· PDF fileCONTENTS Learning Basic ... Miraj, Dist-Sangli, Maharashtra Journal scan : Top 5 ... specify that informed consent was obtained following a full explanation of the

JOURNAL OF PEDIATRIC CRITICAL CAREVOL 1 - NO.2 April - June 2014 1

CONTENTS

Learning Basic Intensive Care

Original Research Article

Best Evidence

From Editors Desk 3

Executive Board IAP intensive care chapter 2013 4

Editorial board 5

Instructions for Authors 6

11

BPICC in India - a success story

Dr Madhumati Otiv

KEM Hospital, Pune

Decline in platelet count as a prognostic marker in critically ill children 13

Dr. Vinayak K.Patki, , Dr. Florence D. Birru, Dr. Vidya V. Patki, Department of Pediatrics, Wanless Hospital, Miraj, Dist-Sangli, Maharashtra

Journal scan : Top 5 articles 22

Dr Soonu Udani, Dr Rekha Solomon,

PD Hinduja Hospital, Mumbai

Recent advances in postoperative care of pediatric cardiac surgical patients 26Dr. Muralidhar KNarayana Hrudayalaya Hospitals, Bangalore

Vasoactive and Inotropic therapy in PICU 39

Dr. Agnisekhar Saha*, Dr. Bichitrovanu Sarkar**

Fortis Hospital, Kolkata*

AMRI Group of Hospitals, Kolkata**

Cardiac arrhythmias in Pediatric intensive care unit 54

Dr Vinay Kukreti* , DrMosharraf Shamim**

*

Cardiac Pacing in Pediatric Intensive Care Unit 63

Dr Neeraj Gupta, Dr Anil Sachdev, Dr Dhiren Gupta

Institute of Child Health, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi.

Pediatric Cardiac Intensive Care

The Hospital for Sick Children, Toronto, Canada.

King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia**

Case Report

Hot Topic Review

Critical thinking

Not all “septic shock” is due to infection 72

Dr VSV Prasad,

Lotus Childrens Hospital, Hyderabad

Cooling after cardiac arrest, A hot topic 75

Dr Utpal S Bhalala,

John Hopkins university School of Medicine.Baltimore,Maryland.USA

PICU Quiz with answers and explanations 85

Dr. Nameet Jerath, IP Apollo Hospital, Delhi


It gives me great pleasure to bring out the second issue of our IAP intensive care journal: Journal of Pediatric

critical care(JPCC) with Original articles, Journal scan, Case report, Reviews and Quiz.

Our main goal remains to initiate and continue regular quarterly publication of peer reviewed original articles

,abstracts, case reports, reviews, quiz, editorials and journal scans related to field of Pediatric critical care with

eventual aim to get it indexed, published monthly and listed in Pubmed over the next few years.

Online submission will commence shortly. It is hoped that various articles and original research work of many

institutions will continue to be submitted for peer review and publication to make this journal get the best impact

factor and become the leading publisher of Indian pediatric critical care data for the rest of the world.

Sincerely

Praveen khilnani MD FAAP FCCM

Editor in chief JPCC

Vice President ISCCM and Director Pediatric Critical Care

and Pulmonology Services

BLK Super Speciality Hospital, New Delhi

E-mail: [email protected]

www.journalofpediatriccritcalcare.com

Tel : 09810159466

April 1st, 2014

From Editors Desk

JOURNAL OF PEDIATRIC CRITICAL CARE3VOL 1 - NO.2 April - June 2014

Executive Board 2013

JOURNAL OF PEDIATRIC CRITICAL CARE4

IAP Intensive Care Chapter

Prabhat Maheshwari Praktish Bora Kundan Mittal

Madhumati Otiv Anil Sachdev Vikas TanejaSantosh T. Soans

Kamlesh Srivastava

D. P. Nakate

Avinash Bansal

Karunakara BP

M. Arif Ahmed

Rashna Das Hazarika

Banani Poddar

Vishram Buche

S.K. Ghorpade

Sanjay BafnaExecutive Members

Maritunjay Pao

Executive Members

[email protected]

Chairman [email protected]

Vice [email protected]

Vice [email protected]

[email protected]

Joint [email protected]

Joint [email protected]

[email protected]

VOL 1 - NO.2 April - June 2014

Executive members :

Dr Arun Bansal

Dr Banani Poddar

Dr Ebor Jacob

Dr Lokesh Tiwari

Dr Partha Bhattacharya

Dr Prabhat Maheshwari

Dr Dinesh Chirla

Dr Devaraj Raichur

Dr Karunakara

Dr Mritunjay pao

Dr Deepika Gandhi

Dr Bhaskar Saikia

Dr Shipra Gulati

Dr. Vikas Taneja

Dr Indira Jayakumar

Dr Sanjay Bafna

Dr Sanjay Ghorpade

Dr Sagar Lad

Biostatistics :

Dr M Jayshree

Dr Jhuma Sankar

Dr Arun Baranwal

Ethics :

Dr Urmila Jhamb

Dr Rakesh Lodha

Dr Meera Ramakrishnan

Dr Vinay Joshi

Website :

Dr Maninder Dhaliwal

Dr Vinayak Patki

Dr Anjul Dayal

Publication :

Dr Rachna Sharma

Dr Pradeep Sharma

Dr Sanjeev Kumar

Editorial Board

Senior Editors and Reviewers :

Dr(Prof) Sunit Singhi

Dr K Chugh

Dr S Udani

Dr S Ranjit

Dr Rajiv Utttam

Dr Anil Sachdev

Dr Madhu Otiv

Dr S Deopujari

Dr Bala Ramachandran

Dr S Soans


Editor-In-Chief :

Dr Praveen Khilnani

Associate Editors :

Dr Nameet Jerath

Dr Kundan Mittal

Dr. Rakshay Shetty

Dr Basavaraj

Dr Gnanam

Executive Editor :

Dr V S V Prasad

Managing Editor :

Dr Dhiren Gupta

International Advisory

Board :

Dr Niranjan Kissoon

Dr Jerry Zimmerman

Dr Joseph Carcillo

Dr Ashok Sarnaik

Dr Peter Cox

Dr Shekhar Venkataraman

Dr Vinay Nadkarni

Dr Mohan Mysore

Dr Utpal Bhalala

Dr Suneel Pooboni

National Advisors :

Dr Y Amdekar

Dr S C Arya

Dr R N Srivastava

Dr C P Bansal

Dr V Yewale

Dr M P Jain

Journal of Pediatric Critical Care (JPCC)

Author Instructions

For JPCC (Journal of Pediatric Critical Care) Manuscript Submission

Manuscript submission will be possible using our online submission system shortly.

All submissions should be made by e mail until further announcement regarding the online submission details and the journal website [email protected]

Journal of Pediatric Critical Care is published quarterly (January, April, July and October) by IAP intensive care chapter. Manuscripts are judged by reviewers solely on the basis of their contribution of original data and ideas, and their presentation. All articles will be critically reviewed within 2 months, but longer delays are sometimes unavoidable. All manuscripts must comply with Instructions to Authors.

COPYRIGHT Submissions considered for publication in JOURNAL OF PEDIATRIC CRITICAL CARE are received on the understanding that they have not been accepted for publication elsewhere and that all of the authors agree to the submission. The journal requires approval of manuscript submission by all authors. A cover letter signed by all authors constitutes submission approval. Manuscripts will not receive a final decision until a completed Copyright Status Form has been received. As soon as the article is published, the author is to have considered transferred his right to the publisher. This transfer will ensure the widest possible dissemination of information . All concepts, ideas, comments, manuscripts, illustrations, and all other materials disclosed or offered to the IAP intensive care chapter on or in connection with this Journal are submitted without any restrictions or expectation of confidentiality. The IAP intensive care chapter shall have no financial or other obligations to you when you do not submit such information, nor shall you assert any proprietary or moral right of any kind with respect to such submissions. The IAP intensive care chapter shall have the right to use, publish, reproduce, transmit, download, upload post, display or otherwise distribute your submissions in any manner without notice or compensation to you.

ETHICS Investigations on human subjects should conform to accepted ethical standards. Fully informed consent should be obtained and noted in the manuscript. For all manuscripts dealing with experimental work involving human subjects, specify that informed consent was obtained following a full explanation of the procedure (s) undertaken. Patients should be referred to by number; do not use real names or initials. Also the design of special scientific research in human diseases or of animal experiments should be approved by the ethical committee of the institution or conform to guidelines on animal care and use currently applied in the country of origin.

STYLE OF MANUSCRIPTS All contributions should be written in English. Spelling should be American English. In general, manuscripts should be prepared according to International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals. JAMA 1997; 269: 927-934. Manuscript should be as concise and clear as possible. Manuscripts not following Instruction to Authors will be returned to the authors.

LANGUAGE Only English articles will be accepted. Prior to submission, manuscripts prepared by authors whose native language is not English should be edited for proper spelling, grammar, and syntax by a professional editor or colleague fluent in English.

MANUSCRIPTS CATEGORIES Materials reviewed for publication in JOURNAL OF PEDIATRIC

:


INTENSIVE CARE include the following:

Editorials

Editorials will present the opinions of leaders in pediatric intensive care

Original articles

Original clinical or laboratory investigation of clinical subjects should be reported. The material should be presented as concisely as possible.

Review articles

Reviews should document and synthesize current information on timely subjects.

Case reports

A case report should describe a new disease, or confirmation of a rare or new disease; a new insight into pathogenesis, etiology, diagnosis, or treatment; or a new finding associated with a currently known disease.

Rapid communications

These should be short papers, brief laboratory investigations and preliminary communications, which report new and exciting results requiring rapid publication.

Letters

These should be submitted in response to material published in the journal to make small clinical points or to introduce a point of view. Letters do not carry an abstract.

Book reviews

Reviews of newly published literature of interest.

MANUSCRIPT Manuscript submission should be made by e mail. Manuscripts should be submitted with text and tables, preferably in a recent Word or Word Perfect for Windows format. If article is submitted electronically, there is no need to send a hard copy. The Copyright Status Form should also be sent by e mail or fax or regular mail.

Manuscripts should be clearly in double spacing on one side of good quality A4 paper (30 x 21 cm), using 2.5 cm margins. Pages should be numbered consequently in the top right-hand corner, commencing with the Title Page and including those containing Acknowledgements, References, Tables, and Figures.

Conventional Manuscript The manuscript should be arranged as follows, with each section beginning on a separate page, except in the category of Rapid communications.

Cover letter A cover letter, in which the authors certify that the work submitted to The JOURNAL OF PEDIATRIC CRITICAL CARE has not been published elsewhere, in any form and that it is not being submitted simultaneously to another journal, should accompany the manuscript. A Copyright Status Form (see next page) signed all authors must accompany each manuscript.

Title page

The category of manuscripts (as listed above) should appear on the title page. The title on the title page should contain no more than 80 letters and spaces. A running title of no more than 40 letters and spaces should be supplied. Each author's first and last name as well as middle initial, highest academic degree, name of department(s) and institutions to which the work should be attributed, and address should appear. The author to whom communications will be directed should be designated and his or her telephone and FAX number and E-mail addresses (obligatory for submission) provided.

Abstract

The abstract should be no longer than 250 words for full-length articles and commensurately shorter for brief communications and case reports. Abstracts should summarize the problem addressed, investigational approach, results, and relevant conclusions.


Key words

No more than nine key words that will assist indexer in cross-indexing the article should be supplied. It is recommended that authors consult the medical subject heading from Index Medicus.

Main text

The text of observational and experimental articles is usually divided into sections with headings Materials and Methods, Results and Discussion. Long articles may need subheading within some sections. The purpose of the article and the rational for the study or observation should be summarized in an introductory paragraph.

Materials and Methods should be described in sufficient detail to leave the reader in no doubt as to how the results were obtained.

Results should be presented in a logical sequence the text.

Tables and figures should not include material appropriate to the discussion.

Discussion

The new and important aspects of the study and the conclusions should be emphasized, without repeating data in detail. This section should consider the implications of the finding and their limitations. Link the conclusions with the goals of the study, and relate the observations to other relevant studies. New hypotheses and recommendations, when appropriate, may be included. Acknowledgement should be made only to persons who have made genuine contributions and who endorse the data and conclusions.

References

References must be double-spaced and cited in text by using Arabic numerals in the order in which they appear in the text. Abbreviate titles of the journals according to Index Medicus. Unpublished data and personal communications should be given in round parentheses in the text and not as references. List all authors or editors, but if the number exceeds six, give six followed by et al.

References must be listed in Vancouver style:Standard journal articles: [1] Rose ME, Huerbin MB, Melick J, Marion DW, Palmer AM, Schiding JK, et al. Regulation of interstitial excitatory amino acid concentrations after cortical contusion injury. Brain Res 2002;935(1-2):40-6.Books: [2] Murray PR, Rosenthal KS, Kobayashi GS, Pfaller MA. Medical microbiology. 4th ed. St. Louis: Mosby; 2002.[3] Berkow R, Fletcher AJ, editors. The Merck manual of diagnosis and therapy. 16th ed. Rahway (NJ): Merck Research Laboratories; 1992.Chapter in a book:[4] Meltzer PS, Kallioniemi A, Trent JM. Chromosome alterations in human solid tumors. In: Vogelstein B, Kinzler KW, editors. The genetic basis of human cancer. New York: McGrawHill, 2002; p. 93-113.World Wide Web: [5] Autism Speaks. Transition Tool Kit: A guide for families on the journey from adolescence to adulthood, 2011. Available at: http://www.autismspeaks.org/family-services/tool-kits/transition-tool-kit. Accessed October 6, 2012

Tables

Limit the number of tables. Data in tables should not be repeated in graphs. Do not use vertical lines to separate information within the table. Tables should be double-spaced and numbered consequently corresponding to in-text citation. A table title and number must be provided at the top. Headings should be concise and use Arabic numbers. Tables should be restricted to one manuscript page unless absolutely necessary. If a table continues past one page, repeat all sequence in heads and the stub (left-hand) column. All non-standard abbreviations should also be explained in the footnotes. Footnotes should be indicated by *, **. Statistical measures such as mean ± SD (standard deviation) should be identified in headings.

Figures

Number figures as Fig. 1, Fig. 2, etc and refer to all of them in the text.

Each figure should be provided on a separate sheet. Figures should not be included in the text.

For the file formats of the figures please take the following into account:

Line art should be have a minimum resolution of 1200 dpi, save as EPS or TIFF


- Do not use faint lines and/or lettering and check that all lines and lettering within the figures are legible at final size

- All lines should be at least 0.1 mm (0.3 pt) wide

- Vector graphics containing fonts must have the fonts embedded in the files

Grayscales (incl photos) should have a minimum resolution of 300 dpi , or 600 dpi for combination art (lettering and images); save as tiff

Do not save figures as JPEG, this format may lose information in the process

Do not use figures taken from the Internet, the resolution will be too low for printing

Do not use colour in your figures if they are to be printed in black & white, as this will reduce the print quality (note that in software often the default is colour, you should change the settings)

For figures that should be printed in colour, please send a CMYK encoded EPS or TIFF

Figures should be designed with the format of the page of the journal in mind. They should be of such a size as to allow a reduction of 50%.

On maps and other figures where a scale is needed, use bar scales rather than numerical ones, i.e., do not use scales of the type 1:10,000. This avoids problems if the figures need to be reduced.

Each figure should have a self-explanatory caption. The captions to all figures should be typed on a separate sheet of the manuscript.

Photographs are only acceptable if they have good contrast and intensity.

Units and Abbreviations

Manuscript should be in metric units. Standard abbreviations may be used and should be defined in the Abstract and on the first mention in the text. In general, a term should not be abbreviated unless it is used repeatedly and the abbreviation is helpful to the reader.

Review and Selection of Papers

All articles will be critically evaluated by at least three reviewers of the editorial board(or known experts in the field) within 2 months, but longer delays are sometimes unavoidable.

Proofs and Reprints

Proofs are sent to the corresponding author, together with a reprint order form approximately 6 weeks prior to the publication. Authors should retain a copy of the original manuscript. Only printer's errors may be corrected; no changes in, or additions to, the edited manuscript will be allowed at this stage, unless in reply to specific editorial queries or requests. Corrected proofs must be returned within 48 hours of receipt, preferably by e mail or fax. If the publisher has not received a reply after 15 days, the assumption will be made that there are no errors to correct, and the article will be published after in-house correction. The reprint order form (with number of reprints requested, invoice and delivery address) should be returned with the corrected proof. Reprints may be ordered prior to publication on the form provided. The designated reviewing author will be responsible for ordering reprints for all authors. Reprints ordered after publication of the journal can be ordered at increased cost by special arrangement.

The publisher (IOS press) will provide to authors with a free watermarked PDF file of their article.

CHECK LIST FOR AUTHORS

Letter to submission Signed Copyright Status Form Three copies of article Title page Category of manuscript Title of article Running title Name (s), academic degrees, and affiliations of author (s) Name, address, telephone and FAX number and e-mail address of corresponding author Abstract including key words (except for Letter to the Editor) Text (double spaced) References (double spaced), on a separate sheet Tables (double spaced), on a separate sheet Figure legends (double spaced), on a separate sheet Figures properly labeled (three sets of glossy prints) Informed consent or certificate of ethical committee if indicated.


JPCC Copyright Status Form

Manuscript Number : JPCC_______ Received Date: _______________ Manuscript Title : ______________

______________________________________________________________________________________

I/We hereby confirm the assignment of all right, title and interest in and on the manuscript named above in all

versions, forms and media, now or hereafter known, to the IAP intensive care chapter effective if, and when it is

accepted for publication. I/We also confirm that the manuscript contains no material the publication of which

violates any copyright or other personal or proprietary right of any person or entity.

I/We shall obtain and include with the manuscript written permission from the respective copyright owners for

the use of any textual, illustrative or tabular materials that have been previously published or are otherwise

copyrighted and owned by third parties. I/We agree that it is my/our responsibility to pay any frees charged for

permissions. I/We affirm that all authors have participated in the study, have been and approved the manuscript,

and accept responsibility for the content of the article and its accuracy; that complied with the "Instructions to

authors".

To be signed by at least all the authors .Please note: Manuscript cannot be processed for publication until the

Editor has received this signed form.

Printed Name ______________________ Printed Name _____________________

Signature ______________________ Signature _____________________

Date ______________________ Date _____________________



Date ______________________ Date _____________________



Date ______________________ Date _____________________


Basic Pediatric Intensive Care Course (BPICC) India

– A Success Story

Dr. Madhumati otiv

Chairperson, IAP intensive care chapter, Pediatric intensive care unit,

KEM Hospital, Pune.

Basic pediatric intensive care course (BPICC) is a joint initiative of Pediatric Intensive Care Chapter (IAP) and the Indian Society of Critical Care Medicine, (ISCCM-Pediatrics section). This two day course was started in Critcare Conference 2009-Agra by the founder conveners Dr Praveen khilnani, Dr Rajiv Uttam and Dr Krishan Chugh. Currently more than 25 courses have been administered nation wide and more than 50 national wide instructors are teaching these courses. As the demand for this course has grown exponentially in past 4 years this additional conveners have been added on to the BPICC team as regional leaders. This addition will surely bring about efficient and effective dissemination and nationwide promotion. Following intensivists have agreed to shoulder the responsibility of being additional conveners.

Dr Anjul dayal (Hyderabad), Dr. Vinay joshi (Mumbai), Dr. Partha Bhattacharya (Kolkata), Dr. Vikas Taneja (New Delhi), Dr. Gnanum (Bangalore)

This skill based program is designed keeping in mind the needs of the Practicing Pediatricians, Intensivists, as well as the residents providing healthcare for the pediatric population requiring emergent and ICU care.

The Course has been also designed to update the delegates about the recent advances in Pediatrics Intensive Care and how they can apply this knowledge into their day-to-day practice. This course comprises of didactic lectures and skill stations. Some of the salient contents of this course are: how to recognize a sick child in emergency room, how to manage a child with neurologic Injury, principles of analgesia and sedation in PICU, antibiotics and antifungal management in PICU, PICU procedures, airway management and adjuncts, how to setup a ventilator, shock & its management, fluid therapy and electrolyte abnormalities, nutrition issues in PICU, blood component therapy in PICU, transport of sick children and many more issues.

During this course mornings are dedicated to didactic sessions while afternoon sessions are interactive workstation with smaller groups. Workstations consist of practice orieneted case studies, hands on training on ventilators, monitors etc. Faculty for these sessions are experienced pediatric intensivists. Several common procedures such as central line placement, arterial line placement, chest tube placement, intraosseous line placement, use of laryngeal mask airway are explained through videos.

This Basic PICU course is recommended for pediatricians interested in the field of pediatric emergencies and basic intensive care. Candidates who are PALS certified will benefit more as this course offers the next level of skill once patient is admitted to the PICU.

BPICC also offers a course manual which is regularly updated by experts and national faculty. A multiple choice question test is also in place to assess the learning by the participant of BPICC.


Some of recently held and upcoming courses are:

·ISCCM Critcare 2012, Pune

·NCPCC 2012, Mangalore

·IAP Pedicon 2013 Jan, Kolkotta

·ISCCM Delhi DCCS Aug 2013

·Bangaluru - Sep12-13 2013

·NCPCC 2013, Mahabaleshwar - Nov 21-22, 2013,

·BC Roy Childrens Hospital, Kolkotta - Dec 16-17, 2013

·Pedicon 2014, Indore - Jan 2014.

·Shishu Sadan Hospital, Kolkotta - March 24-25, 2014

·Hubli, Dharwad, Karnataka - April 26-27, 2014

·Solapur, Maharashtra - April 26-27, 2014

·Fortis Gurgaon, Haryana - May 24-25, 2014

·Rainbow Childrens, Hyderabad - June 29-30, 2014

·BLK - Delhi - Aug 2-3, 2014

·MAX Superspeciality, Delhi - NCPCC2014 Nov 6-7, 2014

·IAP Pedicon, Delhi 2015

·ISCCM Criticare 2015, Bangaluru

To organize the course in your area please contact any of the following:

1. Dr. Madhumati Otiv ([email protected], 09822040950)

2. Dr. Anil Sachdev. Office of IAP intensive care Chapter, Sir Gangaram hospital, Rajinder nagar, Delhi

3. Dr. Rajiv Uttam [email protected] 9810055670

4. Dr. Praveen Khilnani [email protected]


Original ResearchArticle

Introduction

Low platelet count is very common laboratory finding in critically ill adults , children and neonates in intensive care units. Incidence of thrombo-cytopenia has been reported from 13 to 58% in prior studies, depending on type of population and threshold used to define thrombocytopenia. Thrombocytopenia was associated with increased

[1-6] mortality in several studies.

In addition to participation in coagulation and thrombosis, platelets play an increasingly recognized physio-pathological role in the

[7-8]mediation of inflammation and infection. The dynamic nature of daily platelet counts gives

prognostic information of the outcome of critically [8-9]

ill patients. Platelet count is now considered to be predictor of outcome in ICU setting as independent

[10]parameter and various mortality have included it.

Many ICU patients do not have thrombocytopenia at admission but experience decreases in platelet count in ICU falling short of criteria for thrombo-cytopenia. The pathophysiological and prognostic significance of these decline in platelet count is unclear. After major surgical procedure or trauma platelet count decrease, then recover and overshoot

[11-13]the normal range with in few days. Little is known about platelet count decline after ICU admission for other reasons. Potential association between decline in platelet count and survival has

[14-17] been assessed in many adult studies. But these are few studies in pediatric critical care populated to

[18-19] support the data.

