSO has issued guidelines for proper utilization of this modality for optimum patient care.3 Prior to ECMO, the patient should have received and exhausted conventional care for severe ARDS including lung protective ventilation, neuromuscular blockade, recruitment strategies, systemic corticosteroids, anticoagulation, prone positioning, and pulmonary vasodilators. Initiation of ECMO provides adequate oxygenation and allows lung protective ventilation. Patients may be considered for ECMO if they have at least any one of the following:3 ■ PaO2/FiO2 < 50 mm Hg for at least 3 hours. ■ PaO2/FiO2 < 80 mm Hg for at least 6 hours. ■ Arterial blood pH < 7.25 and PaCO2 ≥ 60 mm Hg for 6 hours. Contraindications to ECMO are few and include: ■ Age > 70 years (relative contraindication). ■ Severe comorbidities incompatible with recovery such as metastatic malignancy, unmanageable organ failure, and unreversible neurological impairment. ■ Invasive ventilation duration longer than 10 days with high driving pressure.

TIMING OF EXTRACORPOREAL MEMBRANE OXYGENATION INITIATION During the pandemic, ECMO was seen as a modality of last resort, hence referral for ECMO is frequently delayed. Often patients are on prolonged noninvasive ventilation (NIV) support, with delayed intubation and acute hypoxia/ hypercarbia long after onset of initial symptom. Hence, the duration on NIV should be accounted for while considering eligibility of ECMO initiation since delayed initiation of ECMO has poorer outcome.4

Cannulation Femoro-jugular cannulation with a large drainage cannula is the most common configuration followed by femorofemoral cannulation. Dual lumen cannulation has also been used as these patients can be better mobilized leading

Chapter 152:  Extracorporeal Membrane Oxygenation in COVID-19: Is it Different? to early recovery and rehabilitation in prolonged ECMO. Almost all these patients are on anticoagulants, hence care should be taken during cannulation to prevent bleeding at cannulation site.

Bleeding and Thrombosis—Anticoagulation Management There has been reports of frequent thrombotic events on ECMO including circuit clotting and massive pulmonary embolism. Hence, adequate anticoagulation is to be maintained with unfractionated heparin, and monitored with activated partial thromboplastin time (aPTT) (60–75 seconds) or anti-Xa activity 0.3–0.5 IU/mL. Some centers prefer to use direct thrombin inhibitors. These patients also are at high risk of major bleeding including intracranial hemorrhage. Hence, a balanced anticoagulation regime needs to be followed with regular monitoring of coagulation factors and platelets. COVID-19 patients have higher need of circuit changes, oxygenator failures, pump failures, and cannula conditions compared to non-COVID-19 patients.5 Hence, careful monitoring of circuit and oxygenator is needed.

Cardiovascular Dysfunction Some patients of COVID-19 present with acute myocarditis and acute coronary syndrome, leading to cardiogenic shock. Despite initial treatment with inotropes and vasopressors, some are in severe low cardiac output state needing ECMO support in the form of veno-arterial (V-A) or veno-arterialvenous (V-AV) (hybrid) configuration. Some patients may develop low cardiac output state later, after initiation of veno-venous extracorporeal membrane oxygenation (VV-ECMO). Change of circuit configuration to V-AV is needed to support the circulation in this patient population. ECMO for circulatory support is associated with higher risk of mortality (hazard ratio 1.89, 95% confidence interval (CI) 1.20–2.97). In contrast, children needing VA-ECMO for multisystem inflammatory syndrome in children (MIS-C)related circulatory impairment have very high survival rates.6 Some patients with severe right ventricular dysfunction, most likely secondary to high right ventricular afterload, have worse outcome. Some centers have adopted altered cannulation using ProtekDuo TandemHeart cannula (CardiacAssist Inc., Pittsburgh, Pennsylvania) to provide right atrium-pulmonary artery (RA-PA) right-ventricular assist device (RVAD)/ECMO with good outcome.7,8 Patients with severe COVID-19 needing ECMO support also have high incidence of AKI, hepatic dysfunction, and ischemic stroke, all associated with adverse outcome.9