Hence we decided to study the incidence and the factors associated with thrombocytopenia in PICU

Decline in platelet count as a prognostic marker in critically ill children

Dr. Vinayak K.Patki*, Dr. Florence D. Birru**, Dr. Vidya V. Patki,***

*Pediatric Intensivist,** Sr.Resident,***Sr.Resident

Department of pediatrics,Wanless Hospital,Miraj,Dist-Sangli,416410, Maharashtra

Objectives: To study the variation in platelet count in critically ill children and correlate its association with their outcomes Methods: This was a prospective cross-sectional analysis of 150 critically ill children admitted in PICU of tertiary care hospital over period of 1 year. Laboratory data was collected with daily platelet counts from day of admission till death or discharge whichever was earlier in all patients. The study

9 population was grouped as thrombocytopenic (platelet count < 150 x 10 /L) and non-thrombocytopenic. They were compared with each other with respect to laboratory parameters and risk factors. Survivor and non survivors were compared with variation in platelet count. Decline in platelet count was correlated with mortality. Chi-square test, median test, ROC curve and forward stepwise binary logistic regression was used for statistical analysis. Results: Forty eight (32%) children had thrombocytopenia. They had significantly higher mortality [14(29.16%) vs 14(13.72%)] and bleeding tendency [13(28.08%) vs 4(3.92%) than non-thrombocytopenic children. Admission thrombocytopenia was not found to be risk factor for mortality. Though survivors and non-survivors had decline in platelet count in first four days, non-survivors had significantly higher drop. Platelet counts decline >30% at 72 hours was independent risk factor (odds ratio 4.126) for mortality with high sensitivity(91.7%) and specificity (84.4%) with area under ROC curve of 0.898 which was associated with PRISMII.Conclusion: Decline in platelet count can be used as prognostic marker of poor outcome in critically ill children.

Key words; Thrombocytopenia, decline in platelet count, Pediatric Intensive Care Unit


Correspondence:

Dr.Vinayak K Patki, thIndraprastha, 5 lane, Jaysingpur, 416101,

Maharashtra

E-mail address :[email protected]


ORIGINAL RESEARCH ARTICLE Decline in platelet count as a prognostic marker in critically ill children

setting and to study the correlation between the variation in platelet counts and subsequent outcome in critically ill children.

Material and Methods

This was a prospective, cross-sectional analysis of case records of critically ill children at an eight bedded Pediatric Intensive Care Unit of tertiary care hospital over a period of one year from august 2010 to july2011. Thrombocytopenia was defined as a platelet count of < 150.0/nL. Mild, moderate and severe thrombocytopenia was defined as platelet counts of <150/nL, <100/nL and <50/nl respectively. All consecutive critically ill children admitted staying for a minimum of 48 hours, were included in the study and followed up till discharge or death. The patients were followed-up prospectively.

A detailed history and examination was carried out in every patient. Besides patient's demographical data, primary diagnosis, source of admission, presence or absence of sepsis, bleeding tendency, use of central venous catheter, use of inotropes and mechanical ventilation were recorded. Pediatric Risk of Mortality Score (PRISM II) at admission was used to assess severity of illness.

Laboratory data collected at admission included complete blood count (CBC), blood urea nitrogen (BUN), serum creatinine, serum bilirubin, Blood Sugar Level (BSL), coagulation profile, Arterial Blood Gas (ABG) analysis. These were also repeated with the occurrence of thrombocytopenia. Daily platelet counts was done for all patients and if collection was done more than once in 24 hours, the lowest value was recorded for analysis. Low platelet counts were confirmed by direct examination of the blood smear. Variation in platelet counts was calculated at 24 hrs interval with respect to admission platelet count. Decline in platelet count was calculated by ratio of difference in platelet count to base line admission platelet level and presented as percentage drop.

For the purpose of this study, thrombocytopenia was 3defined as platelets less than 150X10 / L. The

study population of 150 patients was grouped as thrombocytopenic (those with platelet count < 150 x

3 10 /L) and non-thrombocytopenic (those with 3

platelet count > 150 x 10 /L). They were compared with each other to determine the relationship of thrombocytopenia with particular age, sex, source of admission, ventilation, shock, bleeding tendencies, transfusion, CPR, ICU stay, PRISM score, INR, total leucocyte count, bilirubin and sepsis. Survivors and non-survivor were compared with respect to decline in platelet count.

Sepsis was defined in patients with documented or assumed infection in presence of positive acute phase reactants and total leukocyte counts (TLC); (as defined by the American College of Chest

Physicians and Society of Critical Care Medicine).[20]

Bleeding tendency was defined as an episode resulting in a drop in hemoglobin of >2 g/dL within 24h, episodes requiring transfusions within 24h, and any intracranial hemorrhage. Multiple bleeding events at the same site were counted only once for each patient. Shock was defined as the need for vasoactive drugs for at least one hour (>5µg/ kg/mt dopamine/ dobutamine or any dose of epinephrine/ nor-epinephrine).

No informed consent was taken, as the study was purely observational. The hospital ethics and review board's approval was taken before undertaking the study. Statistical Analysis of data was done by using SPSS 19.0 Statistics software. Normally distributed continuous variables were compared with Student's t-test and categorical variables were compared with Chi-square test or Fisher's exact test. For non-normally distributed (skewed) data median was used instead of mean and was compared using “median test”. After determination of individual factors with mortality by univariate analysis, a binary logistic regression model of significant factors associated with mortality was developed. The results of regression model were presented as adjusted odds ratio with 95% confidence interval. Wald's chi square value was used to test unique contribution of each predictor. Regression model adequacy was tested by Omnibus test of model coefficients, Negelkerke R square and Hosmer and Lameshow chi square test. Receiver Operating Characteristic Curve analysis was used to find out the cut-off values for drop in platelet count from the baseline and for PRISM II score to validate predicted


probabilities of death p< 0.05 was considered statistically significant.

Results

During study period of one year, out of 206 total admissions 150 critically ill children who stayed for more than 48 hours were included in study. Fifty six children were excluded because of their stay less than 48hrs.Median age of study population was 69 months (range 2-92 months) with male to female ratio 1.58. Forty eight (32%) children were thrombocytopenic and rest 102 (68%) were non-thrombocytopenic. Both groups were comparable with respect to demographic variables like age, weight, sex and severity of illness [Table 1]. Among thrombocytopenic children 43 (89.5%) had thrombocytopenia at admission while rest 5(11.5%) had developed it eventually during hospital stay. Mild, moderate, and severe thrombocytopenia was present in 18(37.5%), 12(25%), and 18(37.5%) of patients respectively. For the given effect and alpha (0.05,2 tailed) statistical power was 0.975. Source of admission, shock, use of inotropes, total leucocytes count( TLC > 15000 ) , blood urea nitrogen (BUN > 20 mg/dl), serum creatinene >1.2mg.dL had no correlation with thrombo cytopenia. But presence of Sepsis, use of central line, mechanical ventilation, cardio-pulmonary resuscitation (CPR), INR>1.5, Total leucocytes count( TLC < 4000 ) and serum bilirubin >1.5 were significantly associated with the development of thrombocytopenia[Table 1]. After regression analysis, bleeding tendencies (Odds ratio 5.076), CPR (Odds ratio 3.80), Bilirubin > 1.5(Odds ratio 2.44),Ventilation(Odds ratio 2.27) and Sepsis (Odds ratio 2.11) found to have significant correlation with thrombocytopenia [Table 3]

Bleeding tendency [13(28.08%) vs 4(3.92%)] and mortality [14(29.16%) vs 14 (13.72%)] were significantly higher in thrombocytopenic than non-thrombocytopenic children. There was no significant difference of mean length of stay in PICU (4.77±1.79 vs3.76±1.57) between two groups. [Table 2]

Twenty eight (18.66%) children expired. PRISMII score (6.28±2.64 vs11.79±5.188) was significantly higher in non survivors. Use of mechanical ventilation, inotropes and presence of sepsis were

significantly associated with mortality.[Table 4]

Median admission platelet count (290500 vs256500), minimum platelet count median ( 1 9 9 5 0 0 vs 153000), admission thrombocytopenia [34(27.86%) vs 9(32.14%)] or overa l l thrombocytopenia [38(31.15%) vs 10(35.71%)] was not significantly higher in non survivors. [Table 4]

Platelet counts decreased significantly in the initial four days of PICU stay in both survivors and non-survivors.[Table 5]. Absolute platelet counts were lowest on day 4. Though absolute platelet count between survivors and non survivors was not different significantly except on day 3, the decline of platelets was significantly higher in non-survivors till first 96 hrs. [Table 6]

Change in the platelet count was monitored daily and drop in platelet count was studied by receiver operator curve analysis and was compared with that of PRISMII. The values for Area under curve (AUC) for drop of platelet at 24 hrs (0.749), at 48hrs( 0.860) ,at 72hrs (0.898) and at 96 hrs (0.803) were comparable with PRISMII score ( 0.888) [Table 7][Fig 1]. As AUC for Drop at 72 hrs for criteria >31.7 had highest sensitivity and specificity closely matching with respective value of PRISM2 score. Rounded figure of drop more than 30% at 72 hrs as an independent risk factor for mortality was studied with multivariate analysis by using forward stepwise method of binary logistic regression. Values of Omnibus model coefficent(35.23.p-0.000 at df=4) Nagelkerke R square (0.388) and Hosmer and Lemeshow test ( chi-square1.92 at df-7, sig.964) indicated strong predictive value and overall fitness of the regression model. Drop of platelet >30% at 72hrs (odds ratio 4.126,wald-5.391,p-0.02) and PRISMII score (odds ratio1.422 ,wald-11.882,p-0.001) were independently associated with increased risk of death, while use of inotropes(odds ratio 1.772,wald-0.892, p-0.345)and mechanical ventilation(odds ratio0.534 ,wald-1.091, p-0.296) were not found to be independent predictors of mortality.[Table 8]

Discussion

The relationship between drop in platelets counts


during PICU stay and mortality in critically ill children was analyzed in this study. In a large group of medical and surgical ICU patients the prognostic importance of platelet counts extends well beyond initial changes. A total of 48 children (32%) had at least one platelet count <150 × 109/L, this incidence of thrombocytopenia i s comparable to Vanderschueren S et al, Strauss et al, Agrawal et al

[2,15,18,19]and Mussa et al studies. Large difference in study population, different inclusion criteria and definitions used in various studies reflects great variation in incidence of thrombocytopenia ranging

[1,6]from 13 -58%.

Sepsis was found to have association with thrombocytopenia. Platelets play a complex role in sepsis, they are able to modulate not only their own

[9]function but also cells around them. cardio-pulmonary resuscitation has been quoted as risk factor for development of thrombocytopenia by

[15]Strauss et al. We found similar association. Though association of shock with thrombo-cytopenia is well established in Vanderschueren S et

[2]al, we were not able to demonstrate it. Our finding

[18]was consistent with Agrawal et al. Similarly low total leucocyte count (TLC <4000) and disturbed biochemical markers in the form of elevated serum bilirubin>1.5mg/dl and INR >1.5 were also

[18,19]predictive of thrombocytopenia. Mechanical ventilation and central line insertion were described

[12,15]as independent risk factor for thrombocytopenia although this may only reflect disease severity and local ICU preference. INR>1.5 was another factor associated with thrombocytopenia, which was comparable to the significant association of DIC in the evolution of thrombocytopenia found by Strauss

[15]et al . This finding was consistent with Agrawal et

[18] [19]al but contrast to Mussa et al

Thrombocytopenic children had significantly higher mortality found in our study was consistent

[2,3,15,18,19]with prior studies. In consistent with [18]

Agrawal et al admission thrombocytopenia was not associated with risk of death in our study, signifying that predictive value of low platelet count does take disease progression in account. Bleeding tendency was found to be a significant predictor of morbidity associated with thrombocytopenia in our

study. Bleeding can be both a risk factor and cause for thrombocytopenia and this was not elaborated sufficiently in the present study, though most of the patients had bleeding secondary to thrombo-cytopenia rather than vice-versa so per se thrombocytopenia is not a significant factor for high

[18]morbidity or mortality. Agrawal et al found [19]similar results.Similar to findings by Mussa et al

we also could not find prolonged PICU stay in thrombocytopenic children.

Absolute platelet count at admission was lower in non survivors than survivor and remained lower

[19]throughout PICU stay in Mussa et al study In our study admission platelet count and counts during PICU stay were not significantly different between two group except on day three, which can be explained by significantly higher drop of platelets on day 3.

Very few studies evaluated link between declining platelet count and outcome in ICUs.

We found that platelet counts decreased significantly in the initial four days of PICU stay in both survivors and non-survivors. Absolute platelet counts were lowest on day 4. In their adult studies

[14] [16]Moreau et al and Akca S demonstrated decline in platelet count from day one reaching lowest on day four, but differed significantly between survivors and non- survivors only on day 7. Similar

[18]finding was observed by Agrawal et al. We were not able to study the rise in platelet count at stabilization of platelets after day 5 as majority [24(85.7%)] of death occurred within this period.

[18]Agrawal et al found drop of platelets >27% with

[14]increased mortality risk. Moreau et al and Strauss

[15]et al have found >30% decline in platelet count as independent predictor of death with odds ratio 1.54 and 3.73 respectively. With similar decline of >30% in platelets we found odds ratio of 4.126 which was

[14]quite comparable with Moreau et al and Strauss et [15]

al

Limitations of study

The study is not powered to actually work out the cause and effect and can only suggest an association between various factors. Besides small size, various



confounding factors are present in sick children at any given point of time, which cannot be controlled. We did not study the mechanisms that lead to decreased platelet count. Many pre-existing condition or drugs may influence platelet count, which were not studied in present cohort. Results needs to be validated in larger study population as limited number of patients in certain groups doesn't allow more precise estimation of odds ratio.

Conclusions and Recommendation

Thrombocytopenia is common in pediatric intensive care unit as in adult ICUs. Thrombocytopenic children have higher incidence of bleeding and higher mortality. Sepsis, mechanical ventilation and cardiopulmonary resuscitation increase probability of thrombocytopenia. Serial measurements of platelet counts are better predictors of disease progression than one-time values. Decline in platelet count irrespective of thrombocytopenia can be used as prognostic marker of poor outcome in critically ill children.

Similar studies are required with larger number of patients in the critically ill pediatric population to further consolidate the present study's findings.

References

1. Baughman RP, Lower EE, H C Flessa HC and Tollerud DJ. Thrombocytopenia in the intensive care unit. Chest 1993;104:1243-1247

2. Vanderschueren S, De Weerdt A, Malbrain M, et al. Thrombocytopenia and prognosis in intensive care. Crit Care Med 2000; 28:1871–1876

3. Crowther MA, Cook DJ, Meade MO, Griffith LE, Guyatt GH, Arnold DM, et al. Thrombocytopenia in a medical-surgical critically ill patients: Prevalence, incidence and risk factors. J Crit Care 2005; 20:348-53

4. Guida JD, Kunig AM, Leef KH, McKenzie SE, Paul DA. Platelet counts and sepsis in very low birth weight neonates: Is there an organism specific response? Pediatr 2003; 111:1411-5

5. Christensen RD, Henry E, Wiedmeier SE, Stoddard RA, Sola Visner MC, Lambert DK, et al. Thrombocytopenia among exteremely low birth weight neonates: Data from a multihospital

healthcare system. J Perinatol 2006; 26:348-53

6. Roberts I, Murray NA. Neonatal thrombo-cytopenia: Causes and management. Arch Dis Child Fetal Neonatal Ed 2003; 88:359-64

7. Levi M. Platelets. Crit Care Med 2005; 33: 523–525

8. Levi M, Opal SM. Coagulation abnormalities in critically ill patients. Crit Care 2006; 10:222–228

9. Vincent JL, Yagushi A, Pradier O. Platelet function in Sepsis. Crit Care Med 2002; 30:5313-7

10. Pollack MM, Patel KM, Ruttiman UE. PRISM III: An updated pediatric risk of mortality score. Crit Care Med 1996; 24:743-52

11. Stephan F, Hollande J, Richard O, Cheffi A, Maier- Redelsperger M, Flahault A. Thrombocytopenia in a surgical ICU. Chest 1999; 115:1363–1370

12. Aissaoui Y, Benkabbou A, Alilou M, Moussaoui R , E l H i j r i A , A bouqa l R , e t a l . Thrombocytopenia in surgical intensive care unit, incidence, risk factors and effects on outcome. Press Med 2007; 36:43-9

13. Hanes SD, Quarles DA, Boucher BA. Incidence and risk factors of thrombocytopenia in critically ill trauma patients. Ann Pharmacother 1997; 31:285–289

14. Moreau D, Tinsit JF, Vesin A, Garrouste-Oryeas M, de Lassence A, Zahar JR, et al. Platelet count decline: An early prognostic marker in critically ill patients with prolonged intensive care unit stays. Chest 2007; 313:735-41

15. Strauss R, Wehler M, Mehler K, Kreutzer D, Koebnick C, Hahn EG. Thrombocytopenia in patients in the medical intensive care unit: bleeding prevalence, transfusion requirements, a n d o u t c o m e . C r i t C a r e M e d 2002;30:1765–1771

16. Akca S, Haji Michael P, de Medonca A, Suter PM, Levi M, Vincent JL. The time course of platelet counts in critically ill patients. Crit Care Med 2002; 30:753–756

17. Nijsten MW, ten Duis HJ, Zijlstra JG, Porte RJ, Zwaveling JH, Paling JC, et al. Blunted rise in platelet count in critically ill patients is associated with worse outcome. Crit Care Med, 2000; 28:3843-6

18. Agrawal S, Sachdev A, Gupta D, et al. Platelet



counts and outcome in the pediatric intensive care unit. J Crit Care 2008; 12:102-108

19. Russul F. Mussa, Adeba A. Al- Al-Alyasiri and Jasim M. Al-Marzoki. Prognostic Value of Platelet Count in Paediatric Intensive Care Unit. Medical Journal of Babylon 2012;9:833-42

20. Goldstein B, Giroir B, Randolph A. International Consensus Conference on

Pediatric Sepsis. International pediatric sepsis consensus conference: Definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005;6:2-8

Table 1

:Comparative demography in thrombocytopenic verses non-thrombocytopenic children

Parameter

thrombocytopenic

(n=48)

Non-

thrombocytopenic

(n=102)

Pvalue

Mean Age in months

81.96±60.79

62.12±45.99

0.379

Male/female

26/22

66/36

0.141

Weight in kg

12.68±6.93

13.84±7.12

0.688

Admission source-

Ward/ICU

10/38

35/67

0.093

INR>1.5

9

6

0.02

TLC >15000

7

25

0.115

TLC< 4000

8

2

0.012

BUN >20

10

11

0.132

Serum creatinine>1.2

3

7

0.888

CPR n (%)

13 (27.08)

4 (3.92)

0.000

Serum bilirubin >1.5

19

12

0.000

Use of inotropes n (%)

13 (27.08)

34 (33.34)

0.572

Ventilation n (%)

16 (33.34)

16 (15.68)

0.019

PRISMII score(mean)

7.71±3.71

7.07±3.68

0.321

Shock n (%) 10 (20.83) 13(12.74) 0.228

Central line n (%) 12 (25) 8 ((7.83) 0.005

Sepsis n (%) 23(47.91) 15 (14.70) 0.000

CPR=cardiopulmonary resuscitation, PRISM2: Pediatric Risk Of Mortality Score II

Tables & Figures



Table 3: Significant risk factors associated with thrombocytopenia (Regression Analysis)

Table 2: Comparison of morbidity and mortality between thrombocytopenic verses non

thrombocytopenic children

Parameter thrombocytopenic

(n=48)

Non- thrombocytopenic

(n=102) Pvalue

Mean PICU stay in days 4.17±1.79 3.76±1.57 0.454

Mortality n (%) 14(29.16) 14 (13.72) 0.023

Bleeding Tendency n (%) 13(28.08) 4(3.92) 0.000

Variable Odds ratio 95% CI

Bleeding tendencies 5.0763 1.3382 to 19.2570

CPR 3.8055 0.9533 to 15.1915

Bilirubin > 1.5 2.4413 0.8782 to 6.7865

Ventilation 2.2761 0.2405 to 21.5445

Sepsis 2.1146 0.7815 to 5.7215

INR >1.5 0.6702 0.1320 to 3.4030

Central line 0.6140 0.0921 to 4.0952

PRISM II > 8 0.3210 0.1005 to 1.0250

Variables Survivors (n=112)

Non-survivors (n=28)

P-value

Age in months(median) 48 39 0.503

Weight in kg 13.75±8.97 14.05±6.712 0.888

Sex n (% of male) 73 (59.8%) 18(64.3%) 0.792

PRISMII score 6.28±2.64 11.79±5.188 0.003

Mechanical ventilation n (%) 17(13.9%) 15(53.6%) 0.004

Inotropes use n (%) 31(25.4%) 16(57.1%) 0.008

Admission platelet count median(/L) 290500 256000 0.675

Admission thrombocytopenia (%) 34(27.86%) 9(32.14%) 0.652

Minimum platelet count median 199500 153000 0.063

Overall thrombocytopenia (%) 38(31.15%) 10(35.71%) 0.658

Table 4 : Comparison between survivor and non survivors

PRISMII: Pediatric risk of mortality score II



Day of platelet count

Median Platelet Count

Chi square (median test)

Degree of freedom

p-value

Survivors (n=122) Non-Survivors (n=28) N

Day-1 256500 290500

150 1.098 1 0.209

Day-2 218500 210000 150 2.810 1 0.094Day-3 198000 142500 128 8.960 1 0.003Day-4 180000 138000 76 1.024 1 0.312

Day-5 221000 163000 48 1.395 1 0.238

Time Drop in Platelet Count %(median)

Chi square (median test)

Degree of freedom

p-value

Survivors (n=122) Non-Survivors (n=28) N

24 hrs 7.04 25.88

150 12.69 1 0.000

48 hrs 3.97 43.8 128 24.18 1 0.000

72 hrs 2.6 49.55 76 8.016 1 0.00996hrs 0.23 45.68 48 7.111 1 0.006

variable AUC SE P value 95%CI sensitivity specificity criterion

%Drop of platelets 24hrs 0.749 0.0512 0.0001 0.672to 0.816 64.3% 77.9% >21.23

%Drop of platelets 48hrs 0.860 0.0447 0.0001 0.788 to 0.915 85.7% 85% > 27.4

%Drop of platelets 72hrs 0.898 0.0475 0.0001 0.805 to 0.956 91.7% 84.4% > 31.17

%Drop of platelets 96hrs 0.803 0.0475 0.0001 0.805 to 0.956 58.3% 91.7% > 46.62

PRISM2 score 0.888 0.0279 0.0001 0.826 to0.933 92.9% 95.4% >7

Null hypothesis area=0.5, criterion based on predicted probability, AUC: Area under curve; SE: Standard error; PRISM2: Pediatric risk of mortality score II; CI: Confidence interval; ROC: Receiver operating characteristic

Table 7: ROC curve analysis of factors associated with mortality

Table 6: Comparison of drop in Platelet count between survivors and non-survivors

Table 5: Comparison of platelet count between survivors and non-survivor



Variable Wald df P value Odds

ratio

PRISM II score 11.882 1 0.001 1.422

>30% drop at 72 hours 5.391 1 0.020 4.126

Inotropes use 0.892 1 0.345 1.772

Mechanical ventilation 1.091 1 0.296 0.534

Table 8: Multivariate analysis of factors associated with mortality by logistic regression

PRISMII: Pediatric Risk Of Mortality Score II; df: Degree of freedom

Figure1: Comparison of ROC curves




Best Evidence

Effect of Aerosolized Colistin as Adjunctive Treatment on the Outcomes of Microbiologically Documented Ventilator-Associated Pneumonia Caused by Colistin-Only Susceptible Gram-Negative Bacteria

Tumbarello M, De Pascale G, MD; Trecarichi, EM, De Martino S, Bello G, Riccardo M, et al. Chest. 2013;144(6):1768-1775. doi:10.1378/chest.13-1018

Ventilator Associated Pneumonias (VAPs) are not only common but also carry high mortality. Reported rates vary from 10-70%. Kollef's data in 2001 reminded us that using the correct antibiotic was as important as using it early if mortality was to be kept low. Increasingly, we encounter GNB that are Colistin Only susceptible (COS), be they pseudomonas, Acinetobacter or, to a lesser extent, Klebsiella. Efficacy because of poor penetration in tissue remains an issue because of its polycationic /hydrophilic structure. Hence it is a drug with poor lung penetration. Whether aerosolized (AS) colistin solutions enhanced efficacy in VAP was always debated and results from previous studies produced conflicting data.

In this retrospective, adult study spanning seven years, patients given IV Colistin were matched with patients given IV-AS Colistin. Matching was done for severity of illness scores for ICU illness and age. Only those with single isolates of quantitative BAL cultures of either P aeruginosa. A baumanni, or K pneumoniae were taken. Outcomes were blinded during matching. IV-Colistin at 1,000,00 iu/kg/day in 2-3 divided doses plus AS Colistin in the treatment group 1 million units 8 hrly. Both started and stopped together. 288 patients developed VAP caused by COS. 42%(121) received IV –AS Colistin and 104 met enrollment criteria. 104 patients with IV Colistin were analysed. Clinical cure rates were significantly higher (69.2% vs 54.8%) in the IV+AS group (p value 0.03). The median duration of post

VAP ventilation was shorter in the IV+AS group (8 vs 12 days p value = 0.001). AKI onset during colistin therapy was associated with treatment failure. Four previous studies have shown similar results but three of these were not pure COS and other antibiotics were included in the regimen.

Comment: The main drawback is that it is a retrospective data collection study. As COS and XDR GNB become more common organisms for VAP, the addition of AS colistin to the IV regimen may be a value addition.

A randomized trial of hyperglycemic control in pediatric intensive care.

Macrae D, Grieve R, Allen E, Sadique Z, Morris K, Pappachan J, Parslow R, Tasker RC, Elbourne D; CHiP Investigators. N Engl J Med. 2014 Jan 9; 370(2):107-18. doi: 10.1056/NEJMoa1302564.

Tight Glycemic Control. Is the target in sight? Michael SD Agus Ed. NEJM Jan 9 2014.

The debate in adults hasn't ended and the debate for children has gathered steam with this article in the NEJM followed by an editorial comment. This multicentre trial in the UK randomized 675 children to tight glycemic control- 72-126 mg/dl (4-7mmol/l) by a central computerized system delivering Insulin infusions and 694 to conventional control when blood sugar levels exceeded 216 mg/dl (12 mmol/l) in two consecutive blood samples drawn 30 mins apart. Insulin was discontinued at 180 mg/dl (10 mmol/l). Moderate hypoglycemia was taken as 36-45 mg/dl (2-2.5 mmol/l) and severe as <36 mg/dl (<2 mmol/l). More patients 66.6% vs 16.1% in the tight glycemic group received insulin infusions (P< 0.0001) and for a longer duration, 3.2 vs 1.7 days. There was no difference in primary 30 days mortality outcome and free from ventilation days outcome between the two groups. In secondary

Journal scanDr. Soonu Udani, Head of pediatrics and PICU, Hinduja hospital, Mumbai

Dr. Rekha Solomon, Jr consultant, PICU Hinduja Hopsital, Mumbai


BEST EVIDENCE Journal Scan

outcomes, the tight glycemic control groups had a tendency towards lower need of renal replacement therapy. 4.1% of patients who did not receive insulin had hypoglycemia vs 17.9% of those receiving insulin. The proportion was higher in the tight glycemic control group- 12.5% vs 3.1% P< 0.001 for moderate and 7.3% vs 1.5% P<0.001 for severe. 11.1% of those with hypoglycemia died whereas 4.4% of those with no episode of hypoglycemia died, P<0.001. There was no major neurological damage reported from the hypoglycemic episodes.

This study had 60% post operated cardiac surgical patients. The cardiac patients in the tight glycemic control group had a tendency to a higher mortality but this was not statistically significant.

Comment: The finding of an increased mortality in the cardiac surgery sub group cohort is consistent with the NICE-SUGAR study and reinforces the evidence that tight glycemic control is NOT suited to this subgroup. However, the reduction in cost of over $13,000/- per patient demonstrated in the non cardiac group along with the relatively low risk of neurological damage from hypoglycemia, could make a case for using this strategy in this cohort. In conclusion, this study did not show an overall significant effect on major outcomes but tight glycemic control led to a shorter length of stay and lower health costs in the long term. It is as yet not recommended in routine clinical practice and BEST avoided in post op cardiac patients.

Comparison of High-Frequency Oscillatory Ventilation and Conventional Mechanical Ventilation inPediatric Respiratory Failure.

Gupta P, Green JW, Tang X, Gall CM, Gossett JM, Rice TB, Kacmarek RM, Wetzel RC. JAMA Pediatr. 2014 Jan 20.

In the wake of several adult studies showing that High-Frequency Oscillatory Ventilation, when used outside of the rescue mode, has a higher mortality as compared to conventional ventilation (CMV), here comes a study from the Arkansas Children's hospital. The outcomes evaluated included time on

ventilation, ICU LOS, mortality and standardized mortality ratio. The study was non-randomized and data collected from the VPS database (Online critical care network. Prospective, observational, cohort of consecutive ICU admissions from a diverse set of hospitals in the USA).

Of the 26, 534 patients receiving ventilation, 25,208 (95%) received conventional ventilation and only 1266 (4.8%) received HFOV while 60 (0.2%) received liquid ventilation. 9177 patients from 98 hospitals were included for analysis. 902 received HFOV, 483 (53.5%) early< 24 hrs and 419(46.5%) late > 24 hrs. 8275 received (CMV) Propensity score matching was done to determine the likelihood of the patients receiving HFOV. These were put in the matched groups. In all the groups, the mortality in the HFOV groups was higher. HFOV 164/902 (18%) vs 269/8275 (3%) P<0.001. Patients in the late HFOV group had higher standardized mortality rate (3.06; 95% CI, 2.43 – 3.86) compared to patients in the early HFOV group (1.65; 95% CI, 1.35 – 2.03). Increasing interval between intubation and start of HFOV was associated with higher mortality (p=0.01).

Comments:.There was no significant difference in the late vs early HFOV groups. Similar results were seen in the propensity score matched groups. The conclusion drawn was that the application of both, early and late HFOV is associated with increased mortality, increased length of stay and increased days of ventilation. While data collection from multiple sources may help in answering complex questions that require large numbers of patients for analysis, accuracy of data may be an issue. However, this method may leave gaps in case matching that leave many questions unanswered. The question still remains open regarding the efficacy of HFOV as a rescue therapy when CMV settings are at their maximum and ECMO isn't a viable option.

Isotonic Vs Hypotonic maintenance fluids in hospitalized children: a Meta- Analysis. Jingjing Wang, Erdi Xu , yanfeng Xiao. Peds 2014; 133;105

10 RCTs included for analysis from 8 studies.



Medical and surgical patients were in the studies, barring one, which did not include surgical patients. Much of the data, by the authors own admission, was incomplete. Sodium level pNa of <136 mmol/l was taken as an primary outcome and <130 mmol/l and or symptoms as a secondary outcome. Clinical outcomes were also included. The first pna was at 8-72 hours and the solutions used in the 2 arms varied from 0.33-0.45 S in the hypotonic group and Hartman's solution to 0.9S in the isotonic group. The analysis showed a significant hyponatremia RR 2.24, 95%CI 1.52 to 3.31,P<0.001 in the hypotonic fluid group. There were also fewer clinical adverse events in the isotonic fluid group. However, the correlation of these to the hyponatremia is unclear. Only one study reported one case of hyponatremic seizures. Another reported a death in a child with ARDS- the cause being unclear and yet another reported a child developing hypertension in the hypotonic fluid group. A direct relationship between hyponatremia and the SAE cannot be made.

Hypotonic Vs isotonic saline inhospitalised children: a systematic review. K Choong, ME Kho, K menon, D Bohn. Arch Dis Child; 91: 828-835

It is worth relooking at the same issue brought up by Desmond Bohn several years ago. This group has been preaching this gospel for several years now and at least in the PICU, practice has changed to the use of isotonic fluids. This study showed similar results and also demonstrated a higher AEs rate on the forest plot. The clinical significance of these on outcome was unclear.

Hypotonic versus Isotonic Fluids in Hospitalized Children: A Systematic

Review and Meta-Analysis

Byron Alexander Foster, MD, MPH1, Dina Tom, MD1, and Vanessa Hill, Md2

The Jour Peds. In press. 2014 prepublication on line.

A total of 1634 citations were screened. Ten studies (n = 893) identified as independent randomized controlled trials were included. Five studies examined subjects in the intensive care unit setting, including 4 on regularwards and 1 in a mixed setting. The same studies with 2 extra as in the previous studies are cited here. The conclusions are also the

same.

The need for prospective data gathering from multiple centres is probably essential if the literature on this subject is to produce any new material.

Comment: Isotonic fluids would appear to be physiologically more appropriate in sick children. Water and Electrolyte handling also varies with illness and ADH secretion and is a dynamic process. No one recipe can be advocated for all the various problems encountered. Meticulous monitoring and the readiness to readjust fluids in quantity and quality will ultimately give the best results.

Albumin Replacement in Patients with Severe Sepsis or Septic Shock

ALBIOS study

published on March 18, 2014, at NEJM.org.

Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M. et al.

Albumin is the main protein responsible for plasma colloid oncotic pressure; it acts as a carrier for several endogenous and exogenous compounds, with antioxidant and anti-inflammatory properties, and as a scavenger of reactive oxygen and nitrogen species and operates as a buffer molecule for acid–base equilibrium. 100 Italian ICUs -(ALBIOS Albumin Italian Outcome Sepsis) conducted a randomized, controlled trial to investigate the effects of the administration of albumin and crystalloids, as compared with crystalloids alone, targeting a serum albumin level of 30 g per liter or more in a population of ICU patients with sepsis. Randomized centrally, the albumin group received 300 ml of 20% albumin solution from day 1 until day 28 or ICU discharge (whichever came first), on a daily basis, to maintain a serum albumin level of 3 g/dl or more.

Primary outcome was death at 28 days and secondary outcome was death at 90 days. Other secondary outcomes were organ dysfunction and severity of dysfunction. 910 received Albumin + crystalloid and 908 received crystalloid alone. Data was analysed for 888 and 893 pts respectively. Other

treatments, including albumin administration if thought necessary, was given as per physician guidance.

Net daily fluid balance was lower in the Albumin group P<0.0001. Mean blood pressure was higher P =0.03 in the Albumin group, and heart rate was significantly lower P<0.0001.

At 28 days (31.8 vs 32%)and 90 days (41.1 vs 43.6%) there was NO mortality difference. (relative risk, 0.94; 95% CI, 0.85 to 1.05; P = 0.29). No significant difference was observed between the two study groups with respect to either the number of newly developed organ failures or the median SOFA score. No major difference in secondary outcomes with the exception of the time to suspension of the administration of vasopressor or inotropic agents,

which was shorter in the albumin group than in the crystalloid group (P = 0.007)

Comment: The goal of this study was to keep the albumin level normal and not use it as a resuscitation fluid, unlike the SAFE study. The demonstration of lower cardiovascular SOFA scores with earlier freedom from inotropes and better heart rates and mean BPs early in the illness is an advantage in goal directed therapy. The SAFE study showed a small drop in mortality in sub analysis which this study does not show. The cost of Albumin administration on a daily basis vs the advantage gained in achieving these secondary end points that did not impact mortality need to be further discussed.



Introduction

There has been a tremendous technological advancement in diagnostic cardiology, anesthetic/ surgical/ extracorporeal techniques, and improvements in the perioperative management strategies in the last two decades that contributed to successful outcome of surgical procedures performed on neonates, infants and children with congenital heart disease (CHD). This has been associated with a substantial decrease in the morbidity and mortality in these groups of patients despite the complexity of disease pattern. However, improvements in morbidity and mortality are associated with a significant increase in the cost of treatment. The focus in now directed towards provision/delivery of quality care in a cost–effective manner; this includes issues in intensive care unit (ICU) settings like duration of mechanical ventilation & length of ICU and hospital stay: this is gaining attention of both the clinicians and the hospital managers.

Infants and children are not miniature adults:

Problems in children with CHD in ICU settings include the following: (i) Infants and children are

not miniature adults. They have important anatomical/physiological differences when compared to the adults and these concerns need to be addressed when dealing with children with CHD just as with any child with any other organ disorder. (ii) Patients with CHD depend on a delicate balance between circulatory pathophysiology and compensatory mechanisms. The compensatory mechanisms often decrease cardiopulmonary reserve and increase their susceptibility to physiological insult. This diminished margin of safety characterizes the pediatric patient with CHD and dictates the guidelines of care. (iii) Neonates, infants and young children are not able to communicate their level of distress and discomfort. We rely on indirect clinical evidence from autonomic responses to stress, such as hypertension and tachycardia, and make assumptions regarding the level of pain relief or sedation.

Palliation first or primary repair?

Over the past two to three decades, there has been a considerable transformation in the viewpoint of management of cardiac operations on neonates and infants. This relates to performing reparative operation first when the patient presents for surgery

1rather than initial palliation and later repair . The primary aim of early repair is to promote normal growth and development and to limit the pathophysiological consequences of congenital cardiac defects such as volume overload, pressure overload, and chronic hypoxemia. However, because of a limited physiological reserve and the complications associated with extracorporeal circulation (ECC) and surgery, the risk of cardio-respiratory dysfunction in neonates and young infants in the immediate postoperative period may be increased with the strategy of primary repair at the time of initial presentation.


Recent advances in postoperative care of pediatric cardiac surgical patients

Dr. Muralidhar K, MD,FIACTA, FICA, MBA,Director (Academic), Senior Consultant & Professor Anesthesia and Intensive Care

Narayana Hrudayalaya Hospitals, Bangalore

Correspondence:

Dr. Muralidhar K, MD,FIACTA, FICA, MBA,

Director (Academic), Senior Consultant & Professor Anesthesia and Intensive Care, Prof. of International Health, University of Minnesota, USA

Narayana Hrudayalaya Hospitals, #258/A, Bommasandra Industrial Area, Anekal taluk, Bangalore – 560 099, Karnataka, India

Ph (Direct): 080-71222689 or 080-27836966; Fax: 080-27835222/27832648

E-mail: [email protected] / [email protected]


Effects of cardiac surgery on infants and children

1) The effects of prolonged cardiopulmonary bypass (CPB) relate in part, to the interactions of blood components with non-endothelial surfaces of the extracorporeal circuit and result in a systemic inflammatory response syndrome (SIRS). This is magnified in neonates and infants due to the large bypass circuit surface area and priming volume relative to patient blood volume. Humoral responses include activation of proinflammatory cytokines, complement, kallikrein, eicosanoid and fibrinolytic cascades. Cellular responses include endothelial activation, platelet activation, endotoxin release and an inflammatory adhesion molecule cascade stimulating neutrophil activation and release of

2,3proteolytic and vasoactive substances . The clinical consequences of this reaction to CPB include increased interstitial fluid and generalized capillary leak, plus the potential for multi-organ dysfunction. For example (i) total lung water may be increased with an associated decrease in lung compliance and increase in

4alveolar to arterial (A–a) oxygen gradient , (ii) myocardial edema results in impaired ventricular systolic and diastolic function, (iii) fall in cardiac output by 20–30% is common in neonates in the first 6–15 hours following surgery, (iv) decreased renal function and

5oliguria , (v) sternal closure may require delay due to mediastinal edema, ascites, and hepatic congestion, (vi) bowel edema causes a prolonged ileus or delayed feeding.

2) Ischemia-reperfusion injury.

3) Metabolic derangements such as altered glucose homeostasis, metabolic acidosis, salt and water retention, and a catabolic state contributing to protein breakdown and lipolysis are commonly seen following major stress in sick neonates and

6infants . This complex of maladaptive processes may be associated with prolonged mechanical ventilation and ICU stay, as well as increased morbidity and eventual mortality.

4) Complications such as neurological injury, renal failure and respiratory failure (including that

due to diaphragmatic paralysis) sepsis, and gastric stress ulceration

Pre-existing co-morbidity:

These patients provide additional challenge in the ICU because of co-morbidities related to long-standing physiological derangements such as cyanosis/hypoxemia, pulmonary hypertension, or heart failure.

(i) Cardiac failure is most commonly associated with shunt lesions in which the pulmonary to-systemic blood flow exceeds 2:1, in vascular lesions with obstructed forward flow, coarctation of aorta or lesion like anomalous left coronary artery from pulmonary artery. The child with failing heart will increase endogenous catecholamine production and redistribute cardiac output to essential organs, resulting in increased heart rate, decreased skin temperature and metabolic acidosis. The increased work of breathing inhibits nutritional intake in infants and promotes malnutrition and failure to thrive.

(ii) With severe hypoxemia/cyanosis, numerous adaptations occur to allow reasonable levels of oxygen consumption. These compensatory mechanisms include polycythemia, increased blood volume, vasodilatation, neovasculari-zation and alveolar hyper-ventilation with

7chronic respiratory alkalosis . These adaptive mechanisms increase vascular resistance impair global ventricular function and redistribute blood flow to the heart and brain. In addition, peripheral sludging of blood in polycythemic children induces a state of hyperfibrinolysis secondary to intravascular stasis and thrombosis. These children have decreased clotting factors, increased fibrinolysis and reduced number of functional platelets predisposing them to increased postoperative blood loss and morbidity.

(iii) Pulmonary hypertension often complicates the perioperative care of many children with congenital heart disease such as endocardial cushion defects, patent ductus arteriosus

PEDIATRIC CARDIAC INTENSIVE CARE Recent advances in postoperative care of pediatric cardiac surgical patients


(PDA), ventricular septal defect and aortic outflow anomalies. Chronically excessive pulmonary blood flow contributes to progressive dysfunction of the mechanisms of

8pulmonary vasorelaxation . Changes in the pulmonary vascular endothelial surface and increased production, release, or activation of serine elastase in the vessel wall may contribute to development of pulmonary vascular obstructive changes. In addition, endothelin, a potent vasoconstrictor peptide released from endothelial cells is elevated in children with pulmonary hypertension secondary to

9,10congestive heart disease .

Recent trends in monitoring in pediatric cardiac surgical ICU

1) Echocardiography provides real-time, rapid and reliable diagnosis noninvasively that is invaluable to patient care: The following information can be obtained in post operative settings:

i) Structural information

ii) Ventricular filling and preload

iii) valvular regurgitation

iv) Intra cardiac pressures

v) gradients across the valves

vi) Residual shunts

vii) Quantitative cardiac systolic and diastolic function

viii) Presence of vegetation and thrombi

ix) Pericardial collection/ fluid

In addition echocardiography can be use to guide certain procedures like pericardiocentesis in the intensive care unit.

2) Assessment of tissue oxygenation: The factors which influence the transport of oxygen to the tissue is depicted below.

The mixed venous blood obtained from pulmonary artery enables the physician to estimate the mixed venous oxygen saturation (SvO ). The oxygen 2

extraction ratio is 25%normally; and O₂ excretion 11ratio of greater than 50- 60 % is indicative of shock .

When mixed oxygen venous sample is not available blood can be withdrawn from alternate sites including right atrium superior vena cava, external

12, 13&14jugular vein, and inferior vena cava . As cardiac output falls there is a decrease in inferior vena cava, superior vena cava, and external jugular venous saturation. Venous oximetry has been shown to improve outcome in infants & children's at risk of

developing shocks including those with sepsis and hypoplastic left heart syndrome.

3) Acid base and lactate levels have a prognostic value in pediatric cardiac surgical patients. Decrease in serum bicarbonate level and base deficit is indicative of tissue hypoperfusion / hypoxia.

4) Near infrared spectroscopy: Cerebral oximetry uses the infrared technology to assess cerebral oxygenation status irrespective of the pulsatility of blood flow. Cerebral oxygenation saturation is an

Oxygen transport

Cardiac Output Heart rate Heart rhythm Preload Afterload Contractility

Arterial Oxygen content Hb concentration Arterial saturation Ventilatory status V/Q mismatch Mixed venous saturation



indicator of O₂ extraction from cerebral cortex just beneath the probe. There is a good correlation between cerebral oximetry and jugular bulb saturation. In fact, cerebral oxygenation and the hemodynamics closely correlate with the oxygen

15extraction ratio following Norwood procedure .

Respiratory Function after cardiac surgery

1. Early extubation, fast tracking: Fast-tracking can be defined as a perioperative process involving rapid progress from preoperative preparation through surgery and discharge from the hospital. Early extubation is a component of fast–tracking but early extubation and fast tracking are not

synonymous. Pediatric cardiac patients require an anesthetic technique that allows safe early extubation either at the end of the procedure in the OR, or within a few hours in the ICU. A high-dose opioid technique is typically not used for this approach. The necessary elements of a fast track programme are choice and titration of short-acting anesthetic agents, standardized surgical procedures, early extubation rewarming and sustained postoperative normo-thermia, postoperative pain control, early ambulation, alimentation and discharge and follow-up after discharge. The criteria for withdrawal of ventilatory support and extubation and factors which influence the decision to early extubation are high-lighted in the following boxes.

Criteria for withdrawal of ventilatory support and extubation following Pediatric cardiac

surgery

1) Cardiovascular

(i) Stable hemodynamics with no/minimal/moderate inotropic support

(ii) No disturbing arrhythmias

(iii) Evidence of adequate peripheral perfusion e.g., warm peripheries

(iv) No risk of pulmonary hypertensive crises

(v) Normal/acceptable filling pressures (e.g. left/right atrial pressures).

(vi) No hypertension/risk of rupture of suture lines

2) Respiratory

(i) Clear chest (both clinically/radiologically)

(ii) Good blood gas exchange

(iii) Good muscle strength/cough-reflex (full recovery from neuromuscular blockade)

3. Neurological

(i) Adequate neurological status to protect airway from aspiration

(ii) Good/adequate pain control

4. Renal

(i) Adequate/satisfactory urinary output (>0.5 ml/kg/hr)

5. Metabolic

(i) No/minimal acidosis; acidosis not increasing

6. Hematological

(i) No excessive bleeding from chest tubes

(ii) Acceptable hematocrit



2) Central neuraxial and caudal epidural anesthesia to aid early extubation: The use of a neuraxial technique can be beneficial in an attempt to minimize the use of intravenous opioid administration in a fast-track protocol. The use of single shot intrathecal or caudal morphine with or without local anesthetic has been reported, as well as

the insertion of thoracic epidural catheters in children. Particularly in small children, a single shot caudal or spinal technique with a small-bore needle provides adequate pain control for several hours following surgery. Benefits of fast-tracking children following surgery for CHD are listed in the following box:

Considerations which influence the decision to early extubation

Patient factors

Limited cardiorespiratory reserve of the neonate and infant Pathophysiology of specific congenital heart defects Timing of surgery and preoperative management

Anesthetic factors

Premedication Hemodynamic stability and reserve Drug distribution and maintenance of anesthesia Postoperative analgesia

Surgical factors

Extent and complexity of surgery

Residual defects

Risks for bleeding and protection of suture lines

Conduct of CPB

Degree of hypothermia Level of hemodilution

Myocardial protection Modulation of the inflammatory

response and reperfusion injury

Postoperative

management

Myocardial function Cardiorespiratory interactions

Neurological recovery

Analgesia management

POTENTIAL BENEFITS OF FAST -TRACKING IN SURGERY FOR CHD

1. Fewer ventilator associated complications such as:

- Accidental extubation

- Laryngotracheal trauma

- Mucous plugging of endotracheal tube

- Pulmonary hypertensive crisis from endotracheal Suctioning

- Barotrauma from positive pressure ventilation

- Ventilator associated pulmonary infections and atelec tasis

2. Reduced requirements of sedatives (and associated hemodynamic compromise)

3. More rapid patient mobilization

4. Earlier ICU discharge 5. Decreased length of hospital stay 6. Reduced costs (ventilator associated, as well as length of ICU/hospital stay) 7. Reduced parental stress



3) Role of Dexmedetomidine: Dexmedetomidine

is a short acting µ-2 agonist, which is being used increasingly used in children of all age groups including the postoperative care of children following surgery for CHD. Aside from its sedative properties, dexemedetomidine provides effective pain relief with an opioid sparing effect. This proves to be particularly helpful in spontaneously breathing patients in the ICU as part of an anesthetic regimen suited for early extubation. Although hypotension and bradycardia have been reported as side effects, this is not of clinical significance in children following surgery for CHD. It is an useful adjunct for caudal epidural analgesia.