Barotrauma Patients with severe COVID-19-related ARDS on invasive mechanical ventilation, have higher incidence of

barotrauma-related events (14.7%) [pooled estimates, 16.1% (95% CI, 11.8–20.4%)], compared to ARDS due to other causes (6.3%; pooled estimates, 5.7%; 95% CI, 2.1–13.5%).10 Barotrauma can manifest as pneumothorax, pneumomediastinum or subcutaneous emphysema even with lung protective ventilation and VV-ECMO support. These patients have prolonged duration of ECMO and worse outcomes. Mortality in COVID-19 patients who developed barotrauma is 56.1% (pooled estimates, 61.6%; 95% CI, 50.2–73.0%) compared to 10% in non-COVID-19 ARDS.10 Management includes chest tube drainage for significantly large pneumothorax, mechanical ventilation with lower positive end-expiratory pressure (PEEP) and lower driving pressure, and awake ECMO with spontaneous respiration may be attempted.

Adjuvant Therapy—Proning Beneficial effects of proning in COVID-19 have been demonstrated in spontaneously breathing patients as well as in patients on invasive mechanical ventilation. The use of prone position ventilation (PPV) has been attempted in patients on VV-ECMO support. Mobilization of patients on ECMO from supine to prone is dependent on trained manpower support. These patients have ECMO cannulae, either femoro-femoral or femoro-jugular. The patient needs to be monitored continuously during the process to note cannulae displacement or kinking, alteration in flow or hemodynamic instability. PPV is indicated in patients with poor oxygenation in spite of ECMO support. PPV optimizes lung recruitment and perfusion, mitigates VILI, preventing ongoing native lung damage, improves right ventricular function, and overall hemodynamics.11 PPV also eases clearance of secretions.

Adjuvant Therapy—Awake Extracorporeal Membrane Oxygenation To avoid the deleterious effects of invasive mechanical ventilation [ventilator-induced lung injury, ventilatorassociated pneumonia (VAP)], awake ECMO has been advocated, where patient is not on mechanical ventilation.12 Other postulated benefits of awake ECMO being patient are able to actively participate in physiotherapy and interact with family. The inability to monitor and effectively control the transpulmonary pressure, which is the major determinant of patient self-induced lung injury (P-SILI), is the major drawback. Increased breathing efforts and coughing can cause large swings in intrapleural pressure, resulting in reduced blood flow in drainage cannula and subsequent hypoxemia. This can be attempted in patients with air leak syndromes such as surgical emphysema and spontaneous pneumothorax.

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Section 23:  COVID-19 Related Issues

Prolonged Extracorporeal Membrane Oxygenation It is seen that time on ECMO is longer in COVID-19 than in other causes of ARDS, and a large number of patients need prolonged (≥28 days) ECMO support.13 These patients are most likely to need circuit changes. Prolonged ECMO patients stretch human and financial resources as well as logistic support, all of which are scarce during a pandemic. Severe endothelial injury could play a crucial role in the need for prolonged ECMO support as it might take more time to recover. The use of neuromuscular blocking drugs needs to be restricted and early mobilization and rehabilitation should be targeted. Interestingly, greater duration of ECMO support is not associated with death. Prolonged ECMO allows time for lung parenchymal recovery and survival without lung transplantation. Hence, lack of improvement of lung function in the first weeks of ECMO or even temporarily worsening should not be seen as an indication to stop treatment, since favorable outcomes can be expected even after prolonged ECMO support.

NEW ONSET INFECTION COVID-19 patients on ECMO exhibit higher incidence of secondary bacterial and fungal infections during the course of treatment. 85–89% incidence of antibiotic treated VAP has been reported. 44–51% patients had ≥1 treated bacteremia episodes.14 Gram-negative pathogens maintained an overall predominance as causative agents of initial and subsequent infections. High incidence of fungal infections has also been reported. These patients have poor clinical progression and higher mortality. It is postulated that these patients have higher susceptibility due to treatment with broad-spectrum antibiotics and immunosuppressive therapies.15 Septic shock due to secondary infection can lead to multiorgan dysfunction with poor prognosis.