4) Nasal CPAP and noninvasive BiPAP:

5) Respiratory insufficiency following cardiac surgery:

After cardiac surgery, infants and small children are at risk for developing respiratory insufficiency as a result of diminished respiratory functional reserve. The reasons for respiratory embarrassment include (i) type I respiratory failure (oxygenation failure) as a result of inflammatory response to CPB associated with increased vascular permeability and extra-

Respiratory insufficiency complicates post extubation phase in some children after surgery for complex congenital heart disease. The reason for this is multifactorial ranging from alveolar collapse, atelectasis, pulmonary edema, pneumonia etc. This is manifest as respiratory distress and hypoxia unresponsive to O administration. These patients 2

with improve with the application of noninvasive positive pressure ventilation either in the form of nasal CPAP or Bi PAP. This technique provides effective respiratory support by improving ventilation and decreasing work of breathing. Nasal mask BiPAP ventilation is more suitable than the noninvasive CPAP. BiPAP ventilation for respiratory support markedly decreases the work of breathing and the flow-triggered inspiration improves patient comfort. This improvement in respiratory status with noninvasive BiPAP can be partly attributable to 'stenting' of the upper airway and large bronchi.

vascular lung water, leading to interstitial and alveolar edema and impaired surfactant function. This in turn leads to venous admixture, increased (A-a) DO difference and arterial hypoxemia (ii) 2

type II respiratory failure (ventilatory failure) owing to impairment of respiratory mechanics to varying degrees. Pulmonary compliance is decreased associated with increased work of breathing/ respiratory load, decreased neuromuscular competency, and impaired respiratory muscle strength. This is manifested as hypercapnia with a

16,17normal arterial to end tidal CO gradient (iii) low 2

cardiac output and abnormal distribution of pulmonary blood flow results in an increase in ventilation-perfusion ratios, wasted ventilation, and hypercapnia with an elevated arterial to end-tidal

18, 19, 20 &21CO gradient2

Cardiovascular Function and Dysfunction

Postoperative myocardial diastolic and systolic dysfunction occurs due to a wide variety of reasons which can be categorized into preoperative, intraoperative and postoperative factors (i) preoperative heart failure and diminished

22,23cardiovascular reserve . (ii) Intraoperatively some degree of inflammatory response and ischemia–

24, 25reperfusion injury is invariable . (iii) Postoperative reasons. Improvement of cardiac output involves optimizing heart rate, ventricular loading conditions, and myocardial contractility.

Pharmacologic approaches for perioperative

ventricular dysfunction

Inotropic agents

o Catecholamines

o Phosphodiesterase inhibitors o Levosimendan

Vasodilator therapy Pulmonary vasodilators

o Phosphodiesterase inhibitors

(milrinone, sildenafil) o Inhaled nitric oxide

o Prostaglandins (PGI2, PGE1,

iloprost, and derivatives)



Systolic Dysfunction

I) Catecholamines: The catecholamines enhance the myocardial contractility, however, their usefulness may be limited by tachycardia, arrhythmia and increased myocardial oxygen

26consumption . Dopamine and dobutamine provide modest inotropic support in comparison to epinephrine. In contrast to dobutamine, dopamine decreases venous capacitance and as a result ventricular filling pressures do not

27,28decrease . At higher doses (10g/kg/min) with dopamine, systemic vascular resistance begins

to increase as a result of µ-agonist activity. Dobutamine decreases systemic vascular resistance, which is thought to be the result of β-2 agonist activity. Epinephrine provides unparalleled inotropic support and in low doses (0.05– 0.10 g/kg/ min) reduces systemic

29,30vascular resistance . However , the following box h igh- l igh t s the p rob lems wi th catecholamines:

inotropic support, causes vasodilatation of pulmonary and systemic vessels, and exerts a

31lusitropic effect . As a result, ventricular filling pressures decrease while stroke volume and

32cardiac output (CO) increase . A study by

33Hoffman et al evaluated the efficacy and safety of prophylactic milrinone in pediatric patients undergoing cardiac surgery. Patients were randomized to low-dose (25µg/kg/min) or high-dose (75 g/kg/min) milrinone or placebo. High-dose milrinone significantly reduced the risk of developing low CO syndrome compared with placebo, a 64% relative risk reduction, and there was no significant difference in the incidence of hypotension or arrhythmia compared with placebo.

I) Phosphodiesterase inhibitors: Milrinone acts through selective inhibition of the enzyme phosphodiesterase-III increasing the intracellular concentration of cyclic-AMP. The advantages of milrinone over catecholamines are that i t is not chronotropic and arrhythmogenic, it does not increase myocardial VO , and it is unaffected by adrenergic receptor 2

desensitization. Milrinone provides modest

I) Vasodilators and nitric oxide donors: One of the strategies for treating systolic dysfunction is optimization of ventricular loading conditions. Nitroglycerin in low to moderate doses (0.5to3g/kg/min) increases venous capacitance without much effect on the arterial resistance

34vessels . As a result, ventricular filling pressures decrease, whereas stroke volume is unaffected to a large extent. High-dose of

Advantages of Phosphodiesterase Inhibitor

Administration

•

Increased myocardial contractility

(left and right ventricles)

•

No/minimal increase in heart rate

•

No/minimal increase in MvO2

•

Pulmonary vasodilation

•

Resolution and prevention of

ischemia

•

Minimal drug side effects if

administered while on

cardiopulmonary bypass

•

Avoidance of mechanical

intervention

•

Prevention of a “failed wean”

Disadvantages of Catecholamines

• Increased myocardial oxygen

consumption

• Tachycardia

• Arrhythmias

• Excessive peripheral

vasoconstriction

• Coronary vasoconstriction

• Receptor downregulation and

decreased drug efficacy



nitroglycerin and nitroprusside increase venous capacitance and reduce systemic vascular resistance and reduce ventricular afterload. This is associated with fall in filling pressures and

35significant rise in stroke volume and CO .

ii) Natriuretic Peptides: The natriuretic peptides act primarily as counter regulatory hormones to the renin–angiotensin–aldosterone system. Atrial and B-type natriuretic peptides are produced primarily by myocardium in response

36to chamber wall stress . Stimulation of natriuretic peptide receptors causes vasodilation of venous capacitance and arterial resistance vessels, a dose-dependent natriuresis/diuresis, and improved ventricular relaxation. Nesiritide is the human recombinant form of B-type natriuretic peptide. In contrast to nitroglycerin and nitroprusside, tachyphylaxis does develop

37to the hemodynamic effects of nesiritide and its use is not associated with reflex stimulation of

38systemic and cardiac adrenergic activity . Studies in adults have demonstrated its efficacy in treating congestive heart failure, whereas

39studies in children have been limited . A study 40

by Jefferies et al evaluated the safety and efficacy of nesiritide in pediatric decom-pensated heart failure by prospectively monitoring 55 separate infusions in 32 patients. They found results similar to those found in adults: a significant increase in diuresis; reduction in ventricular filling pressures and increase in CO; and a marked improvement in the mean New York Heart Association functional class. No hypotension or arrhythmias were noted during 478 cumulative days of therapy and serum creatinine levels trended downward after therapy.

iii) Levosimendan: Levosimendan is calcium 41sensitizers which is currently available for use .

Levosimendan offers modest inotropic support by enhancing the sensitivity of the myofilaments to the existing cytosolic calcium concentration in the intracellular milieu. Myocardial oxygen consumption remains

unchanged because less energy is consumed in the cycling of calcium. Levosimendan decreases systemic and pulmonary vascular resistance by stimulation of adenosine 5-

+triphosphate-dependent K channels in vascular smooth muscle cells. Unlike other vasoactive agents, levosimendan has a long duration of action as a result of the generation of active metabolites with an elimination half-life of 3–4 days. Namachivayam and colleagues evaluated levosimendan in 15 children with severe ventricular dysfunction who were cate-

42cholamine-dependent . A combination of a loading dose and continuous infusions (24–48 hrs) allowed for a substantial reduction in catecholamine infusions with discontinuation in a majority of patients. A prospective randomized trial conducted by Momeni and

43colleagues on children undergoing cardiac surgery in which patients received either milrinone or levosimendan with initiation of CPB for up to 48 hrs. There was no difference between groups in terms of serum lactate levels (primary aim) or oxygen extraction; however, the rate-pressure index was significantly greater in those receiving milrinone.

iv) Cardiac resynchronization therapy: Cardiac resynchronization therapy after surgery is a relatively new strategy to improve cardiac function. Cardiac resynchronization therapy involves nonconventional pacing strategies targeting prolonged atrioventricular and intraventricular conduction, which may improve ventricular fillingand lessen the degree

44,45of discoordinate ventricular contraction . Several studies have evaluated cardiac resynchronization therapy after pediatric cardiac surgery. A study by Zimmerman and

4 6colleagues demonstrated significant improvements in hemodynamics and CO by using multisite ventricular pacing after pediatric cardiac surgery in 29 patients with single and biventricular anatomy and prolonged QRS duration. In a follow-up study from the same center, 26 single ventricle patients regardless of



electrocardiographic criteria demonstrated improved hemodynamics and CO with multisite

47ventricular pacing . A study by Janousek and

48,49colleagues demonstrated improved blood pressure using atrial synchronous right ventricle and biventricular pacing for primarily atrioventricular and intraventricular conduction delay after pediatric cardiac surgery.

Diastolic Dysfunction

Diastolic dysfunction is characterized by impaired myocardial relaxation during diastole and reduced ventricular compliance; operating end diastolic volumes are decreased despite an elevated filling pressure. In a patient with pure diastolic dysfunction, the systolic function is reasonably preserved and hence inotropic and after load-

50-3reducing agents are of little benefit . Nitroglycerin, natriuretic peptides, and milrinone have been shown

to provide lusitropic support. However, because these agents also cause venodilation and an increase in venous capacitance, venous return and ventricular

54-58filling may decrease . Atrial pacing and sequential atrial-ventricular pacing is necessary to maintain atrial kick mechanism for ventricular filling in the patients who exhibit diastolic dysfunction.

Right ventricular failure:

Right ventricular failure after cardiac surgery is multifactorial. Most commonly, it is a result of elevated pulmonary artery pressure and increases in the after load to the RV. Ischemia-reperfusion injury occurs in some patients, which contributes to the impairment of RV contractility. RV failure is associated with RV dilation, decreased contractility and low output state. Left-wards shift of the interventricular septum lowers LV filling and reduces cardiac index.

RV failure

↑ RA pressure Left ward shift of IVS ↓ RV output RV dilation

Opening of PFO with R → L shunt

Decreased systemic venous return

Functional TR

Compressed LV cavity

↓ LV output

Low cardiac output Hypoxemia

Effective treatment of RV failure remains challenging and includes maximizing coronary perfusion pressure, reducing RV after load,

maintaining preload by judicious fluid adminis-tration and maintaining inotropy of the RV.



There has been a tremendous evolution in the practice of pediatric cardiology and cardiac surgical services. Challenges in running a large volume cardiac post surgical ICU include ( i) use of protocol based management is recommended in view of different groups of health care professionals working for the common interest of patient welfare (ii) monitoring : cohort of patients needing intensive monitoring must be identified and manages separately, perhaps the most experienced doctors and nurses in areas requiring close monitoring (iii)resource allocation both in terms of personnel ,equipment and finances (iv) rigid adherence to infection control and surveillance (v) timing of tracheal extubation of complex procedures usually done at day time or in the early morning(vi) ongoing training progarmmes and incentives to prevent attrition among physicians and nurses (vii) review of reports done in a multidisciplinary rounds and project follow up plans in close co-ordination with cardiac surgeons, anesthesiologists and cardio-logists etc. (viii) leadership :– one individual to take leadership role and give directions (ix) split the unit to small areas with a team leader in each of the area

and (x) importantly close communication with patient's kith and kin.

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Introduction

Pharmacological support for the circulatory system is an integral part of intensive care. These vasoactive drugs aim to improve perfusion pressure by increasing cardiac output and modulating the vascular tone. Cardiac output (CO) can be increased by optimising preload (with adequate fluid resuscitation), and by augmenting myocardial contactility (Inotropy), enhancing diastolic relaxation (Lusitropy – thereby improving coronary circulation), and sometimes by increasing heart rate (Chronotropy) while some of the medications as well as mechanical ventilation itself help with reducing the afterload. Various agents have traditionally been used in different clinical scenarios. We review the current available evidences and recommendations on use of various vasoactive and inotropic medications in the Pediatric intensive care settings.

Physiological considerations

Before we embark on the clinical applications – it is worthwhile to recap the physiology and pharmacology of the different agents. We will only briefly consider those aspects which are clinically important for an Intensivist. For a detailed discussion on these – the reader may consult any standard pharmacology textbook.

Receptor subtypes

The classical Inotropes act via different receptors. They are as follows -

Adrenergic receptors

Alpha 1

They are present on vascular smooth muscles, sphincters of gastrointestinal(GIT) and urinary tract and muscles of the iris. Their activation leads to vasoconstriction leading to increased systemic vascular resistance(SVR) and therefore increased blood pressure(BP) and reduced blood flow to the organs. They also lead to contraction of the sphincters and dilated pupil.

Alpha 2

They are present in central nervous system(CNS) as well as in blood vessels, GIT and other areas. Their predominant function is to decrease release of nor-epinephrine(NE) from pre-synaptic membrane by negative feedback. They are not clinically important as far as Inotropes are concerned although they have clinical use as anti-hypertensives and sedatives.

Beta 1

They are present in the heart and kidney. Their stimulation leads to increased rate of phase 4 depolarisation in sino-atrial (SA) node and increased velocity of conduction through atrio-ventricular (AV) node. This leads to increased heart rate (+ve chronotropy). It also leads to increased contractility of the myocardium (+ve inotropy) thereby increasing stroke volume. Both effects augment CO. Beta1 stimulation also leads to increased renin release from the kidneys.

Beta 2

They are present in smooth muscles of airway, blood vessels, uterus, detrusor muscle of urinary bladder, liver .. They are also present in the myocardium - although much less predominant than Beta 1. Their stimulation leads to bronchodilation, vasodilation - mostly in muscles and increased blood sugar due to glycogenolysis and neo-glucogenesis in liver among other effects. It also has some +ve chronotropic and +ve inotropic effect.

Vasoactive and Inotropic therapy in PICUDr. Agnisekhar Saha*, Dr. Bichitrovanu Sarkar**

* Consultant Pediatric Intensivist, Fortis Hospital, Kolkata

** Consultant Pediatric Intensivist, AMRI Group of Hospitals, Kolkata

Correspondence:

Dr. Agnisekhar Saha

Consultant Pediatric Intensivist, Fortis Hospital, Kolkata

E-mail : [email protected]


PEDIATRIC CARDIAC INTENSIVE CARE Vasoactive and Inotropic therapy in PICU


Dopaminergic receptors

There are five types of them which are divided into two sub-types - D1 like (D1 and D5) and D2 like (D2, D3 and D4). As far as cardiovascular system(CVS) is concerned - D1 and D4 receptor stimulation cause increased contractility of the myocardium but the effect is less pronounced than beta receptor effects. In the vasculature - D1 activation cause vasodilatation - mostly of renal and mesenteric vessels; activation of D2 receptor cause either constriction or dilatation depending on the location of the vascular bed. Overall effect remains

coronary vasodilatation.

Pharmacology of individual agents

Epinephrine (Adrenaline) :- It stimulates all adrenergic receptors leading to increased contractility, heart rate and SVR. Increased contractility causes increased stroke volume. Increased stroke volume combined with increased heart rate leads to increased CO. Increased CO combined with increased SVR leads to increased systemic and pulmonary BP. At low dose - Beta affects predominate and Alpha effect i.e. vasoconstriction become more pronounced at

Agent

Receptor type Effect on CVS

α 1 β 1 β 2 Heart rate Contraction Vasoconstriction

Dopamine ++ ++++ ++

Dobutamine + ++++ +++

Norepinephrine ++++ ++

Epinephrine ++++ ++++ +

Phenylepphrine ++++

Isoprenaline ++++ ++++

Relative affinity for Adrenergic receptors and resulting effects of different agents :-

that of vasodilatation leading to a fall in SVR.

Vasopressin receptors

V1 receptors are widely present in vascular smooth muscle causing intense vasoconstriction. They are also present in the myocardium and most likely have mild +ve inotropic effect. V2 receptors are present in renal collecting ducts making them permeable to water. They are also present in vascular endothelium causing release of coagulation factors. V3 receptors are mostly central and lead to ACTH release. Vasopressin also acts via oxytocin receptors causing nitric oxide (NO) mediated vasodilatation. It also acts via some purinergic receptors in myocardium causing increased contractility and selective

higher doses. As heart rate and SVR rise – cardiac oxygen demand also increase. However, coronary vasodilatation due to local effects leads to increased coronary flow. Beta effects cause hyperglycemia. Epinephrine also increases lactate production and therefore contributes to metabolic acidosis. However, there is no evidence to suggest that this increase in lactate is associated with any adverse outcome.

Dose range - .05 - 1 mcg/kg/min

Norepinephrine (Noradrenaline) :- This is mostly a pressor agent causing intense vaso-constriction and increased SVR – thereby increasing both systolic BP(SBP) and diastolic BP(DBP). It also has


some +ve inotropic effect. It has minimal +ve chronotropy due to reflex bradycardia which is often advantageous in patients with intrinsic tachycardia. At high dose it can compromise perfusion of mesenteric, renal and cutaneous vasculature which has always been a concern although no clinical study has as yet proved this. It relatively spares both cerebral and coronary circulation.

Dose range - .05 - 1 mcg/kg/min

Dopamine :- Dopamine binds to both dopaminergic and adrenergic receptors making its action somewhat complex. At dose range of up to 5mcg/kg/min it predominantly activates dopa-minergic receptors leading to increased contractility and vasodilatation mostly in the renal and mesenteric bed. This is the basis of the 'renal dose' of dopamine which has never been substantiated and is now not practiced with the possible exception of post-operative kidney transplant. At 5 - 15 mcg/kg/min – Beta1 effects predominate leading to increased contractility and heart rate – both augmenting CO and SBP with minimal effect on DBP. At >15 mcg/kg/min - Alpha affects predominate causing disproportionate vaso-constriction. This may lead to increased BP at the expense of often reduced CO and markedly increased cardiac oxygen consumption. Dopamine centrally modulates secretion of prolactin, growth hormone, thyroid hormone and possibly glucocorticoids in a complicated manner which might have important neuro-endocrine and immunological effects in critical illness much of which is still unknown.

Dose range - 5 - 20 mcg/kg/min

Dobutamine :- This synthetic compound mostly stimulates Beta 1 receptors causing increased contractility. Beta 2 stimulation leads to vasodilatation and reduced SVR. +ve chronotropy is less than that of dopamine. So, dobutamine increase CO and improves perfusion but may not increase BP substantially. It would be a good choice in those situations where perfusion is poor and the SVR is intrinsically high due to vasoconstriction. It has weak Alpha activity so that at high dose rates - the vasodilation is blunted.

Dose range - 5 - 20 mcg/kg/min

Phenylephrine :- It is effectively a pure Alpha agonist with almost no Beta activity. Consequently, it cause marked vasoconstriction and increase BP which may be associated with reflex bradycardia. Cardiac output may actually fall. It is mostly used as a bolus to correct sudden severe hypotension but may also be used as a vasopressor infusion in refractory cases. Bolus doses are also used to treat hypotension associated with left ventricular outflow tract obstruction like aortic stenosis, hypertrophic cardiomyopathy as it maintains coronary perfusion.

Dose range - 2-10 mcg/kg stat, then 1-5 mcg/kg/min

Isoproterenol/Isoprenaline :- This synthetic compound is almost pure non-selective Beta agonist with no Alpha action. So, it increase contractility and cause systemic and pulmonary vasodilatation. Therefore it can even cause hypotension especially if the patient is hypovolaemic. Coronary perfusion may actually fall. It also causes bronchodilation.

Dose range - 0.05 - 1 mcg/kg/min

Some important common features of all classical adrenergic Inotropes

These features are common for all agents although individual variations do exist.

A. Half life of epinephrine and nor-epinephrine is 2-2.5 minutes and that of dopamine and dobutamine is 22-25 minutes. So, they are short acting and needs continuous infusions for persistent effect.

B. All needs to be given intravenous(IV) for inotropic effect. Agents with significant pressor effects i.e. norepinephrine, epinephrine, vasopressin and higher concentration of dopamine should be given centrally, as infusion through peripheral veins can cause intense local vaso-constriction and extra-vasation can lead to tissue necrosis and sloughing. However, it is also recognised that getting a central access in small children can be difficult and time consuming. In view of this, in the Pediatric

1update of 'Surviving Sepsis' guideline , peripheral infusion of epinephrine up to 0.3 mcg/kg/min is recommended. In life saving situations, this might be relaxed while a central access is being obtained but prolonged



peripheral infusions are definitely not recommended. All inotropes are compatible with each-other and are usually given through a dedicated lumen of the central line which should never be flushed or used for bolus injections.

C. Myocardial oxygen demand is increased by all agents. As heart rate and SVR increase myocardial oxygen demand increase. As heart rate increase, time for diastole i.e. time for coronary perfusion decrease. This can critically affect oxygen delivery to heart at very high heart rates, further compounding the problem.

D. All are arrhythmogenic, especially in higher doses and in presence of electrolyte abnormalities and hypoxia. Dopamine is probably the worst.

E. Correctable factors such as acidosis, either metabolic or respiratory, significantly reduce effectiveness. Various mechanisms have been suggested like reduced sensitivity to calcium, reduced number of receptors, reduced cAMP level .. In animal models – effect of acidosis could often be overcome by using a higher dose to produce the same effect on contractility. Hypoxia also has the same effect on all agents. It seems that effect of hypoxia is more pronounced and could not be overcome by simply increasing the dose. Reduced serum calcium, primarily the free ionic portion – is another correctable and common factor that can reduce effectiveness.

F. Non-correctable factors causing reduced effectiveness : There is a group of patients who do not respond well to inotropes and it is this group who fare badly. Prolonged use often leads to reduced effectiveness in varied clinical scenarios. A number of mechanisms have been suggested like desensitisation and down regulation of receptors, reduced generation of new receptors, down-regulation of adenylate cyclase, G-protein mediated methods. During sepsis endotoxins, nitric oxide(NO), inter-leukins and relative adrenal insufficiency – all may have roles. Steroid replacement in inotrope resistant shock is often practiced. But as of now, there is no established clinical intervention to

address the other non-correctable factors. However, this is an area of active research and future development.

Phospho Diesterase III Inhibitors(PDI)

All classical adrenergic inotropes act via adrenergic receptors. Activated Beta receptors in myocardium and vascular smooth muscles combine with stimulatory G proteins. This stimulates adenylate cyclase which converts adenosine-tri-phosphate (ATP) to cyclic adenosine-mono-phosphate (cAMP). Phospho diesterases(PD) are a group of 11 iso-enzymes that breakdown cAMP to AMP. PD-III is predominant in myocardium and vascular smooth muscles. PDIs specifically inhibit PD-III and therefore increase cAMP concentration in the myocardium and vascular smooth muscles. cAMP stimulates cAMP associated protein kinases, which leads to increased intracellular calcium concen-tration in myocardium leading to increased contractility and chronotropy. It also leads to increased calcium concentration in sarcoplasmic reticulum in vascular smooth muscles leading to vasodilatation and reduced afterload in both systemic and pulmonary circulation. They also reduce diastolic dysfunction and make the ventricles more relaxed and receptive during diastole thereby reducing pre-load which is called lusitropy. Therefore, PDIs increase contractility, and reduce both after load and pre-load and are often referred to as inodilators. The overall effect is an increase in CO and therefore perfusion with no or minimal increase in myocardial oxygen consumption. This effect is receptor independent and therefore remains effective in presence of receptor down-regulation. However, the reduced SVR can lead to hypotension specially in hypovolaemic subjects and in situations where the intrinsic SVR is not high and BP is borderline. So, PDIs are useful in situations with a low CO where BP is not low and SVR is high, often with peripheral vasoconstriction. Effect on pulmonary circuit also makes it useful in pulmonary hypertension and acute right ventricular failure. They are commonly used in post-operative cardiac patients and in selected patients with sepsis. There are two main agents namely Milrinone and Inamrinone (previously known as Amrinone).



Hypotension is the main concern. Unlike adrenergic agents, half-life of both milrinone and inamrinone is in hours (Milrinone - 2.3 hours, Inamrinone - 5.8 hours). So, effects are long-standing which makes the potential for hypotension even more concerning. Both agents are known to cause supraventricular, junctional as well as ventricular tachy-arrythmias which is more likely in presence of hypokalemia.

Milrinone is the most widely used PDI. It is mostly excreted in urine making dose adjustment necessary in renal impairment. Inamrinone has an additional disadvantage of inducing thrombocytopenia in 2.4% of patients. So, platelets should be monitored and Inamrinone stopped if platelet count goes below 50,000/cmm.

Milrinone is recommended to start as a bolus of 50 - 75 mcg/kg over 1 hour and then run as an infusion at 0.5-0.75 mcg/kg/min. Inamrinone is started as a bolus of 1 - 3 mg/kg over 1 hour and then run as an infusion at 5 - 15 mcg/kg/min. If there is particular concern about hypotension then the bolus may be reduced or even avoided. Both are incompatible with furosemide.

Vasopressin(VP)

Vasopressin is a natural hormone secreted from posterior pituitary and is also known as anti diuretic hormone. It acts via its receptor systems as described before. In normal physiologic states, it has minimal role in maintaining BP and it is primarily involved in maintaining plasma volume or water balance with serum osmolarity being the main regulator. It is now recognised that VP has many other diverse functions like maintaining sleep cycles, hemostasis,

2temperature regulation . Normal serum level is 4 - 20 pg/ml depending upon serum osmolarity and other factors. However, in shock the level massively increase up to even 1800 pg/ml and it seems VP is another hormone normally produced by body as part of stress response. It is at this level that VP exerts significant control over vascular tone and thereby influences BP. In adult studies, a relative deficiency of VP was found in up to one-third of patients with sepsis. It also seems that normally there is a biphasic response of VP and its level actually drops as the shock state continues. This relative or absolute

deficiency constitutes one of the main physiological basis of use of VP in shock. However, pediatric studies have been inconsistent with some studies showing a deficiency while others shown high levels

3continuing as long as 96 hours after shock . It is well evidenced that unlike adults who almost universally present with a high CO, low SVR, vasoplegic state - pediatric patients present in a variety of states and some may present in a high SVR, low CO state - the so called 'cold shock'. Whether the inconsistency in the level of VP in pediatric studies is a reflection of this and there is a sub-group of pediatric patients who would benefit from VP is not yet clear. VP has a short half-life of 10-20 minutes so needs to be given as an IV infusion. It is mostly metabolised by vasopressinase from kidney and liver. As a pressor agent – it has a number of advantages over classical adrenergic agents. It has no chronotropy which can be very useful as base line heart rate can often be 180-190/min. in pediatric patients. It remains effective even in presence of acidosis. As it has its own receptor system so it remains effective in presence of adrenergic receptor down-regulation. Actually, it seems to potentiate nor-epinephrine by as yet unknown mechanisms. As intrinsic VP level is frequently low in shock states – subjects are often actually found to be highly sensitive to it, so that, even a small dose, which would have no effect in a normotensive, healthy subject can significantly increase BP in a patient with shock. Besides its use as a pressor agent it has other important clinical uses in diabetes insipidus, variceal bleeding .. which will not be covered in this review.

Dose range - It has been extrapolated from adult studies. As a pressor agent the range is 0.0003 - 0.0009 unit/kg/min.

Choice of inotropes in different Clinical Situations

Resuscitation

Pediatric cardio-pulmonary resuscitation(CPR) has always been an area where finding evidence is very hard. Most of the evidences are extrapolated from either animal or adult studies. Both have serious flaws - especially considering the fact that most



adult arrests are primarily cardiac in origin whereas pediatric arrests are mostly respiratory in origin. Epinephrine has been used for CPR for ages. Although the beginning of this practice was not following any study – it is apparent that it works. It is thought that the vasoconstrictor effect of epinephrine is as important as the inotropic effect to increase the coronary circulation during CPR. Epinephrine is also thought to make the myocardium more likely to respond to de-fibrillation attempts although no definite evidence is there to support this. The standard IV dose is 0.1 ml/kg of 1:10000 solution i.e. 0.01 mg/kg followed with a flush every 3-5 minutes along with chest compression and positive pressure ventilation. Intra-tracheal dose is taken to be 10 times that of IV dose although IV administration is by far the preferred route. Of course, it can be given intra-osseosus in CPR situations and the dose is same as IV as per standard pediatric life support guidelines. The standard IV dose in adults is 1 mg. These doses are essentially empirical without much evidence and have been questioned. Proportionately the pediatric dose is actually less than the adult dose. There have been adult studies of higher doses of epinephrine of up to even 5 mg compared with standard dose. Although, return of spontaneous circulation (ROSC) was often found to be higher with larger doses – they have mostly failed to translate to higher survival to hospital discharge or neurologically

4intact survival . As a result, the current recommen-dation remains to use the standard dose.

It was found that subjects who were successfully resuscitated had higher vasopressin levels compared to non-survivors. This has led to the use of vasopressin in CPR scenarios. In a large adult study of more than 1000 out of hospital arrests, people with asystole receiving 40 units of VP were more likely to get admitted to hospital than those receiving standard dose of epinephrine. Indeed, the ability of VP to increase BP by increasing SVR and at the same time increasing flow in the coronary, pulmonary and cerebral circulation seems to be ideally suited for the CPR situation. Both the current (2010) American Heart Association and the European Resuscitation Council adult guidelines have mentioned 40 units of vasopressin as an

alternative to epinephrine. There are some pediatric retrospective case series of use of vasopressin 0.4 unit/kg/dose during prolonged CPR with variable

2outcomes . The largest such series has shown that it is still used only in 5% of arrests, used only after prolonged arrests and is actually associated with

5worse ROSC but no difference in discharge survival. At present there is no definite recommendation for vasopressin use in CPR.

Septic Shock

Sepsis is definitely one of the commonest if not the commonest indications for inotropes. Much of pediatric practice is extrapolated from adult evidence, but this is an area where significant differences do exist. In adult practice, the current situation is rather settled. It is now well evidenced that almost all adult sepsis patients present in a state of profound vasoplagia with high CI and low SVR and primarily needs a vasopressor – Dopamine and Nor-Epinephrine being the two obvious contenders. The Sepsis Occurrence in Acutely Ill Patients

6(SOAP) study , which involved 1058 patients who were in shock, showed that the administration of dopamine was an independent risk factor for death in the intensive care unit. Dopamine has been found to be associated with higher heart rate and more arrhythmic events than nor-epinephrine. This increase in arrhythmia is also found in the latest

7Cochrane review . This has tilted the balance against dopamine so that there is now a general consensus on nor-epinephrine being the first choice agent in sepsis and is reflected in the latest Surviving Sepsis

82012 guidelines .

However, the situation is much different in pediatrics. It is well known that pediatric sepsis patients present in a variety of haemodynamics. For

9example – in a pediatric case series of fifty children with fluid-refractory septic shock, as many as 58% presented with low CO and responded to just inotropes with or without vasodilators, 22% presented with both cardiac contractility and SVR issues and needed both inotropes and vasopressors and only 20% presented with high CO and low SVR and responded to vasopressors alone. The same study also clearly showed that a single child may



change from one state to another as the illness evolves. This makes the choice of inotropes/ vasopressors/dilators in pediatric septic shock patients interesting and complex. This difference has been recognised in different guidelines including the 2012 Surviving Sepsis guidelines.

As far as evidence goes – there is not much out there. 7The latest Cochrane review on vasopressors for

hypotensive shock included 3212 patients in 23 studies and compared six vasopresors – namely norepinephrine, dopamine, vasopressin, epi-nephrine, terlipressin and phenylephrine along with dobutamine in different combinations and found no evidence of superiority of any agent or combination of agents over the other. It concluded – 'Probably the choice of vasopressors in patients with shock does not influence the outcome' and 'The choice of a specific vasopressor may therefore be indi-vidualized and left to the discretion of the treating physicians'.

Vasopressin has reduced the need of other vasopressors and significantly increased BP in many studies but has not shown mortality benefit. Vasopressin is often used as a last resort vasopressor

10in severe shock. VAAST – by far the largest multi-centre adult randomised controlled trial (RCT) (N=778) involving VP also did not find any difference in 28 day or 90 day mortality between VP and nor-epinephrine. However, contrary to the research hypothesis, mortality was significantly reduced in the vasopressin group in the prospectively defined subset of patients with less severe shock rather than more severe shock. The

11largest multi centre pediatric RCT (N=69) involving vasopressin in vasodilatory shock compared vasopressin with placebo and did not find any significant difference in any of the outcomes. Actually, mortality in the vasopressin group was double that of the control group – though it did not reach statistical significance. However, vasopressin is still largely used as a rescue vasopressor in severe vasodilatory shock where nor-epinephrine has not been effective.

The clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care

1Medicine is possibly the most well-known and followed guidelines for pediatric sepsis. It recommends to optimise preload first by fluid boluses and start dopamine peripherally. Once central access is obtained – dopamine should be increased and if that does not work – catecholamines should be started or further increased. Shock not responding to these measures are termed catecholamines resistant shock and they are further classified into 3 categories - 1) Cold Shock with Normal BP – Low CI/High SVR; 2) Cold Shock with Low BP – Low CI/Low SVR; and 3) Warm Shock with Low BP – High CI/Low SVR.

For Cold Shock with Normal BP – Low CI/High SVR, who has not responded to fluid and epinephrine, it recommends nitrosovasodilators like nitroprusside or nitroglycerine as the first line vasodilators and in the event of toxic side effects or continued low CO state, it recommends milrinone or inamrinone as the next line. Levosimendan and enoximone has also been suggested. However, the 2012 guideline does not mention the primary vasodilators as first line. It rather mentions PDIs first and that probably reflects practice of most pediatric intensivists.

For Cold Shock with Low BP – Low CI/Low SVR, who has not responded to fluid and epinephrine, the update recommends adding norepinephrine to increase DBP and SVR. Once an adequate BP is achieved, PDIs or levosimendan can be added to improve CI and Scvo . 2

For Warm Shock with Low BP – High CI/Low SVR, who have not responded to fluid and nor-epinephrine, next line includes low dose VP, angiotensin and terlipressin, but as these potent vasoconstrictors can reduce CO, it is recommended that these are used with CO/ScVO monitoring, and 2

if these are low, additional inotropes like low dose epinephrine or dobutamine may be needed or vasopressors may need to be reduced.

In order to assess CI and SVR – some sort of CO monitoring (invasive or non-invasive) needs to be used along with invasive BP monitoring. However, CO monitoring is still not widely used – especially in resource-poor settings. In such a situation – we have to depend on clinical assessments like pulse



volume, capillary refill time (CRT) and pulse pressure. DBP is expected to be around half of SBP. DBP significantly higher than this is taken as a marker of vasoconstriction and high SVR and conversely, DBP significantly less than half of SBP is considered a marker of vasodilatation and low SVR.

The clinical end-point or the goal of such therapy is also fairly standardised. As per the Surviving sepsis

guidelines, they are – CRT ≤ 2 seconds, normal pulses with no differential between the quality of peripheral and central pulses, warm extremities, urine output >1 mL/kg/h, targeted perfusion pressure as per Table 1, normal mental status and subsequently – mixed venous saturation (ScvO ) > 2

270% and cardiac index (CI) of 3.3-6 l/min/m . Among them – the last two require central neck lines and some form of CO monitoring – and are often not available. Besides the BP and the urine output – other measures are somewhat subjective.

One important consideration is the target BP for inotrope therapy in a patient with septic shock. Not much evidence could be found. However, the guideline states the perfusion pressure target quite clearly (please note, this is MAP – CVP and not just the MAP) based mostly on 1987 second task force

12report on BP . It is noteworthy that the target perfusion pressure is 60 mm Hg for any post-neonatal infant and from one year onwards – the perfusion pressure target is 65 mm Hg for the entire pediatric age group, which is also the target for the adult population. Having a universal target MAP is very user-friendly and handy to remember. However, it is well-established that normal BP increase with age in the pediatric population. As for example – as per the normative BP data of the latest

13update (1996) of the second task force report – which has been referenced in the surviving sepsis guideline – between 1 year and 16 year of age – the SBP increase on an average by 32 mm Hg and the DBP by 28 mm Hg. In view of this – having the same target MAP for a 2 year old as that for an adult i.e. 65 mm Hg is probably non-physiological. Often, it might be quite difficult to achieve, especially in small children and necessitates a very high dose of inotropes. In such a situation – if the child is consistently showing other signs of good perfusion i.e. good urine output, CRT < 2 sec, improving base deficit on blood gas and reducing serum lactate – then it would be the discretion of the intensivist whether to increase the inotropes further to achieve the target perfusion pressure or to settle for a lower perfusion pressure while keeping a close eye on both the BP and the other markers of perfusion. It is well evidenced that higher inotrope use is associated with worse outcome – but the cause and effect relationship is indeed difficult to tease out. This same principle is also applicable to the next section i.e. Myocarditis/Cardiogenic shock – where there is a general consensus that inotropes use should be kept to the minimum that is adequate to perfuse the organs just adequately.

Myocarditis / Heart failure

Inotropic support is required only in acute heart failure that is complicated by hypotension and peripheral hypoperfusion. An ideal inotrope in this setting would be one that (1) improves systolic and diastolic myocardial function, (2) while decreasing systemic and pulmonary vascular resistance, (3) wi thout increas ing myocard ia l oxygen consumption. Unfortunately none of the available

1Table 1. Threshold Heart Rate and Perfusion Pressure goals for different age groups

Age Heart Rate (bpm)

Perfusion Pressure (MAP - CVP)

Term Newborn 120 - 180 55

Up to 1 yr 120 - 180 60

Up to 2 yrs 120 - 160 65

Up to 7 yrs 100 - 140 65

Up to 15 yrs 90 - 140 65



agents completely fulfil all these 3 criteria. Adult studies show that the use of inotropes can actually

14 adversely impact survival . Indeed, in chronic heart failure setting there is very good adult and pediatric evidence suggesting beta-blockers improve

14morbidity as well as mortality . So, inotropes should be used only if necessary and as less as possible. Pediatric data is scanty and practices relating to use of inotropes in children with heart failure are mostly extrapolated from adult studies. The most commonly recommended initial inotropic therapies for refractory hear failure HF are dobutamine, dopamine and milrinone that are used to improve cardiac output and enhance diuresis by improving renal blood flow and decreasing systemic vascular resistance without exacerbating systemic

16 hypotension . Among them, dopamine has been shown to increase mortality in cardiogenic shock (not specifically myocarditis) when compared to

17 norepinephrine. In desperate situations epi-nephrine at low dose may also be used and this should prompt consideration for ventricular mechanical support device if available. Positive pressure ventilation – either invasive or non-invasive depending on the severity is of course helpful by both decreasing the work of breathing and reducing the left ventricular afterload.

Catecholamines are limited by several acute and chronic factors including (1) down-regulation of adrenergic receptors, (2) increased myocardial oxygen consumption, and (3) excessive chrono-tropy. PDIs, on the other hand, exhibit positive inotropy and enhanced lusitropy, and reduce systemic and pulmonary vascular resistance while having the advantage of not increasing myocardial oxygen consumption. However; milrinone can sometime cause severe systemic hypotension, necessitating the co-administration of additional pressor therapies. These medications are thus often used in combination thus offsetting the limitations of each other. Randomized comparisons of milrinone and dobutamine have demonstrated

18-20 similar clinical outcomes. Levosimendan, a calcium sensitizing agent – has recently generated a lot of interest in this clinical situation. We have discussed levosimendan in a separate section.

Post-Cardiac Surgery

Low Cardiac Output Syndrome (LCOS), arbitrarily defined as a decline in cardiac index to < 2.0 L/min

2per m , is very common, typically occurring between 6 and 18 hours after a cardiopulmonary bypass surgery and contributes significantly to postoperative morbidity and mortality following cardiac surgeries. This fall in cardiac index may also be associated with an elevated SVR and a rise in pulmonary vascular resistance. Causes of LCOS are multifactorial and include myocardial ischemia during aortic cross-clamping, effects of cardioplegia, activation of inflammatory and complement cascades and alterations in systemic

and pulmonary vascular activity as well as any residual cardiac lesions that may also adversely impact the postoperative course. Prevention of this hemodynamic deterioration may have significant implications for clinical outcome. Preload adjustments do not always suffice to provide adequate cardiac output and pharmacological support is often necessary. The primary aim is to support myocardial contractility without increasing the workload and oxygen consumption of the heart. Traditionally, inotropic agents and vasodilators have been used to enhance tissue perfusion and facilitate

postoperative recovery. Many prefer to use dopamine first in doses of 3-10 mcg/kg/min; but doses above 15 mcg/kg/min are rarely used as dopamine is known to cause vasoconstriction and tachycardia at very high doses. Alternatives to dopamine include dobutamine and low-dose epinephrine. The use of catecholamines has several drawbacks, including increased myocardial oxygen consumption, tachycardia, increased end-diastolic pressure and afterload and risk of arrhythmias. The less compliant neonatal myocardium, may raise its end-diastolic pressure during higher-dose infusions of catecholamines, further impairing ventricular compliance and further reducing ventricular

21filling. PDI milrinone has emerged as an important vasoactive agent for use in post-cardiac surgery children. A large multicenter, randomized, double-blind, placebo-controlled PRIMACORP (PRophy-lactic Intravenous use of Milrinone After Cardiac OpeRation in Pediatrics) trial evaluated the efficacy and safety of the prophylactic use of milrinone in



pediatric patients at high risk of developing LCOS after cardiac surgery. The trial concluded that the prophylactic use of high-dose milrinone after pediatric congenital heart surgery reduces the risk of

22 LCOS, and since the publication of this trial in 2003, many units have begun to prefer milrinone for maintaining cardiac output in postoperative patients.

Norepinephrine and vasopressin are used infrequently in a select group of patients with states of refractory vasodilation as may sometimes occur after cardio-pulmonary bypass in children. Vasopressin is particularly useful when patients have tachyarrhythmias or sinus rates that prohibitively limit the length of diastole.

Levosemandan is a relatively new agent that have generated a lot of interest – especially in post-operative LCOS states. (Please note section under 'Newer inotropes'.)

Post-cardiac Arrest Syndrome

Post–cardiac arrest syndrome is a unique and complex combination of pathophysiological processes, which include (1) post–cardiac arrest brain injury, (2) post–cardiac arrest myocardial dysfunction, and (3) systemic ischemia/reperfusion response, often complicated by a fourth component: the unresolved pathological process that caused the cardiac arrest.

Hemodynamic instability is common after cardiac arrest. Resumption of spontaneous circulation (ROSC) after prolonged, complete, whole-body ischemia is an unnatural pathophysiological state created by successful CPR. Vasodilation may occur from loss of sympathetic tone and from metabolic acidosis. Persistence of reversible vasopressor dependency has been reported for up to 72 hours after out-of-hospital cardiac arrest despite preload optimization and reversal of global myocardial

23dysfunction.

In terms of treatment, a critical knowledge gap exists for post-arrest interventions in children. Therefore,

management strategies are based primarily on general principles of intensive care or extrapolation of evidence obtained from adults, newborns, and animal studies.

The optimal hemodynamic targets in the post-resuscitative period remain unclear. The optimal MAP for post–cardiac arrest patients has not been defined by prospective clinical trials. Post-cardiac arrest anoxic brain injury is a major cause of morbidity and mortality, and is responsible for approximately two thirds of the deaths in the post-

24cardiac arrest period. The loss of cerebrovascular pressure auto-regulation makes cerebral perfusion dependent on cerebral perfusion pressure (CPP=MAP–ICP) and hence predominantly on MAP. In general – it is assumed that hypotension must be avoided and BP should be kept at somewhat high levels. Good outcomes have been achieved in published studies in which the MAP target was as

25 low as 65 to 75 mm Hg or as high as 90 to 100 mm 26,27

Hg for patients admitted after out-of-hospital cardiac arrest.

The simultaneous need to perfuse the post-ischemic brain adequately without putting unnecessary strain on the post-ischemic heart is unique to the post–cardiac arrest syndrome. This makes selection of inotropes difficult. There is a paucity of data about which vasoactive drug to select first but dopamine, dobutamine, epinephrine are all used to treat post-arrest myocardial dysfunction. Vasopressin infusion has recently been used and shown to have higher

28,29short term survival. Although inotropes improve hemodynamic status of the patient and ensures blood flow to the heart and the brain, this improvement in organ perfusion does not necessarily translate into an improvement in

30outcome which still remains low.

Brain Dead Child

Normally brain-stem death constitutes a case for withholding or withdrawing life sustaining medical

treatment. But life sustaining interventions may be needed to be continued on a brain dead child under some special circumstances when family requests continuation of life support for some time for family members to visit or other reasons and also for organ harvesting for a heart-beating donor organ transplant. The maintenance of blood pressure becomes crucial in these patients in order to maintain perfusion not only to the other organs but


also to the heart itself. After some time – brain dead patients often develop marked hemodynamic instability – presumably due to loss of brain-stem reflexes. The first priority when managing a brain dead patient with hypotension is to maintain an adequate effective intravascular volume. 80% of brain-stem dead patients develop diabetes insipidus and it is common for them to be hypovolemic.

Catecholamines are liberally used by transplant 31

retrieval services. Dopamine has traditionally been 32-34

used for the first-line cardiovascular support.

Low dose vasopressin infusion, which is routinely used for treating diabetes insipidus during brain death evaluation and organ recovery, has also been shown to restore vasomotor tone, improve blood pressure and reduce exogenous catecholamine

35,36 requirements and is increasingly being used as first line pressor support. Low-dose vasopressin may allow reduction or complete elimination of catecholamine use in such circumstances.

Terlipressin has also been used for similar purposes.37,38

Canadian guidelines recommend vasopressin as the first-choice vasopressor for donor resuscitation, the second-line agents for hemodynamic support being norepinephrine, epinephrine and pheny-

39lephrine.

How to prepare Infusions of Vasoactive Medications

The universal Rule of Six for Infusion Calculations

applies to the preparation of infusions of vasoactive medications as well.

6 x Body Weight (kg) = Amount (in mg) to mix in 100ml of Solvent to give 1ml/hr = 1 microgram /kg/min.

In the PICU, infusions are usually prepared in 50ml syringes, and the calculations can be derived from this “Rule of Six” adjusted to the volume status of the child and the concentration of the infusion that can be allowed via a central or a peripheral venous line. A standard chart is presented in Table 2.