OUTCOME Though initial reports of ECMO in COVID-19 from China reported dismal outcome with mortality of 83%.16 Later studies from large volume centers have reported better outcomes. Barbaro et al. in their initial study of 1,035 patients on ECMO reported mortality of 39%.5 In another metaanalysis of 1,896 patients by Ramanathan et al. mortality rate was 37.1%.17 These data show mortality rate is comparable to that of ECMO for non-COVID-19 ARDS. Shaefi et al. found significantly lower 60-day mortality in patients receiving ECMO 35.3% (95% CI 27.2–43.5%) versus invasive mechanical ventilation 47.9% (95% CI 44.9–50.8%) in acutely hypoxic respiratory failure (PaO2/FiO2 ratio 60 days of ECMO runs.22 Similarly before declaring futility in those who do not fulfill the criteria for transplant, sufficient time on ECMO should be given and all factors discussed with the patient’s attendants.

Chapter 152:  Extracorporeal Membrane Oxygenation in COVID-19: Is it Different?

COMMUNICATION Since COVID-19 patients are cohorted in isolation wards, where the relatives usually do not have access. The ECMO team members should develop efficient communication with the relatives and the patient, discussing all the relevant aspects of patient’s condition, allaying anxiety, and providing reassurance, formulating appropriate expectations about outcome, since many of the patients have prolonged ECMO support, and some have significant adverse events and outcomes.

CONCLUSION Extracorporeal membrane oxygenation has been used to support patients with severe COVID-19 ARDS with satisfactory outcome. Since the pathophysiology of the disease and its manifestations differ, the management of ECMO and other treatment in these patients need to be carefully monitored and altered as dictated by changes in clinical condition of the patient. Data analysis and research in this field would help us understand the disease process better and formulate and refine ECMO management in these patients. With reducing burden on ECMO units, patient care shall improve, with likely improvement in clinical outcomes.

REFERENCES 1. Gattinoni L, Chiumello DC, Caironi P, Busana M, Romitti F, Brazzi L, et al. COVID-19 pneumonia: different respiratory treatments for different phenotypes? Intensive Care Med. 2020;46:1099-102. 2. Habashi NM, Camporota L, Gatto LA, Nieman G. Functional pathophysiology of SARS-CoV-2-induced acute lung injury and clinical implications. J Appl Physiol (1985). 2021;130(3):877-91. 3. Badulak J, Antonini MV, Stead CM, Shekerdemian L, Raman L, Paden ML, et al. Extracorporeal Membrane Oxygenation for COVID-19: Updated 2021 Guidelines from the Extracorporeal Life Support Organization. ASAIO J. 2021;67(5):485-95. 4. Li X, Hu M, Zheng R, Wang Y, Kang H, et al. Delayed Initiation of ECMO Is Associated With Poor Outcomes in Patients With Severe COVID-19: A Multicenter Retrospective Cohort Study. Front Med (Lausanne). 2021;8:716086. 5. Barbaro RP, MacLaren G, Boonstra PS, Iwashyna TJ, Slutsky AS, Fan E, et al. Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry. Lancet. 2020;396(10257):1071-8. 6. Belhadjer Z, Meot M, Bajolle F, Khraiche D, Legendre A, Abakka S, et al. Acute Heart Failure in Multisystem Inflam­ matory Syndrome in Children in the Context of Global SARSCoV-2 Pandemic. Circulation. 2020;142(5):429-36. 7. Mustafa AK, Alexander PJ, Joshi DJ, Tabachnick DR, Cross CA, Pappas PS, et al. Extracorporeal Membrane Oxygenation for Patients With COVID-19 in Severe Respiratory Failure. JAMA Surg. 2020;155(10):990-2.

8. Cain MT, Smith NJ, Barash M, Simpson P, Durham LA 3rd, Makker H, et al. Extracorporeal Membrane Oxygenation with Right Ventricular Assist Device for COVID-19 ARDS. J Surg Res. 2021;264:81-9. 9. Huang S, Zhao S, Luo H, Wu Z, Wu J, Xia H, et al. The role of extracorporeal membrane oxygenation in critically ill patients with COVID-19: a narrative review. BMC Pulm Med. 2021;21(1):116. 10. Belletti A, Todaro G, Valsecchi G, Losiggio R, Palumbo D, Landoni G, et al. Barotrauma in Coronavirus Disease 2019 Patients Undergoing Invasive Mechanical Ventilation: A Systematic Literature Review. Crit Care Med. 2021. doi: 10.1097/CCM.0000000000005283. Online ahead of print. 11. Garcia B, Cousin N, Bourel C, Jourdain M, Poissy J, Duburcq T, et al. Prone positioning under VV-ECMO in SARS-CoV2-induced acute respiratory distress syndrome. Crit Care. 2020;24(1):428. 12. Azzam MH, Mufti HN, Bahaudden H, Ragab AZ, Othman MM, Tashkandi WA. Awake Extracorporeal Membrane Oxygenation in Coronavirus Disease 2019 Patients Without Invasive Mechanical Ventilation. Crit Care Explor. 2021;3(6):e0454. 13. Dreier E, Malfertheiner MV, Dienemann T, Fisser C, Foltan M, Geismann F, et al. ECMO in COVID-19-prolonged therapy needed? A retrospective analysis of outcome and prognostic factors. Perfusion. 2021;36(6):582-91. 14. Schmidt M, Langouet E, Hajage D, James SA, Chommeloux J, Bréchot N, et al. Evolving outcomes of extracorporeal membrane oxygenation support for severe COVID-19 ARDS in Sorbonne hospitals, Paris. Crit Care. 2021;25(1):355. 15. Marcus JE, Sams VG, Barsoumian AE. Elevated secondary infection rates in patients with coronavirus disease 2019 (COVID-19) requiring extracorporeal membrane oxygenation. Infect Control Hosp Epidemiol. 2021;42(6):770-2. 16. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475-81. 17. Ramanathan K, Shekar K, Ling RR, Barbaro RP, Wong SN, Tan CS, et al. Extracorporeal membrane oxygenation for COVID-19: a systematic review and meta-analysis. Crit Care. 2021;25(1):211. 18. Shaefi S, Brenner SK, Gupta S, O’Gara BP, Krajewski ML, Charytan DM, et al. Extracorporeal membrane oxygenation in patients with severe respiratory failure from COVID-19. Intensive Care Med. 2021;47(2):208-21. 19. Barbaro RP, MacLaren G, Boonstra PS, Combes A, Agerstrand C, Annich G, et al. Extracorporeal membrane oxygenation for COVID-19: evolving outcomes from the international Extracorporeal Life Support Organization Registry. Lancet. 2021;398(10307):1230-8. 20. Riera J, Roncon-Albuquerque R Jr, Fuset MP, Alcántara S, Blanco-Schweizer P; ECMOVIBER Study Group. Increased mortality in patients with COVID-19 receiving extracorporeal respiratory support during the second wave of the pandemic. Intensive Care Med. 2021;47(12):1490-3. 21. Cypel M, Keshavjee S. When to consider lung transplantation for COVID-19. Lancet Respir Med. 2020;8(10):944-6. 22. Walter K. Lung Transplants for COVID-19—The Option of Last Resort. JAMA. 2021;326(1):14-6.

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Approach to Shock in COVID Patients

153 C H A P T E R

Manasi Shahane, Sameer Jog, Srinath Marreddy

INTRODUCTION Shock is a state of circulatory insufficiency charac­terized by impaired cellular oxygen utilization or delivery.1 Of the 5–10% patients infected with SARS-CoV-2 that land up into the intensive care unit (ICU), almost up to 67% patients develop shock.2 Shock is diagnosed on the basis of clinical, hemodynamic, and biochemical signs broadly grouped into three components. First, there usually is systemic arterial hypotension with systolic blood pressure (BP) being 95% at room air.1 Treating team of intensivist and obstetrician must assure that patient is maintaining oxygen saturation at what method of oxygen supplementation whether facemask, nasal cannula, or high flow nasal cannula (HFNC). ■ In this group of patients, oxygen saturation should be monitored very strictly. Every patient should be asked to monitor her oxygen saturation specially during walking. If this is decreasing up to 95% or less than that, she should be advised hospitalization for further management and monitoring because these patients can deteriorate very fast. ■ Treating team should follow every patient for any clinical signs of deterioration such as use of accessory respiratory muscles, gradually increasing respiratory rate, unable to talk full sentence, or any signs of hypoxia such as cyanosis. These patients should be placed on oxygen therapy and advised to get admitted in higher center. ■ Once these patients improve and clinician is planning to discharge from the hospital, the level of oxygen must be reassessed at rest and during walking. All preventing measures should be taken at discharge including patient education regarding warning signs.