Changing Inotrope Infusions – Double-pumping vs Quick Change

Inotrope infusion syringes need to be changed under many circumstances which include infusion running out, changing the strength of the infusion (for fluid restriction), changing the diluent of the infusion (in hypo- or hyper-glycemic states), changing the site of infusion (eg. between femoral and neck veins). Serious adverse incidents can take place if due care is not exercised when changing syringes of inotrope infusion, particularly in patients with very labile blood pressure and high inotrope requirement. Preparing the next syringe should never be left until the last minute. Inotrope infusions should never be allowed to run out. Some patients are very dependent on their inotropes and will not tolerate them being turned off for even a short period of time. On the other hand, inotropes should never be purged

Table 2. Infusions of Vasoactive Medications

Drug Dose Dilution to Volume Infusion Rate Equivalent Dose Range Epinephrine - Central 0.3 mg/kg 50 ml D5 or NS 0.1 – 10 ml/hr 0.01 – 1 mcg/kg/min Dobutamine - Central 30 mg/kg 50 ml D5 or D10 or N

S 0.5 – 2 ml/hr 5 – 20 mcg/kg/min

- Peripheral

3 mg/kg 50 ml D5 or D10 or NS

5 – 20 ml/hr 5 – 20 mcg/kg/min

Dopamine - Central 30 mg/kg 50 ml D5 or D10 or NS

0.5 – 2 ml/hr 5 – 20 mcg/kg/min

- Peripheral

3 mg/kg 50 ml D5 or D10 or NS

5 – 20 ml/hr 5 – 20 mcg/kg/min

Milrinone 1.5 mg/kg 50 ml D5 or NS 0.6 – 1.5 ml/hr 0.3 – 0.75 mcg/kg/min NorEpinephrine - Central

0.3 mg/kg 50 ml D5 or NS 0.1 – 10 ml/hr 0.01 – 1 mcg/kg/min

Vasopressin 1.5 IU/kg 50 ml D5 or NS 0.2 – 0.5 ml/hr 0.0001 – 0.00025 IU/kg/min

D5 = 5% Dextrose; D10 = 10% Dextrose; NS = Normal Saline



either – because this results in uneven doses of inotropes being delivered leading to sudden huge changes in hemodynamics and also runs the risk of causing life-threatening arrhythmias, particularly with drugs like epinephrine.

Two different techniques for changing inotrope syringes are commonly used in most units to overcome this problem viz. Double-Pumping (also known as piggy back) and Quick Change (also called Switching Technique).

When starting an inotrope infusion, it is a good practice to include a three-way tap to facilitate syringe changes. Double-pumping involves starting the second infusion through a three way tap while the first is still running. When the blood pressure starts to rise, the first infusion is stopped immediately. The switching technique involves running the new infusion at the same rate as the old and connecting it to the patient (preferably via a three-way tap) while turning the old infusion off.

Randomized-controlled trials comparing the two methods did not find any statistically significant difference in respect with the variation in mean arterial pressure but found the quick change technique to be the quickest and more cost-effective

40-42method. The quick change technique is now used more frequently than it was in the past. Old infusion devices were not as reliable as modern ones, so it was considered safer to titrate a new infusion alongside one ready for change (Double Pumping) in case the infusion device failed. This is no longer necessary, as the newer devices are able to deliver at their set rate immediately.

Newer Inotropes

Levosimendan(LM)

Levosimendan is a calcium sensitizing agent that has generated a lot of interest in recent years. It binds to cardiac troponin C in a calcium-dependent process thereby changing the configuration of tropomyosin which leads to increased contractility. It also opens up potassium channels in sarcolemmal membranes causing muscle relaxation in vasculature leading to reduced SVR and coronary vasodilatation. As they do not increase intracellular

calcium concentration – so diastolic relaxation is not compromised. It does not increase myocardial oxygen demand either. Overall, stroke volume, CO and heart rate increase while mean arterial BP and Pulmonary arterial pressure decrease. Atrial fibrillation is more common with LM compared with either placebo or even dobutamine. Ventricular arrhythmias are more common than placebo but not more than dobutamine. No other significant adverse effects are noted so far except mild hypokalemia. The elimination half-life is 1.5 – 2 hours. However, it has an active metabolite OR-1896 – with an elimination half-life of 70-80 hours which is measurable in serum even 14 days after stopping the

43infusion . It is believed that the hemodynamic effects of LM persists for days after stopping because of this. This might be concerning if LM cause hypotension. However, in most pediatric studies – both hypotension and tachycardia was found to be transient after initiation of the infusion. It is excreted both in the urine and faeces.

Pediatric dose varied but the most commonly used is as follows –

IV Loading dose of 12 mcg/kg over 10 minutes followed by continuous infusion of 0.1 – 0.2 mcg/kg/min. A convenient way is to dissolve 0.3 mg/kg of LM in 5% dextrose and run at 12 ml/hr for 10 minutes and then reduce the infusion to 1 – 2 ml/hr. The range of loading doses have been 6 – 24 mcg/kg and the range of infusion has been from 0.05 – 0.6 mcg/kg/min.

44Adult studies like the LIDO trial, the CASINO trial

45and the SURVIVE trial have compared LM with 46dobutamine whereas the REVIVE and the

47RUSSLAN trials evaluated LM in a placebo-controlled fashion. The study population essentially had low-output heart failure of different etiologies. While all these studies have demonstrated hemodynamic benefits with greater increase in cardiac output in the LM group, the REVIVE and the SURVIVE trials could not demonstrate survival

48 benefits. A meta-analysis of 45 adult studies with 5480 patients, which includes all previously mentioned big studies have shown a significant mortality benefit with 6% absolute risk reduction giving a number needed to treat of 17. A multicentre



UK trial is underway to study the effect of LM in sepsis (LeoPARDS study). Pediatric studies have been retrospective case series and till now, four randomized controlled trials have been conducted. Overwhelming majority of them have been in post-operative LCOS situations and LM has often been compared with milrinone. They showed a trend toward an improvement in hemodynamics, a reduction in lactate, a reduction in the need for conventional inotrope use and an ability to wean

49-51 catecholamines. So far, mortality benefit has not been proven. Clearly, more data is needed to further establish the role of this promising agent.

Istaroxime

This is another new molecule with ino-lusitropy. However, unlike milrinone or LM – it has a short half-life which may be useful – given the potential for hypotension. It also seems to reduce heart rate. However, besides some animal experiments – only

52one dose escalation adult study has been reported so far. As of now, there is no reported pediatric experience and it is still considered as an experimental molecule.

Conclusion

Inotropes remain one of the most commonly used group of drugs in intensive care setting. They are used to support the circulation in different situations. However, there is not much evidence base; either pediatric or even adult – especially regarding the classical adrenergic agents. This is somewhat surprising – more so considering the fact that they have been in use for a long time. There remains a significant void and there is a need of more robust clinical studies to generate more evidence. On the other hand, recently there have been important new entrants; like milrinone, in the group with properties that are significantly different from the traditional agents and they have found their well earned place in modern therapeutics. There are some newer agents; like levosimendan – which has been used for some time and their role in Pediatric practice is being established. There are yet other molecules – which are in the process of development. So, this is an area where we would expect exciting new advances in future. So, keep watching!

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Cardiac arrhythmias in Pediatric intensive care unitDr. Vinay Kukreti*, Dr. Mosharraf Shamim**

Departments of Critical Care, Pediatric Critical Care Unit, The Hospital for Sick Children, Toronto, Canada*, Department of Pediatric Critical Care King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia**


Introduction

Arrhythmias are a common dilemma confronting pediatric intensivists and are most likely to occur in patients with structural heart disease. The inciting factor is usually related to hypoxia, ischemia, catecholamines, electrolyte imbalance or central lines. The physiological impact of given arrhythmia depends on ventricular response rate, duration as well as underlying cardiac function. Patient's underlying cardiac status is the key to management. Bradyarrhythmias may decrease cardiac output in patients with relatively fixed stroke volumes. Similarly, tachyarrhythmias may decrease diastolic filling and reduce cardiac output, resulting in hypotension, in addition to producing myocardial ischemia. In cardiac emergencies, accurate differentiation of ventricular and supraventricular tachyarrhythmia is essential for appropriate management.

This review provides an updated approach to current concepts of diagnosis and acute management of arrhythmias in Pediatric intensive care unit. A systematic approach to diagnosis and evaluation will be presented followed by consideration of specific arrhythmias.

Approach to Arrhythmia in PICU

Artifacts , mechanical problems due to central line and electrolyte problems(potassium,calcium and magnesium related)must be thought of in all cases of arrhythmias in PICU . Rhythm problems once confirmed need to be urgently categorized into two

categories : stable or unstable.A twelve lead EKG should be attempted and a rhythm strip printed.

In general atrial arrhythmias such as atrial ectopics,supraventricular tachycardias,first degree AV block,atrial flutter,occasional ventricular ectopics are considered stable but need close monitoring for deterioration .In general all ventricular arrhythmias are potentially unstable. Treatment modalities such as cardioversion, defibrillation and urgent pacing are decided by ventricular response and effect on the cardiac output.

Always remember that first principle in managing arrhythmias is to treat the patient rather than the electrocardiogram. Evaluation heart rate and rhythm quickly and assessing the level of significance in terms of hemodynamic alterations; blood pressure and peripheral perfusion. If the patient loses consciousness or becomes hemodynamically unstable in the presence of a tachyarrhythmia, prompt electrical cardioversion is indicated. If the patient loses consciousness or becomes hemodynamically unstable in the presence of a bradyarrhythmia, prompt medical therapy or cardiac pacing(external or internal) is indicated. If heart rate is below 60 in a newborn or infant, cardiac compression must be instituted in addition to on going treatment.

Classification of arrhythmias:

Arrhythmias are commonly classified according to rate, rhythm and electrocardiographic findings. Electrocardiographically, arrhythmias can be characterized as bradycardias, tachycardias or extrasystoles. Bradycardias are further subdivided into the level of dysfunction i.e sinus node or atrioventricular dysfunction. Tachycardias can be

Correspondence:

Dr. Vinay Kukreti

Department of Critical Care, Pediatric Critical Care Unit, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.



further classified according to the anatomic level of origin as supraventricular or ventricular and functional mechanism reentry, automaticity or triggered activity.

Evaluation of Tachyarrhythmias:

The first step in the evaluation of the critically ill patient with an arrhythmia is to assess hemodynamic stability. Next step in the evaluation is to determine whether the arrhythmia is supraventricular or ventricular in origin based on width of QRS complex. A narrow QRS complex (<120 msec) represents supraventricular tachycardia(SVT). The site of origin may be in the sinus node, the atria, the atrioventricular node, the His bundle, or some combination of these sites (Figure-1).

Pathogenesis involves three electrophysiological mechanisms: (a) reentry (b) Increased automaticity

1(c) triggered automaticity . Reentry is the most common mechanism. If SVT'S are regular and narrow complex, consider reentry. Examples include atrioventricular nodal reentrant tachycardia (AVNRT), atrioventricular reentrant (AVRT), ectopic atrial tachycardia, and atrial flutter. In cases of irregular narrow complex SVT's, consider increased automaticity which includes Atrial Fibrillation (AF), multifocal atrial tachycardia, atrial flutter with variable block, and sinus tachycardia with frequent premature atrial complexes and junctional ectopic tachycardia.

A widened QRS tachycardia (≥ 120 msec) occurs when ventricular activation is abnormally slow. The most common reason that a QRS is widened is that the arrhythmia originates outside of the normal conduction system (eg: ventricular tachycardia). Alternatively, a supraventricular arrhythmia can produce a widened QRS if there are either preexisting or rate-related abnormalities within the His-Purkinje system (eg: supraventricular tachycardia with aberrancy), or if conduction occurs over an accessory pathway. Thus, wide QRS complex tachycardias may be either supra-ventricular or ventricular in origin


Regular Rhythms

Sinus Tachycardia

Sinus tachycardia is a rhythm in which the rate of impulses arising from the sinoatrial (SA) node is elevated. Common potential causes include anxiety, pain, fever, hypovolemia, anemia, hypoxemia, medications, and, occasionally, alcohol withdrawal. Less common causes include thyrotoxicosis,

(2) pheochromocytoma and methemoglobinemia.Treatment focuses on identifying and trying to correct the underlying cause.

Atrioventricular reciprocating tachycardia (AVRT):

The most common type of reentrant SVT in children is AVRT, involving both atrial and ventricular tissue. They display a fixed 1:1 AV relationship. Orthodromic reciprocating tachycardia (ORT) is the most common AV reentrant tachycardia in normal infants and is the most common mechanism of

3,4SVT . In ORT, antegrade conduction is over AV node, whereas retrograde conduction to the atria occurs via an accessory pathway (Figure-2). QRS morphology and duration are usually normal, with retrograde P wave following each QRS complex.

Figure-1: Showing the normal conduction system of the heart

PEDIATRIC CARDIAC INTENSIVE CARE Cardiac arrhythmias in Pediatric intensive care unit

Figure-2 URAP-Unidirectional retrograde anomalous pathway

When the accessory pathway conducts impulses in the antegrade direction (atrium to ventricle)two parallel routes of AV conduction are possible: one is subject to delay through the AV node, and the other occurs without delay through the accessory pathway and results in preexcitation of the ventricle .The result is a characteristic ECG pattern during sinus rhythm consisting of a short PR interval, a "delta wave" (both of which reflect preexcitation), and a widened QRS complex due to the delta wave. This ECG pattern is referred to as the Wolff-Parkinson-White (WPW) pattern (Figure 3). It is important to appreciate that many patients with the WPW pattern do not develop SVT; when episodes of SVT do occur, the patient is said to have the WPW syndrome. A natural history study in young men suggested that, among patients with WPW syndrome, the incidence of SVT is only about 1

5percent per year .


Antidromic reciprocating tachycardia (ART) is much less common in which circuit is reversed: antegrade conduction occurs via accessory pathway resulting in preexisted QRS. As a result, ART is not readily distinguishable from Ventricular tachycardia by ECG features alone.

Permanent junctional reciprocating tachycardia (PJRT): In most cases, conduction through the accessory pathway is quite rapid and comparable to the conduction velocity of normal myocardium. Permanent junctional reciprocating tachycardia (PJRT) is a variant of orthodromic AVRT in which the retrograde conduction in the accessory pathway

6is slow . Slow retrograde conduction through the accessory pathway coupled with the normally slow conduction antegrade through the AV node creates a stable reentrant circuit. As a result, PJRT is an incessant SVT, in contrast to the typically

7paroxysmal nature of most SVT .

AV nodal reentrant tachycardia (AVNRT):

AV nodal reentrant tachycardia (AVNRT) is the most common cause of SVT in older children and

8adults . It is seen less common in infants (3,4) AV nodal reentrant tachycardia (AVNRT) is mediated by the presence, within the AV node, of two conducting pathways that are designated fast and slow. The fast pathway has a short conduction time but long refractory period. The slow pathway has a long conduction time but short refractory period. These distinct pathways allow for a reentrant loop using one pathway in the antegrade direction and one in the retrograde direction. Typical AVNRT utilizes the slow pathway in the antegrade direction and the fast pathway in the retrograde direction. Atypical AVNRT employs the fast pathway in the antegrade direction and the slow pathway in the retrograde direction.

Treatment of Reentrant Tachycardia:

Acute management of a infant or child who presents in the emergency department depends upon hemodynamic status. If the child is hemo-dynamically unstable, synchronized DC cardio-

9,10version with 0.5 -2.0 J/kg should be performed . In

Figure-3 Short PR interval,wide QRS and delta waves classic findings of WPW



children who are hemodynamically stable and have mild or no symptoms, vagal maneuvers should be attempted. Vagal maneuver for infants or young children include application of a bag filled with ice and cold water over the face for 15 to 30 seconds. This elicits the diving reflex, frequently interrupting

11the arrhythmia . This maneuver is successful in 30

10,12,13to 60 percent of cases . If the vagal maneuver is unsuccessful pharmacological agents can be tried. Adenosine is the drug of first choice. It is given by rapid intravenous injection over one to two seconds at a site as close to the central circulation as possible. The usual initial dose is 0.1 mg/kg; if no response is

14seen within two minutes, the dose is doubled . Adenosine terminates 80 - 95 percent of episodes of AVRT, which accounts for almost three-quarters of

15episodes of SVT and approximately 75 percent of

14,16,17episodes due to other causes of SVT . Early recurrence of the SVT after termination occurs in 25

14,16to 30 percent of cases Side effects, include flushing, nausea, vomiting, feeling of discomfort, chest pain, and dyspnea.These are transient and resolve rapidly. Adenosine should be avoided or used with caution in the following settings.

- In patients with Wolff-Parkinson-White (WPW), 18

AF can degenerate into ventricular fibrillation

- In patients with a wide QRS complex tachycardia, if the specific arrhythmia is not identified, since adenosine can provoke severe hemodynamic deterioration in those who have ventricular tachycardia rather than an SVT.

- In patients with pre-existing second or third degree heart block or sinus node disease where it is contraindicated.

Atrial Tachycardia (AT):

Atrial tachycardia (AT) is a subset of SVT originating entirely from atrial tissue and does not require the atrioventricular (AV) junction, accessory pathways, or ventricular tissue for initiation and maintenance of the elevated heart rate(Figure-4). Atrial fibrillation and atrial flutter, although fulfilling this definition, are usually not included in the designation of AT and are typically identified as specific entities. Atrial ectopic tachycardia (AET)

represents 10-20% of SVT in pediatric population. Its an automatic arrhythmia that presents as an

13incessant rhythm .In addition arrhythmia has been associated with chronic cardiomyopathy. Focal atrial tachycardia (FAT), also due to a single focus, behaves in a paroxysmal manner, starting and stopping abruptly. Microreentry or triggered activity are thought to be the most common cause. Multifocal Atrial tachycardia (MAT) or chaotic atrial rhythm is defined by 3 or more P-wave morphology, atrial rate >400 and ventricular rate of

19150-250/min .

Treatment of AET/MAT:

Atrial ectopic tachycardia is generally responsive to medical therapy, and there are high chances of spontaneous resolution. In several case series, spontaneous remission rates vary from 40 to 75 percent for patients up to 18 years of age within 10 to

20,2128 months of diagnosis . Medical treatment involves Digoxin which decreases ventricular response rate by slowing AV conduction but has no effect on ectopic focus. Other drugs that can be used are amiodarone and propafenone. In patients with chronic or frequently recurrent conditions who unresponsive to medical therapy, ablation therapy is suggested.

Multifocal atrial tachycardia resolves completely


Figure-4


after six months and the prognosis for long-term outcome is excellent in children. In some cases, MAT is seen in patients with structural heart disease, and the outcome is dependent upon the

19underlying condition . Medical therapy is therapy is directed at controlling the ventricular response rate with a combination of oral digoxin, beta blocker, and calcium channel blocker.

Atrial Flutter: May present during utero or newborn period. It is a macroreentry tachycardia which involves electrical circuit between the inferior vena cava and the tricuspid valve annulus, the cavotricuspid isthmus. It manifests as a sawtooth pattern on ECG, usually with atrioventricular block.(Figure-5A) Atrial flutter in patients who have undergone surgery for congenital heart disease is referred to as Intraatrial Reentrant tachycardia (IART). A high incidence of this arrhythmia has been noted in long-term follow-up, particularly in patients after intraatrial surgeries such as the Mustard or Senning procedure for palliation of d-transposition of the great arteries and the Fontan

22,23procedure for single ventricle physiology . Atrial fibrillation (AF) involves multiple, simultaneous atrial reentry wavelets which appear on a rhythm strip as a low amplitude or choppy, irregular baseline with a variable R-R interval.(Figure-5B)

Treatment: Newborn with atrial flutter can be treated with digoxin, amiodarone and esmolol. Unlike older

children and adults, calcium channel blocking agents should always be avoided in infants, due to substantial risk of potentially fatal cardiovascular collapse. If medical therapy does not result in conversion to sinus rhythm, electrical cardioversion

24,25can be attempted .

Junctional Ectopic Tachycardia (JET): JET occurs due to enhanced automaticity in the region of AV node. It is characterized by narrow complex tachycardia with AV dissociation and ventricular rate higher than atrial rate. It may be congenital, most common post-surgical form and paroxysmal

26,27JET described primarily in adults congestive heart failure is the frequent presenting sign in

28congenital form . Post operative JET is most commonly seen following ventricular septal defect

29closure .

Treatment: For congenital form of JET amiodarone is most useful. Postoperative JET can be treated by cooling, sedation and AV sequential pacing to restore AV synchrony .

Ventricular tachycardia (VT)

Ventricular tachycardias include all tachycardias that arise exclusively within the ventricle below the bifurcation of the bundle of His. VT is defined as three or more consecutive beats on ECG. SustainedVT is defined as more than 30 seconds of

30,31ventricular beats at a rate of more than 100 bpm . The mechanisms by which ventricular arrhythmias occur are the same as those that result in supraventricular arrhythmias: reentry, automaticity, and triggered automaticity.

VT is most frequently associated in patients with tetralogy of Fallot, although it may occur in patients with other congenital defects (eg, transposition of the great arteries, Ebstein's anomaly, and lesions

32,33with left ventricular outflow obstruction . Several genetic disorders are associated with VT and they are classified as channelopathies or cardio-myopathic disorders.

Channelopathy:

The long QT syndrome (LQTS) is a disorder of

Figure-5A Atrial Flutter with classical 4:1)

Figure-5B Atrial fibrillation



myocardial repolarization characterized by prolonged QT interval and T wave abnormalities. QT intervals usually exceed 0.46. Patients with LQTS present with syncope, seizures, or cardiac arrest. A family history of sudden death, seizures, recurrent syncope, or unexplained drowning should heighten the suspicion of LQTS. The LQTS can be congenital, as an inherited disorder usually involving a mutation of an ion channel gene, or can be acquired secondary to drugs, metabolic

34,35abnormalities, or bradyarrhythmias . Torsades de pointes is the specific arrhythmia associated with Prolonged QT syndromes and is responsible for the symptoms. This characteristic arrhythmia is recognized by progressive undulation in the QRS axis, resulting in a “twisting” appearance(Figure-6)

Brugada syndrome is associated with characteristic ECG findings of ST segment elevation in leads V1 to V3 and a right bundle branch block pattern in the

36right precordial leads . Implantation of a defibrillator is the only established effective treatment and is indicated for symptomatic

37patients .

cardiomyopathy (ARVC) and myotonic dystrophy.

Other causes: Include acquired ones like coronary heart disease, myocarditis, Chagas disease, electrolyte and metabolic disturbances. Hyper-kalemia can lead to variety of conduction abnormalities and arrhythmias. Tricyclic anti-depressants (TCA) toxicity can cause widening of

(41)the QRS complex and ventricular arrhythmias. Sodium bicarbonate is the antidote of choice for TCA toxicity.

Treatment:

Treatment is determined by the degree of hemodynamic compromise. Acute management of a child who presents with wide QRS complex tachycardia and is based upon the 2005 American Heart Association, American Academy of Pediatrics, and International Liaison Committee on Resuscitation (AHA/AAP/ILCOR) guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care (ECC) of pediatric

42patients . In stable patients with VT, the guidelines recommend that i.v amiodarone at a dose of 5 mg/kg (maximum dose 300 mg) be given slowly over 20 to 60 minutes. Additional doses can be given in patients who remain in VT and do not have signs of toxicity. If amiodarone is not available i.v procainamide can be administered as a 15 mg/kg bolus over 30 to 60 minutes ECG and blood pressure monitoring are required as amiodarone and procainamide can prolong the QT interval and cause hypotension. Synchronized cardioversion (0.5-1joules/kg can be used to treat perfusing ventricular arrhythmia, if the rhythm is pulseless defibrillate immediately (2-4joules/kg). If the rhythm is consistent with torsades de pointes, intravenous magnesium at a dose of 25 to 50 mg/kg may be given.

Figure-6


Catecholaminergic polymorphic ventricular tachycardia (CPVT):

Patients with CPVT has characteristic feature of ventricular tachycardia with beat-to-beat alternation of the QRS axis occurring with physical or emotional stress and can be asympto-matic(Figure-7) Mutations in the cardiac ryanodine receptor gene (RyR2) or cardiac calsequestrin (CASQ2) underlie catecholaminergic

38-40bidirectional ventricular tachycardia . Therapies include beta blockers or Intracardiac defibrillator.

Cardiomyopathy: VT is often associated with inherited cardiomyopathies such as hypertrophic cardiomyopathy, Arrhythmogenic right ventricular

Figure-7 Exercise induced polymorphic ventricular tachycardia in patient.


Bradyarrhythmias:

Bradycardia is defined as heart rates below the lowest normal values set for age. There are two main mechanism for bradycardia. Either it is due to sinus node defect resulting in sinus bradycardia or It may be due to abnormalities of AV conduction including first, second or third degree heart block.

Sinus Bradycardia : Sinus bradycardia is present when there is a normal sinus appearing P-wave on the 12-lead ECG but the rate is below normal for age. Causes include increased vagal tone, raised intracranial pressure, hypoxia, hypothyroidism, Drugs (digoxin,β blocker, calcium channel blocker) and post cardiac surgery

Abnormalities of AV conduction:

Atrioventricular (AV) block is defined as a delay or interruption in the transmission of an atrial impulse to the ventricles. The conduction can be delayed, intermittent, or absent. Heart block is divided into three catogeries.

1. First-degree AV block occurs when the PR-interval is greater than the upper limits of normal for age.(Figure-8)

Figure-8

2. Second-degree AV block is further divided into two categories based on ECG findings, Mobitz type 1 and type 2.

In Mobitz type 1 block (also referred to as Wenckebach block), there is progressive prolongation of the PR-interval until a P wave fails to be conducted.(Figure-9)

In Mobitz type 2 block, the PR interval remains unchanged prior to the P wave that suddenly fails to conduct to the ventricles.(Figure-10)

Figure-10

3.Third-degree AV block is also referred to as complete heart block. On ECG, there is complete dissociation of the atrial and ventricular activity(Figure-11)

Figure-11

Treatment:

First thing is to seek the underlying cause. It is particularly important in intensive care setting where airway compromise is the most common cause of acute bradycardia. Raised ICP, electrolyte imbalance produces bradycardia which may require intervention. No intervention is needed for sinus bradycardia as long as cardiac output is maintained. No treatment is necessary for first degree or Mobitz type-I heart block. Mobitz type-II and third degree are always pathological.

For hemodynamicaly significant bradycardia, after managing airway, initial treatment is usualy pharmacological, whether the cause is sinus node slowing or AV nodal block. Atropine transiently ameliorates bradycardiac effect. Continuous infusion of epinephrine and isoproterenolol may be instituted. Consider cardiac pacing, particularly if a conduction defect is detected or suspected. In PICU, temporary pacing is most commonly used after surgery.

Conclusion:

Artifacts,mechanical problems due to central line and electrolyte problems must be thought of in all cases of arrhythmias in PICU. Rhythm problems once confirmed need to be urgently categorized into two categories : stable or unstable. If the patient


Figure-9


loses consciousness or becomes hemodynamically unstable in the presence of a tachyarrhythmia, prompt electrical cardioversion is indicated. However If the patient loses consciousness or becomes hemodynamically unstable in the presence of a bradyarrhythmia, prompt medical therapy or cardiac pacing(external or internal) is indicated.

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Introduction

In both the intensive care and cardiac care units, we frequently deal with patients who require cardiac pacing. Depending upon the etiology, a child may require pacing support for a short duration or for a more prolonged time. Despite many existing indications for pacing, till now, it has been a dormant modality in pediatric intensive care units (PICU). This might be attributed to many factors like delayed or non-identification of suitable indications, non availability of pacing facilities, less familiarization with pacing modes and some times pacing procedure phobia in nursing or medical staff. In this

article, we have tried to simplify this fancy looking term called as 'pacing' with a systematic approach from basic physiology to bed side application.

Normal cardiac electrical activity

Electrical impulses are generated at the sinoatrial (SA) node, which is located in the right atrium of the heart. From SA node, the electrical impulse spreads through the right and left atria and then enters the atrioventricular (AV) node situated at the AV junction. The AV node is important as it slows down the conduction to allow time for atrial contraction

1and emptying (figure1).

Cardiac Pacing in Pediatric Intensive Care UnitDr Neeraj Gupta*, Dr Anil Sachdev**, Dr Dhiren Gupta*

*Pediatric Intensivist, **Director Pediatric Emergency, Critical Care and Pulmonology, Department of Pediatrics, Institute of Child Health, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110060, India

Figure 1. Cardiac electrical impulse generation and conduction through normal pathway


Correspondence:

Dr. Neeraj Gupta


Pediatric Intensivist, Institute of Child Health, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110060, India

After the AV nodal delay, the impulse travels through the ventricles through a specialized conduction system called the bundle of His. The His bundles then divides in to two branches, the right bundle branch (RBB) that navigates its way through the right ventricle and the left bundle branch (LBB)


that navigates through the left ventricle. Following these bundle branches the impulse finally passes to the terminal points called Purkinje fibers. These Purkinje fibers are embedded in the entire thickness of the myocardium and activate the entire myocardial mass from the endocardial surface to the

2epicardial surface .

Normal ECG

Figure 2 depicts the normal ECG wave form. Each waveform may be simplified as below:

·P wave – atrial depolarization

·PR interval – time interval from beginning of P wave to beginning of QRS.

·QRS – Ventricular depolarization (duration of ventricular muscle depolarization).

·ST-T segment – Ventricular repolarisation.

·QT interval – duration of ventricular depolarisation and repolarisation.

·T wave – ventricular repolarisation.

·U wave – Purkinje system repolarisation.

·RR interval – suggests ventricular rate.

Indications of cardiac pacing

·Arrhythmia with hemodynamic compromise

·I n a p p r o p r i a t e s l o w r a t e w i t h hemodynamic compromise

·I n a p p r o p r i a t e f a s t r a t e w i t h hemodynamic compromise

Reasons for arrhythmias requiring pacing

·Short term – these might require temporary cardiac pacemaker (TCP)

o Conduction pathway damage

during surgery

o Edema surrounding surgical site

o Electrolyte imbalances

o VSD/ASD patches

·Long term – these usually require permanent cardiac pace maker (PCP)

o Congenital arrhythmias

o Chamber hypertrophy

Figure 2. Normal ECG tracing

Table 1.


PEDIATRIC CARDIAC INTENSIVE CARE Cardiac Pacing in Pediatric Intensive Care Unit

Types of cardiac pacing

Invasive electrical pacing is used to initiate myocardial contraction when intrinsic stimulation is insufficient, the intrinsic impulses are not being conducted or the heart rate is too slow to maintain an

3adequate cardiac output . Electrical impulses of sufficient strength are delivered to and which then stimulate the myocardium to depolarize at a

4preselected rate . There are a number of various routes and methods available to deliver cardiac pacing (figure 3). The common goal of each approach to pacing is to contribute to hemodynamic stability and to correct symptoms of reduced cardiac output through support of the heart rate by providing safe, potentially life-saving therapy in a variety of

1clinical situations .

Temporary cardiac pacing sites

Epicardial

Epicardial pacing is the most commonly used pacing in post-op cardiac patients. During cardiac surgery, electrodes (epicardial wires) are attached directly to the epicardial surface of the atrium and/or the

5ventricle . The wires then exit through the patient's

sternum where they are then connected to a pulse generator. Epicardial pacing is often used following cardiac surgery for the management of surgically

1related bradydysrrhythmias .

Transvenous (Endocardial)

Transvenous leads may be balloon-tipped which will allow for floating placement in the ICU, or non-floating pacing catheters which require fluoroscopic

1guidance for placement . A Swan-Ganz balloon-tipped floating bipolar transvenous pacing wire is a commonly used example. This is advanced via a vein (usually the subclavian routed through to the superior venacava) to the endocardial surface of right atrium (RA), or most commonly, the right

5ventricle . The presence of pacing spikes and restoration of a fixed heart rate on the ECG will confirm placement of the wire.

Transesophageal

This method is used when there are no epicardial wires or when wires do not adequately pace the heart.

Transcutaneous (External)

External transcutaneous pacing is temporary means

Figure 3. Types of cardiac pacing



of pacing a patient's heart during an emergency as it 6can be rapidly achieved . Adhesive skin pads

(electrodes) are applied to the patient's chest and back, which are then connected to a defibrillator unit. A fixed rate is set and the output current is dialed up until capture is displayed on the ECG. Current between 50-150 milliampere (mA), depending upon the size of the patient and

5transthoracic impedence, are usually sufficient . This procedure can be painful for the patient, therefore, sedation and analgesia should always be considered.

Indications for temporary cardiac pacing (TCP)

Table 2. Indications of temporary cardiac pacing (TCP)

Temporary Pacing

Temporary pacing of the myocardium is used for a 3variety of emergency and elective conditions (table

2). Sinus bradycardia and AV block are common early postoperative dysrhythmias and conduction block is more common and transient after valvular surgery as a result of direct injury and increased

1edema to the myocardium . Heart blocks following surgery are usually transient. It may be caused by ischemia, manipulation of cardiac tissue with resultant edema, perioperative myocardial

7infarction or mechanical injury during surgery .

Unipolar and Bipolar pacing

'Unipolar' and 'bipolar' pacing is not synonymous as 'single-chamber' and 'dual chamber' pacing. Terms unipolar and bipolar refers to the pacing electrodes.

Unipolar pacing is usually used in permanent pacing systems. In this there is only one conducting wire and electrode, electric current returns to the

5pacemaker via body fluids .

Bipolar pacing is the method of choice for TCP. There are two conducting wires and two electrodes. The impulse from the pulse generator passes down one electrode, then passes through cardiac tissue to cause depolarization and the circuit is then completed via second electrode, which delivers the

8current back to generator .

Demand and Asynchronous pacing

Demand pacing is most commonly used type of pacing. In this, pacing is provided on demand, when the patient's own rhythm falls below the set rate. If the pacemaker is sensing inappropriately, there is potential to deliver pacing stimulus during atrial or ventricular repolarisation, which could precipitate tachycardia and fibrillation as myocardial cells are vulnerable during this period.

In asynchronous pacing, pacing stimulus is provided at a set rate regardless of underlying rhythm. It is safe only if there is no to minimal electrical activity. As soon as patient's native electrical activity re-emerges, demand mode must be introduced, to prevent tachyarrythmias.

·Bradydysrhythmias/Heart blocks

a. Second degree AV bock: Type I (occasionally) & Type II

b. Bifascicular or trifascicular block

c. Complete AV block

d. Complete asystole

·Sick sinus syndrome

a. Symptomatic sinus arrest

b. Atrial fibrillation (fast or slow)

c. Bradycardias/tachycardias

d. Symptomatic sinus bradycardia

·Cardiovascular surgery

a. Prophylactic use during cardiac surgery in patients with history of Acute Coronary Syndrome or cardiac dysrhythmias

b. Treatment for heart blocks developing during or after surgery

c. Cardiac output augmentation post-operatively

·Drugs

a. Digoxin

b. Amiodarone



Pacing codes

The North American and British Group (NBG) generic pace maker codes are used for easy

5identification of pacing modes . The table 3 shows five pacing codes, however, in clinical practice the first three letters are predominantly used.

Terminology

·Threshold – the least amount of electrical current required to cause depolarisation of myocardium

·Capture – the ability of the pacing box's electrical impulse to initiate a cardiac

response (indicated by pacing spike followed by respective wave, P or QRS, on ECG)

·Sensitivity – the ability of the pacemaker to sense the intrinsic (patients own) cardiac electrical activity. This prevents pacemaker from competing with the patient's own rhythm. The pacemaker should initiate a contraction if does not sense the patients own rhythm.

·Triggered – the atrial rate can be measured (sensed) by the box and the ventricle will be paced at the same rate, even if that is higher than the rate set in the box.

Table 3

Position I Position II Position III Position IV Position V Chamber (s) paced

Chamber (s) sensed

Response to sensing

Rate modulation Multisite pacing

O = None O = None O = None O = None O = None A = Atrium A = Atrium T = Triggered R = rate

modulation A = Atrium

V = Ventricle V = Ventricle I = inhibited V = Ventricle D = Dual (A+V) D = Dual (A+V) D = Dual (T+I) D = Dual (A+V)

Figure 4 a



·Inhibition – the patient can inhibit the pacing box. This means that if the patient's heart rate is faster than the box, the box should not pace the chamber. However, the box should not allow the patient's rate to go below the rate set on the box.

Depending upon first three positions (Table 3 ?), cardiac chambers can be paced independently (Figure 4 a) or simultaneously (Figure 4 b), hence pacing modes may be described accordingly.

Hemodynamic effects of TCP

The common goal of all techniques of cardiac pacing is to contribute to hemodynamic stability by resuming cardiac output through support of heart rate, as cardiac output depends upon the heart rate and stroke volume.

Single chamber pacing

Atrial pacing (AOO or AAI) is preferable to ventricular pacing (VOO or VVI) as this maintains AV synchrony. However, for applying atrial pacing, AV nodal pathway must be intact with normal

9functionality . Ventricular single chamber pacing can reduce cardiac output significantly as AV synchrony is absent.

Dual chamber pacing

Stimulation of both atria and ventricles can be

accomplished by using a dual chamber pacing mode (DDD) with a set interval between atrial and ventricular stimulation (AV interval). AV interval must be set as close as possible to the normal PR interval, which is normally 140 to 200 msec. This allows optimization of cardiac filling for ventricular contraction. As, DDD pacing ensures synchrony, it is superior to VVI pacing.

Capturing and sensing

Capturing is the ability of an electrical impulse to initiate a cardiac response and is detected by

3examining an ECG . It is both an electrical and mechanical event. Capture is indicated by a pacer spike followed by a corresponding P wave in atrial pacing and QRS complex in ventricular pacing or both in dual chamber pacing. When a pacing stimulus successfully generates ECG wave (P or QRS), it is said to have captured the corresponding chamber (atria or ventricles).

Sensing refers to ability of the generator to detect and recognize the myocardial intrinsic activity. In demand pacing, sensing of an intrinsic QRS complex will inhibit the pacemaker from delivering an impulse so as not to interfere with patient's own electrical activity. The sensitivity is measured in millivolts (mV) and is initially set to about 2-5 mV. Failure to sense means pulse generator is under-sensing and has not seen the heart's intrinsic beat and

Figure 4 b



so continues to pace, even when not required, causing dysrhythmias such as ventricular fibrillations. This can be managed by decreasing the sensitivity threshold (making the pacer more sensitive). If pacemaker is over sensing then it may be detecting beats that are not actually occurring, from electronic devices which causes electro-mechanical interference. This is bad because patient will not get a pacing stimulus when one is required and wil l be hemodynamical ly compromised. In this scenario, sensitivity threshold should to be increased to block out the artifacts (thus making the pacer less sensitive).

Commonly used pacing modes with their indications

VOO – used in emergency situation in complete heart block or severe bradycardia

VVI – used as backup in sudden unexpected bradycardia or in patients with identified AV conduction block in whom AV synchrony is not thought to be necessary or achievable.

Atrial pacing – used in patients with sinus bradycardia or sinus arrest with intact AV conduction

AOO – advantage of simplicity, may cause arrhythmia as asynchronous

AAI – advantage of adding atrial systolic contribution to cardiac output

DVI (AV sequential) – usual indication is AV conduction block

DDD (AV universal) – paces and senses the atrium and ventricle and can act in different modes depending on the underlying rhythm.

Initiating TCP

Epicardial wire identification – During cardiac surgery, epicardial wires are pulled through the skin and secured to the external chest wall, ready to be attached to a temporary pulse generator. The patient may have only atrial wires or ventricular wires or both atrial and ventricular wires.

Atrial wires – The wires exiting the sternum on the right side are always atrial wires, one each for positive and negative electrode.

Ventricular wires – The two wires, for positive and negative electrodes, exiting on left side of sternum are ventricular wires.

Connecting pacing wires to a bipolar pacing cable – The two metal pins (positive and negative electrodes) of pacing wires (both atrial and ventricular wires separately) are plugged in the pacing cables, which are then connected to pacing box (Figure 5).

Figure 6 demonstrates operational instructions of TCP.

Setting the pacing box

Rate – set according to age and physiological needs of patient

Output – start with 10 milli ampere (mA) and increase until the capture is gained

Sensitivity – start at 0.5 mV for atria and 2-5 mV for ventricles and adjust according to sensing

AV sensing – set AV interval to 140-200 ms (pulse generator defaults to 170 ms)

The intensivist should recognize the pacemaker generated cardiac rhythm and associated problems and their solutions (figure 7 a & b).



Figure 5. Medtronic 5388 dual

chamber temporary pacemaker

Figure 6. Operational instructions of Medtronic 5388 dual chamber temporary pacemaker

An ECG of a paced rhythmFigure 7a



Figure 7b

Consideration for transition to a Permanent pacemakerOccasionally, a patient may become permanently dependent on the TCP and so consideration must be given to transition to a permanent pacemaker . Optimal timing for this decision will depend on clinical course, but at 4-5 days it is reasonable to consider a PPM as by then epicardial wires may

9begin to fall .

References:

1. Timothy, P. R. and Rodeman, B.J. Temporary

Pacemakers in Critically Ill Patients: Assessment and

Management Strategies. AACN Clinical Issues

2004; 15:, 305 – 325

2. Kirk, M. 2006 Chapter 1 Basic Principles of Pacing.

In Chow, A. W. C. and Buxton, A. E. (eds)

Implantable Cardiac Pacemakers and Defibrillators:

All you need to know. Blackwell Publishing,

Massachusetts

3. Overbay, D. and Criddle, L. Mastering Temporary

Invasive Cardiac Pacing. Critical Care Nurse 2004;

24: 25 – 32

4. Dennis, M. and Gallagher, R. 2007 Chapter 19

Support of Cardiovascular Function. In Elliott, D.,

Aitken, L. and Chaboyer, W. (eds) ACCCN's Critical

Care Nursing, Mosby Elsevier, Marrickville, NSW

5. Donovan, K, D. and Hockings, B, E, F. 2009 Chapter

19 Cardiac Pacing and Implantable Cardioverter

Defibrillators. In Bersten, A.D. and Soni, N. (eds) th Oh's Intensive Care Manual, 6 edn, Butterworth

Heinemann Elsevier, Philadelphia

6. Gibson, T. A Practical Guide to External Cardiac

Pacing. Nursing Standard 2008; 22: 45 – 48

7. Marolda, D. and Finkelmeier, B, A. 2000 Chapter 22

Postoperative Patient Management. In Finkelmeier,

B, A. (ed) Cardiothoracic Surgical Nursing, 2nd edn,

Lippincott, Philadelphia

8. Adam, S.K. and Osborne, S. Critical Care Nursing:

Science and Practice. 2nd edn 2005, Oxford

University Press, Oxford9. Reade, M.C. Temporary epicardial pacing after

cardiac surgery: a practical review Part 1: General considerations in the management of epicardial



Case Report

Case Report :

A 3 month old previously healthy and well infant male child presented at the outpatient department(OPD) with a history of high grade fever of one day duration without an obvious clinical focus. On examination, the infant was active, alert and feeding normally. General examination did not reveal any clues to the focus of infection. Systemic examination was unremarkable, with a supple neck and normal anterior fontanelle. In view of his age and presentation hospitalization was advised for observation and investigations. Standardized testing to exclude a “ serious bacterial infection” followed with commencement of empiric intravenous antibiotic therapy pending cultures. His initial complete blood count showed : Hb -9.2 gm/dL, ,TLC-13,400 with 51% neutrophils, Platelet Count of 4,74,000 / cu.mm, and a C-Reactive Protein Level of 40.7. He was commenced on intravenous(IV) Cefotaxime and discharged on resolution of fever after twelve hours duration in the hospital. A lumbar puncture and CSF examination was deferred as the parents did not consent for the procedure. Chest Radiograph was normal and urinalysis was normal. He returned to the OPD on

rd3 day of IV antibiotic therapy with high grade

fever and a left cervical nuchal mass with erythema and induration . At admission he developed two episodes of generalized tonic clonic seizures with shock.He was intubated, fluid resuscitated , and mechanical ventilation was initiated. During the first forty eight hours he needed multiple inotropes with norepinephrine, dobutamine and adrenaline.The rapid clinical progression was suggestive of an occult serious bacterial infection with the high possibility of meningitis with septic shock. Laboratory testing revealed an elevated leucocyte count of 20,700 / cu.mm with a differential count of 75 % neutrophills and Platelet count of 5,09,000 / cu.mm. Following blood cultures, his antibiotics were upgraded to intravenous Meropenem and Vancomycin. Shock was categorized as catecholamine resistant and therefore he was administered a stress dose of hydrocortisone. To assess left ventricular function and intravascular volume status a two dimensional (2D) Echo-cardiogram was performed which showed normal left ventricular function and normal filling of the inferior vena cava.

Intravenous immunoglobulin therapy was initiated for the septic shock. (2 gm/ kg). Cerebrospinal fluid examination was suggestive of partially treated meningitis with 6 cells, all lymphocytes, CSF sugar 43.3mg/dl, proteins 62.09mg/dl. He was extubated

thon the 5 day of admission. Post extubation, the infant continued to have high grade fever. Blood Cultures were repeated, and investigations for the possible etiology directed to detect ventilator

Not all 'Septic Shock ' is due to infection !Dr. VSV Prasad MD

Chief Consultant, Pediatric Intensivist,Chief Executive Officer Lotus Children's Hospital,Hyderabad, India.

Abstract : We describe a case of Atypical Kawasaki disease presenting as septic shock in a 3 month old

male baby. Atypical Kawasaki disease should be considered in all infants with unexplained fever for ≥5 days associated with 2 or 3 of the principal clinical features of Kawasaki disease . Because young infants may present with fever and few clinical features, echocardiography should be considered in any infant aged

<6 months with fever of ≥7 days' duration, laboratory evidence of systemic inflammation, and no other explanation for the febrile illness

Key words: Incomplete Kawasaki disease, Thrombocytosis, Coronary Aneurysm


Correspondence:

Dr.V.S.V. Prasad

Chief Consultant, Pediatric Intensivist, Chief Executive Officer, Lotus Children's Hospital, 6-2-29,Lakdikapul, Hyderabad, India.

E mail : [email protected]

CASE REPORT Not all 'Septic Shock ' is due to infection !

associated pneumonia, urinary tract infection were performed. Empiric intravenous fluconazole therapy was commenced for possible fungemia on day 7. With common sites for persistent infection excluded, diagnostic workup was directed to rule out non infectious etiologies . HLH (Hemophagocytic Lympho Histiocytic Syndrome) was considered as a possibility. Laboratory results showed elevated while cell counts with a falling hemoglobin, and high inflammatory markers ( Hb of 9.0 gm/dl with 20,200 total leucocytes and platelets 10,20,000 and toxic granules. C-Reactive Protein (CRP) level was 47.6 and erythrocyte sedimentation rate (ESR) was 85 mm and 125 mm at 30 minutes and at 1 hour respectively ).

The constellation of laboratory findings of thrombocytosis, raised ESR and CRP and persistent high fever,a 2D Echocardiogram was repeated to exclude Kawasaki Disease.The findings on 2D Echocardiography revealed the right coronary artery having proximal segmental aneurysmal dilatation of 2.8 mm with normal distal segment of 1.7 mm diameter with the left main coronary artery being uniformly dilated with 2.1 mm diameter. The left anterior descending and the left circumflex vessels were normal.

With the findings clearly suggestive of Kawasaki Disease, a repeat retrospective interrogation of the mother recalled and confirmed prior conjunctival injection and oral mucosal erythema which was not revealed at the time of admission. A diagnosis of Kawasaki Disease was made and the child was commenced on a second dose of intravenous immunoglobulin at 2 gm / kg and anti-inflammatory doses of Aspirin to be followed by antithrombotic doses. The child's fever defervesced subsided 12 hours after commencing Aspirin. The infant there after made good recovery and feeds were established fully before discharging home from hospital.