■ In pregnancy, maternal and fetal oxygen consumption is

IN-HOSPITAL MANAGEMENT

increased by 40% over nonpregnant. To provide increased oxygen requirement (by 20%), there is physiological dyspnea with decreased PaCO2 and HCO3−. There is decreased functional residual capacity (FRC), because of which there is decreased intolerance for apnea and hypoventilation. ■ While treating pregnant females with COVID-19, anatomical and physiological changes of pregnancy have to be kept in mind and target of treatment should be to achieve levels equivalent to non-COVID pregnant females.

All patients’ vitals should be strictly monitored by nursing staff, frequency and level of monitoring depends upon severity and criticality of that particular patient. Noninvasive monitoring should be preferred but invasive cardiovascular monitoring can be considered if indicated in hemodynamically unstable patients. All vital signs, including respiratory rate, heart rate, and level of respiratory support should be recorded every 1  hour. Along with patient, monitoring of fetus is of paramount importance that includes cardiotocography monitoring. Option of delivery would be considered based on gestational age, and severity of maternal disease status.

IMPACT OF OXYGEN SATURATION AND HYPOXIA IN PREGNANCY ■ In nonpregnant patient, the recommendation for SpO2

is 92% but in case of pregnancy, these recommendations

Methods for Oxygen Delivery ■ Nasal cannula ■ Face mask: “Nonrebreather”

812

Section 23:  COVID-19 Related Issues ■ Venturi face mask ■ HFNC ■ Use noninvasive ventilation (NIV): Bilevel positive airway

pressure (BiPAP) or continuous positive airway pressure (CPAP). Selection of mode of oxygen delivery should be based on the degree of hypoxia and other clinical parameters of the patient.

IN-HOSPITAL TREATMENT OF SEVERE DISEASE Treating team must train the nursing staff and patient including attendants regarding the early warning signs of disease deterioration and progression. These include the following: ■ An increased severity of breathlessness ■ Poor oxygen saturation (SpO2 95% with O2 supplementation ■ Hypotension mean arterial pressure (MAP) 95% in spite of oxygen therapy. The inability to maintain and protect upper airway due to altered mental status or Glasgow Coma Scale of < 9 should also be considered for intubation as well.

INDICATIONS OF PRONE POSITION ■ To improve oxygenation, prone positioning can be

performed in pregnant and postpartum patients, including the recently delivered. ■ “Awake prone positioning” can be practiced in patient without intubation. Patient herself can change her

positions, either the lateral decubitus or fully prone position, this may improve patient comfort and can also avoid intubation in some patients of less severity. Change in position should be done typically for about 2 hours in each position.

NEUROMUSCULAR BLOCKADE (PARALYTICS) All ventilated patients, neuromuscular blockade is one pharmacological intervention that decreases oxygen demand in moderate and severe acute respiratory distress syndrome (ARDS), especially if instituted early. Therefore, paralysis and deep sedation can be considered in COVID-19 with refractory hypoxemia in pregnant patients.

USE OF EXTRACORPOREAL MEMBRANE OXYGENATION Extracorporeal membrane oxygenation (ECMO) is one of the advanced ventilatory method of management for these patients, especially who are having refractory hypoxia. A pregnant patient with severe hypoxia is not a contraindication to the use of ECMO. However, there may be many logistical challenges related to procedure. Despite these challenges, this modality should not be withheld from a pregnant patient for whom it may potentially benefit if the patient is otherwise a candidate. In general, ECMO for a pregnant patient should occur in a center with significant experience with its use.4

INDICATIONS OF ANTICOAGULATION IN CRITICALLY ILL COVID-19 PREGNANT PATIENTS COVID-19 patients who are suffering with critical illnesses are at increased risk of thromboembolic-related complications. Patients who are admitted in ICU and on mechanical ventilation should receive prophylactic unfractionated heparin or low-molecular weight heparin, except when there are some contraindications to its use. However, clinical data is nonconclusive that early anticoagulation is beneficial in this group of patients.5 Three different dosing strategies can be practiced such as prophylactic, intermediate-dose, and full anticoagulation. There are no significant differences in primary outcome when we compare prophylactic verses intermediate dosing schedule.

INDICATIONS AND USE OF PHARMACOLOGICAL AGENTS FOR COVID-19 Various therapeutic agents have been investigated for the treatment of COVID-19 disease. While some have shown benefit in decreasing hospital stay or improving other outcomes, there is no cure or optimal and agreed-upon comprehensive approach. Pregnant patients with clinical

Chapter 154:  Full-term Pregnancy with COVID-19: An Intensivist’s Perspective findings of COVID-19 should be admitted in a hospital and need monitoring during pharmacotherapy treatment.

Remdesivir The Adaptive COVID-19 Treatment Trial investigated the use of antiviral agent, remdesivir, among patients requiring oxygen therapy due to COVID-19 infection and demonstrated a decreased duration of disease in treated patients. National Institutes of Health (NIH) COVID-19 Treatment Guidelines Panel recommends remdesivir for treatment of COVID-19 in hospitalized patients with SpO2 ≤ 94% at room air or those who needed oxygen therapy. The Panel also recommends remdesivir for patients of COVID-19-associated pneumonia and respiratory failure and are on invasive mechanical ventilation or ECMO.6 There is no known fetal toxicity associated with remdesivir. With result of various trials, Society for Maternal-Fetal Medicine (SMFM) recommends that remdesivir should be given to pregnant patients with COVID-19.

Dexamethasone RECOVERY trial demonstrated that dexamethasone was associated with a decreased risk of mortality among people requiring mechanical ventilation and also demonstrated a small but statistically significant decrease in mortality risk among those requiring oxygen for COVID-19. The Panel recommends against using dexamethasone in patients with mild disease of COVID-19 who are not hypoxic and do not require oxygen therapy. 7 These recommendations are not specific to pregnant patients. Since the benefit of mortality reduction outweighs the risk of fetal steroid exposure for this short course of treatment, SMFM recommends that this treatment can also be instituted in pregnant patients with COVID-19 requiring respiratory support in form of oxygen supplementation or mechanical ventilation: ■ If systemic steroids are indicated for fetal lung maturity, dexamethasone 6 mg twice a day for 2 days, followed by up 10 days of 6 mg dexamethasone daily. ■ If steroids are not indicated for fetal lung maturity, 6 mg dexamethasone daily for up to 10 days as in nonpregnant patients.

Monoclonal Antibodies These drugs such as casirivimab, imdevimab, and bamlanivimab are not routinely recommended by NIH COVID guidelines. However, there is no absolute contraindication to their use in pregnant patients.

TIMING OF DELIVERY IN CRITICALLY ILL PREGNANT PATIENTS Timing of delivery in critically ill patient is very important and has to be individualized depending on maternal status, associated comorbidities, and gestational age. In pregnant patient at term who is suffering with severe disease and having refractory hypoxemia, delivery must be considered because it will allow for further optimization of care. The severity of illness may dictate earlier delivery. Major neonatal morbidity occurs infrequently at these gestational ages as well: 8.7% at 32 weeks, 4.2% at 33, 4.4% at 34, 2.8% at 35, and 1.8% at 36 weeks of gestation.10 In the third trimester, the pressure of the uterus can decrease expiratory reserve volume, inspiratory reserve volume, and FRC, which can increase the risk of severe hypoxemia in pregnant patients, especially those who are critically ill.11 Although available data in literature about optimal delivery timing and acute respiratory distress syndrome are limited, it is reasonably good to conduct delivery in the setting of worsening disease. In case of disease progression in COVID-19, teams should discuss individualized delivery criteria in the setting of deteriorating maternal status, worsening fetal status, or no improvement in maternal disease status. In these patients, mechanical ventilation alone is not an indication for delivery. If delivery is considered based on degree of hypoxemia, other treatment options should also be discussed among the team such as prone positioning, ECMO, and use of other advanced ventilator methods, especially in patient of gestational age is