Discussion:1-5

Kawasaki disease is characterized by fever, bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, changes in the extremities, rash, and cervical lymphadenopathy. Coronary

artery aneurysms or ectasia develop in appro-ximately 15% to 25% of untreated children with the disease and may lead to myocardial infarction (MI), sudden death, or ischemic heart disease. Kawasaki disease needs to be considered in fever lasting longer than 5 days and 4 of the 5 following main clinical features; Initial erythema or edema of the palms and soles, followed by membranous desquamation of the finger and toes; Polymorphous generalized rash but may be limited to the groin or lower extremities; Erythema, fissuring, and crusting of the lips; strawberry tongue; diffuse mucosal injection of the oropharynx ; Bilateral, non exudative, painless bulbar conjunctival injection; Acute non purulent cervical lymphadenopathy with lymph node diameter greater than 1.5 cm, usually unilateral. Acute phase reactants are almost always increased and include erythrocyte sedimentation rate and C-reactive protein, toxic granulations within the neutrophils can be seen. Anemia may be seen especially with prolonged inflammation. A characteristic feature of Kawasaki disease is thrombocytosis; however, this finding usually occurs in the second week of the illness ( subacute phase ). Hypo-albuminemia is common, as are increased serum transaminase levels. Sterile pyuria can also be seen.Atypical

Kawasaki disease depicts Fever ≥5 days with 2 or 3 of the above clinical criteria . In infants, atypical Kawasaki presents with high grade fever with or without focus of infection and may present as septic shock. Hence echocardiogram to look for coronaries should be done for any infant who presents with high grade fever and septic shock with or without a focus of infection and does not respond to appropriate antibiotics. Coronary artery aneurysms or ectasia may lead to myocardial infarction (MI), sudden death, or ischemic heart disease. Treatment of Kawasaki disease in the acute phase is directed at reducing inflammation in the coronary artery wall and preventing coronary thrombosis, whereas long-term therapy in individuals who develop coronary aneurysms is aimed at preventing myocardial ischemia or infarction.


Conclusion:

Atypical Kawasaki disease should be considered in

all infants with unexplained fever for ≥ 5 days associated with 2 or 3 of the principal clinical features of Kawasaki disease . Because young infants may present with fever and few clinical features, echocardiography should be considered in

any infant aged <6 months with fever of ≥7 days' duration, laboratory evidence of systemic inflammation, and no other explanation for the febrile illness,to prevent serious cardiac sequalae related to coronary aneurysms or ectasia.

References:

1. Burns JC, Glode MP. Kawasaki syndrome. Lancet.2004;364 (9433):533– 544

2. Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a

statement for health professionals from the Commit tee on Rheumat ic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association [published correction appears in Pediatrics. 2005;115(4):1118]. Pediatrics.2004;114 (6): 1708-33

3. Yanagawa H, Nakamura Y, Yashiro M, et al. Incidence survey of Kawasaki disease in 1997 and 1998 in Japan. Pediatrics. 2001;107 (3) :E33

4. Yanagawa H, Nakamura Y, Yashiro M, et al. Results of the nationwide epidemiologic survey of Kawasaki disease in 1995 and 1996 in Japan. Pediarics.1998;102 (6) :E65

5. Anderson MS, Todd JK, Glode MP. Delayed diagnosis of Kawasaki syndrome: an analysis of the problem. Pediatrics. 2005 Apr;115(4):e428-33


CASE REPORT Not all 'Septic Shock ' is due to infection !


Hot Topic Review

Introduction:

Sudden cardiac arrest is the leading cause of death in the US and all over the world. About 450,000

1Americans have cardiac arrest annually . Following in-hospital pediatric cardiac arrest only 13% to 27%

2,3of children will survive to discharge . Outcomes following pediatric out-of-hospital arrests are much worse than after in-hospital arrests with <10% of children surviving and 50% with severe neurologic

4 5sequel . Though, a recent study by Girotra et al showed an overall increase in the number of pediatric cardiac arrest survivors without severe neurological disability over time, a significant number of children continue to exhibit neurologic disability after cardiac arrest. There are currently no therapies to improve neurological function in children who survive cardiac arrest.

Pediatric cardiac arrest most commonly arises from severe hypoxia or complete asphyxia, producing severe arterial hypotension and eventually asystole. Consequently, the brain undergoes incomplete ischemia during severe hypoxic hypotension and complete ischemia in the case of asystole. Following resuscitation, the brain can partially recover energy production as long as the duration of arrest is not too prolonged. However, cellular and molecular processes trigger a cascade of events that produce

secondary neuronal degeneration despite sustained 6perfusion . Reperfusion leads to inflammatory cell

infiltrates from nonspecific immunologic reaction, migration of peripheral leukocytes, macrophages, and lymphocytes into the brain, activation of

7microglia and subsequent neuronal cell death . Much of our knowledge is derived from adult rodent models in which global ischemia are restricted to the forebrain. Rats undergoing carotid artery occlusion exhibit a significant neuroinflammatory response that is sustained up to 270 days post-injury and these rats experience lasting impairments in learning and

8memory abilities . Neuroinflammation has been evaluated in adult forebrain ischemia models and to a lesser extent in neonatal models of forebrain

9-13hypoxia–ischemia . A limited amount of work has been performed on the neuroinflammatory response

14in a juvenile rat model of asphyxic cardiac arrest . Some evidence suggests that blocking the inflammatory reaction promotes neuroprotection and shows therapeutic potential for clinical

15-18treatment of ischemic brain injury . Therapeutic hypothermia (TH) can inhibit or mitigate all the mechanisms of neuronal injury, including

18-20neuroinflammation .

History of Therapeutic Hypothermia After Cardiac Arrest:

Though, therapeutic hypothermia was tried in human for malignancy, schizophrenia and intractable pain in 1930s-1940s; use of hypothermia in cardiac arrest victims was described first in 1950s.

In 1958, Drs. Frank C Spencer and G. Rainey Williams described four cases of cardiac arrest with improved outcome following exposure to therapeutic hypothermia at The Johns Hopkins

21Hospital, Baltimore, USA . A year later, Dr. Donald Benson and co-investigators published a review of

Cooling after pediatric cardiac arrest: A hot topicDr. Utpal S Bhalala, MD, FAAP

Assistant Professor

Anesthesiology Critical Care Medicine and Pediatrics, The Johns Hopkins University School of Medicine

Baltimore, MD, USA

Correspondence:

Dr. Utpal S Bhalala, MD, FAAP

Chair In-Training Section of Society of Critical Care Medicine, USA

Principle Investigator, Therapeutic Hypothermia After Pediatric Cardiac Arrest (THAPCA) Trials, Johns Hopkins Medical Institution Site, USA

The Johns Hopkins Hospital, Bloomberg Children's Center, 1800 Orleans Street, Suite 6349B, Baltimore, MD 21287, USA. Phone: (410) 955-6412

Email: [email protected]

HOT TOPIC REVIEW Cooling after pediatric cardiac arrest: A hot topic


27 cases of cardiac arrest which occurred at The Johns Hopkins Hospital supporting the value of using hypothermia as a therapeutic intervention in

22the immediate post-cardiac arrest period . Unfortunately, because of increased risks of ventricular arrhythmia and bacteremia which were noted in patients exposed to very low temperatures (< 30 º C), therapeutic hypothermia lost its popularity as a neuroprotective treatment after global brain injury.

In late 1990s, reports of significantly improved survival and neurologic outcome from induced hypothermia in animal models of cardiac arrest generated a renewed interest in therapeutic

23hypothermia .

Based on animal research and findings of two multicenter, randomized, clinical trial of therapeutic

24, 25hypothermia , American Heart Association (AHA, 2002) and European Resuscitation Council (ERC, 2003), recommended use of mild, induced hypothermia for unconscious, out of hospital cardiac arrest (OHCA) adult victims.

Recent systematic reviews and meta-analyses of use of hypothermia for neonatal hypoxic ischemic encephalopathy demonstrated that hypothermia improves survival and neurodevelopmental outcome at 18 months among term infants with

26moderate or severe HIE .

Mechanism of neuroprotective effects of therapeutic hypothermia:

The primary neuroprotective effect of induced

Figure 1. Dr. Donald Benson, Professor of Anesthesiology at Johns Hopkins Hospital

Figure 2. The diagram shows relationship of hypothermia and fever with the spectrum of neuronal injury after cardiac arrest. Hypothermia shifts cellular injury from necrosis to apoptosis to recovery whereas fever tends to worsen the degree of neuronal injury from apoptosis to necrosis.


hypothermia is believed to be related to decrease in cerebral metabolic rate. For each degree centigrade drop in core body temperature, the cerebral metabolic rate is reduced by 6-7%. Therapeutic hypothermia also reduces seizure threshold after global ischemic injury. It improves pH of cerebral milieu and therefore helps correct acid-base imbalance across neuronal cell membrane. It tends to abolish neuronal injury pathways, including oxygen free radical injury. It blocks microglial activation and proliferation and release of proinflammatory cytokines from activated

18-20microglia .

Current evidence of use of hypothermia after cardiac arrest:

Last decade has seen a remarkable increase in interest in induced hypothermia as a neuroprotective strategy after cardiac arrest. Much of the evidence to support hypothermia-induced neuroprotection comes from adult cardiac arrest victims and neonates and infants with hypoxic ischemic encephalopathy.

Evidence of use of hypothermia after cardiac arrest in adults:

In 2002, two randomized clinical trials showed 24,25

improved neurological outcome in unconscious OHCA adult victims, who were cooled to 32–34 °C for 12–24 hours shortly after return of spontaneous

24circulation. The HACA trial also showed a substantial decrease in mortality within six months in patients treated with mild therapeutic hypothermia. Both these trials included only patients with initial VF/VT rhythm. A good number of observational studies looked at effect of therapeutic hypothermia on outcome from non-VF/VT arrest. Hypothermia After Cardiac Arrest Regis t ry (HACA-R) was a mult icenter observational study of 587 patients resuscitated from cardiac arrest, around 18 % of which had occurred in hospital. The rate of survival to hospital discharge was significantly higher in patients treated with mild therapeutic hypothermia after arrest. The rate of poor neurologic outcome was not

significantly lower in hypothermia group and the study had 2 major limitations – lack of multivariate analysis to account for peri-arrest factors and

27selection bias . In a large, retrospective study by Don et al., patients with VF/VT treated with hypothermia had significantly higher rates of survival to hospital discharge and favorable neurological outcome as compared to the pre-hypothermia control patients. But, there were no significant improvements in patients with non-

28VF/VT rhythms . In a study involving French database of adult OHCA victims, mild therapeutic hypothermia was associated with a significantly better neurological outcome at discharge in VF/VT patients, but there was a trend towards a worse

29outcome in non-VF/VT patients . So, in adults, mild therapeutic hypothermia has been consistently demonstrated to improve outcomes after VF/VT cardiac arrest, its use in patients with non-VF/VT arrest has produced conflicting results.

The optimal target temperature and ideal time to begin lowering body temperature in resuscitated OHCA were recently explored in 2 large randomized trials of post arrest hypothermia. In the Target Temperature Management (TTM) trial, conducted in 950 unconscious adults after OHCA of presumed cardiac origin, hypothermia to target temperatures of either 33°C or 36°C, maintained for up to 36 hours, showed comparable survival and

30neurologic outcomes at 6 months .

In a randomized study of 1359 patients with prehospital cardiac arrest, cooling to 34°C through cold saline infusion did not improve survival or neurological status in patients with or without prehospital ventricular fibrillation. Patients in the prehospital cooling group rearrested more often and

31had more transient pulmonary edema .

Evidence of use of hypothermia in neonates with Hypoxic Ischemic Encephalopathy (HIE):

In a landmark study of childhood outcomes after hypothermia for neonatal encephalopathy, Shankaran and co-authors demonstrated an 18 percent reduction in death and mental disability among cooled infants, compared to a similar-sized



control group that had not undergone cooling but received “usual care” for HIE. The goal temperature of 92.3 ºF was achieved and maintained for 72 hours in cooled infants using a whole-body cooling

32blanket . There are five more published randomized controlled trials (RCTs) of induced hypothermia in term or near-term infants for HIE. In Cool Cap trial of infants with moderate or severe encephalopathy and abnormal aEEG, head cooling had no effect in infants with the most severe aEEG changes but was beneficial in infants with less severe aEEG

33changes .

The Total Body Hypothermia for Neonatal Encephalopathy (TOBY) trial randomized infants with moderate to severe HIE to whole-body hypothermia (rectal temperature of 33°C to 34°C for 72 hours) or usual care. The primary outcome was death or severe neurodevelopmental disability at 18 months. Survival without disabilities was significantly higher in the cooled group compared with the usual care group. The rate of CP was lower, and improved mental and psychomotor indices were noted in the hypothermia group as compared with

34the usual care group, all P<.05 .

Selective head cooling (34°C nasopharyngeal and rectal temperatures for 72 hours) or usual care RCT in China enrolled 256 infants with encephalopathy. The primary outcome – death or severe disability occurred in 49% control and 31% hypothermia

35group infants (OR 0.47 [0.26–0.84, P = .01]) .

In the European Network RCT, 129 infants with moderate or severe encephalopathy and an abnormal aEEG were enrolled. In the whole-body hypothermia group, a rectal temperature of 33°C to 34.0°C was maintained. Death or severe disability occurred in 51% of the hypothermia group and 83% in the normothermia group (OR, 0.21 [0.09–0.54], P

36= .001) .

The most recent RCT - the Infant Cooling

Evaluation (ICE) trial (n = 221) initiated whole-body cooling at the referral hospital after clinical diagnosis of encephalopathy. The trial demonstrated significantly reduced mortality, whereas survival free of disability was increased in the hypothermia

37group compared with the control group .

Evidence of use of hypothermia after cardiac arrest in children:

In a retrospective study of survival and neurological outcome in children after cardiac arrest with and without hypothermia, 95% of patients suffered an in-hospital cardiac arrest (IHCA) often with associated chronic cardiac conditions (71%) and after surgery (59%). In patients with cardiac arrest duration of at least three minutes and who survived to 12 hours after ROSC, the use of therapeutic hypothermia was associated with increased 30 day mortality, increased six month mortality (unadjusted OR 3.62, 95% CI 1.37 to 9.62; P = 0.009) and an unfavorable neurological outcome (Pediatric Cerebral Performance Category – PCPC* score 4 to 6) (unadjusted OR 2.92, 95% CI 1.1 to 7.69; P = 0.031). However, patients exposed to therapeutic hypothermia were sicker due to longer duration of arrest, more pharmacological and extracorporeal interventions, and higher multi-organ dysfunction score and more renal replacement therapies. Logistic regression analysis showed that the use of therapeutic hypothermia did not statistically increase the risk of 30 day mortality (adjusted OR 2.5, 95% CI 0.55 to 11.49; P = 0.238), six month mortality (adjusted OR 1.99, 95% CI 0.45 to 8.85; P = 0.502) or unfavorable neurological outcome

38(adjusted OR 2.0, 95% CI 0.45 to 9.01; P = 0.364) .

A single-center, retrospective study by Fink et al also showed no significant difference in mortality and gross neurological outcomes for patients treated with ei ther therapeutic hypothermia or

39normothermia after cardiopulmonary arrest .

Therapeutic Hypothermia After Pediatric Cardiac Arrest (THAPCA) Trials:

40THAPCA trial is the largest randomized, controlled pediatric trial for studying efficacy and safety of hypothermia as a neuroprotective intervention after cardiac arrest in children. With growing evidence of beneficial effects of therapeutic hypothermia in a subset of adult cardiac arrest victims and in neonates with HIE, a group of pediatric critical care experts sought to study use of hypothermia after cardiac arrest in children. This trial, which is funded by the US National Heart Lung



and Blood Institution (NHLBI) aims to enroll about 900 children over 6 years at approximately 37 clinical centers throughout the US and Canada. This currently active trial is led by Frank Moler, MD of University of Michigan and J.Michael Dean, MD of University of Utah. In this trial, the children between 48 hours to 18 years of age who achieve ROSC from cardiac arrest after at least 2 minutes of CPR are randomized into either hypothermia (32-34°C) or normothermia (36-37.5°C). The study uses a surface cooling (Blanket) device to regulate the temperature. Those who are randomized to hypothermia intervention are cooled for a set period of time followed by slow rewarming to normothermia range and maintained within normothermia range as per study guidelines. All the clinical and laboratory parameters of study patients are tightly monitored for efficacy and safety of the intervention during study period as per the guidelines. The patients are followed periodically for clinical outcomes, especially neurologic outcome. The Out of Hospital Cardiac Arrest (OHCA) enrollment completed in 2013 and the trial is actively recruiting In Hospital Cardiac Arrest (IHCA) cases. The results of outcome of hypothermia after OHCA in children are soon to be released.

The rationale for THAPCA trials:

There are distinct anatomic, physiologic and developmental differences between children and adults. Neither children are small adults, nor are adults small children. There are distinct pathophysiologic, epidemiologic and outcome differences of cardiac arrest in adults compared to children. Cardiac arrest in adults is primary cardiac in origin, whereas in children, most cardiac arrests result from refractory hypoxia and/or hypotension. VF/VT arrest is commoner in adults compared to children. Extrapolating the findings of hypothermia trials in adult cardiac arrest victims to infants and smaller children might not be a rational approach.

Therapeutic Hypothermia – Practical

Considerations:

Methods of inducing and maintaining hypothermia – There are multiple methods of cooling – surface cooling versus internal cooling, head cooling versus whole-body cooling and intravenous versus intra-nasal approach. The commonest mode of surface cooling is use of a cooling blanket. There are many different commercially available cooling blankets, most of which work through rapid infusion of cold water (or warm water, depending upon set temperature) within the blanket. The blanket is connected through tubing system to a large water reservoir, which has a built-in, programmable, temperature regulating system. Some commercially available cooling blankets are cold air-forced. The device allows either an automatic or manual temperature regulation. Automatic mode is practically safer and more user-friendly mode for inducing and maintaining hypothermia and also for different rates of rewarming from hypothermia. In case one blanket placed above or below the patient is not able to achieve target temperature, one could try placing 2 simultaneous blankets both above and below the patient (sandwich technique) to achieve and maintain goal temperature. The drawbacks of cooling blanket device are relatively slower hypothermia induction, difficulty with patient evaluation and care under the blanket, difficulty with temperature regulation if blanket taken off frequently by bedside team for patient evaluation and care, inability to use in patients with breach in skin integrity (bedsores, wounds, burns), potential water leak from water reservoir and tubing and bacterial overgrowth in water if not changed periodically. The simpler approach to surface cooling is exposure to cooler environmental temperature, ice packs, cold water packs, rubbing or applying cold water over body surface. But, the major drawback to this approach is deregulated temperature control with potential for over or under-cooling and wide temperature fluctuations. Head cooling device like Cool Cap is potentially useful in neonates and infants, whereas whole-body cooling is useful in any age and size patient.



Figure 3. Schematic diagram of cooling blanket. The blanket is placed below patient. The cold water circulates to and from water reservoir within the blanket through tubing to regulate temperature.

Certain clinicians and investigators argue about efficacy of surface cooling device, especially the rate of reduction of brain and core body temperature. There is a recent increase in innovations with internal cooling devices and approaches like intravenous cooling system within the central venous line for rapid reduction in core body temperature and intranasal air-flow system for rapid reduction in brain temperature. Some of these devices are still in experimental phase for use in children. The simpler internal cooling approach is intravenous infusion or enteral lavage of ice-cold saline, but it potentiates risks of rapid fluid-

electrolyte shifts and fluid overload situation.

Potential Risks and Drawbacks of Hypothermia - Though therapeutic hypothermia is non-invasive and otherwise easy-to-deploy intervention, it is not free of adverse effects. The main risks reported are shivering, cardiac arrhythmia, sepsis, coagulopathy, and electrolytes and metabolic disturbances. Shivering is the commonest adverse effect of hypothermia. It depends predominantly on rate of drop of core body temperature and degree of hypothermia. Shivering after cardiac arrest is deleterious and adversely affects neurologic outcome because it increases cerebral and overall metabolic rate, potentiates inflammation and neuronal injury mechanisms. Shivering during therapeutic hypothermia should be prevented and aggressively managed through adequate sedation



and paralysis. Therapeutic Hypothermia increases risk of ventricular tachyarrhythmia. The risk of VF/VT is increased substantially with target temperature below 30°C. Therapeutic Hypothermia (TH) also alters coagulation cascade with potential increased risks of bleeding. It suppresses immune system, thereby increasing risk of systemic infection. Through its effects on renal perfusion and tubular function, it induces diuresis and loss of electrolytes. Many large clinical trials and meta-analyses, however, reported these adverse effects to be infrequent. A trend toward increased incidence of sepsis has been noted. One of the biggest challenges of use of hypothermia in comatose survivors of cardiac arrest is neurologic assessment and monitoring. Since patients who are exposed to TH needs to be maintained on continuous sedation and paralysis to prevent shivering and discomfort induced by therapeutic hypothermia, neurologic assessment is often limited. Also, TH is believed to alter drug metabolism with potential increased effects of sedatives and often a state of suspended animation. This further adds to complexity of neurologic assessment, especially brain death evaluation.

Monitoring during Hypothermia - Neurologic failure and hemodynamic instability are two major causes of death during post-resuscitation phase among survivors of cardiac arrest. Aggressive, goal-directed, post-cardiac arrest care in intensive care setting improves outcome. During induced hypothermia after ROSC, close monitoring of temperature, hemodynamic, respiratory and metabolic functions is crucial. During early induction phase of hypothermia when patient is being actively cooled, one should frequently monitor core temperature to avoid under or over-cooling the patient. Monitoring core body temperature through rectal/bladder or esophageal temperature probe allows continuous temperature monitoring. Placement of esophageal temperature probe should always be confirmed through chest radiograph before beginning hypo or normothermia intervention. Since active cooling potentially alters cardiac output through increase in systemic vascular

resistance and/or ventricular arrhythmia, close monitoring of hemodynamic parameters like HR, BP, CVP, urine output, serum lactate levels, systemic mixed venous saturations, electro-cardiogram and echocardiography are warranted. During rewarming phase, there is increased risk of vasodilation and hypotension, especially if temperature is allowed to rise rapidly. Laboratory parameters of fluid-electrolyte-renal function, pancreatic and liver function, complete blood count and coagulation system should be assessed frequently. Since hypothermia can suppress immunity and increase the risk of systemic infection, daily microbiologic tests, especially blood, urine and respiratory cultures are recommended. Since rewarming is associated with increased inflammatory response, release of proinflammatory cytokines and vasodilation, one should follow a protocol of slow rewarming (increase in temperature by 0.5 to 0.7°C every 4 hours) with close monitoring of temperature, hemodynamic and renal parameters.

Guidelines and recommendations:

·The International Liaison Committee for Resuscitation recommends that comatose adult patients with spontaneous circulation after cardiac arrest should be cooled to 32-34°C for

4112-24 hours .

·Therapeutic hypothermia (32-34°C) may be beneficial for adolescents who remain comatose after resuscitation from sudden, witnessed, out-of-hospital, ventricular fibrillation cardiac

42arrest .

·Therapeutic hypothermia (32-34°C) may be considered for infants and children who remain comatose after resuscitation from cardiac

42arrest .

·In neonates with evidence of hypoxia-ischemia (moderate to severe HIE), cooling (32-34°C)

43should be offered for 72 hours .

Expert Opinion:

While results of large, multi-center, randomized,



controlled trials in children (THAPCA Trials) are eagerly awaited, early, aggressive, goal-directed management of comatose pediatric survivors of cardiac arrest is warranted. In the absence of definitive evidence, it is reasonable to consider therapeutic hypothermia for comatose adolescent survivors from a shockable rhythm cardiac arrest. Therapeutic hypothermia may also be considered for infants and children who remain comatose after resuscitation from cardiac arrest. In all cases one

should always avoid hyperthermia (≥38°C).

For infants and children in whom the team decides to commit to therapeutic hypothermia after cardiac arrest,

- Begin hypothermia induction within 6 hours of ROSC

- Achieve target temperature of 32-34°C as soon as possible

- Maintain temperature of 32-34°C for 24-48 hours

- Monitoring temperature, hemodynamic and fluid-electrolyte-renal function

- Monitor end organ function

- Monitor for infection

- Provide optimal sedation and paralysis to avoid shivering

- Monitor neurologic function preferably with continuous EEG

- Avoid enteral feeds (due to hypothermia-induced bowel hypoactivity) and provide parenteral nutrition

- Allow slow rewarming at the end of hypothermia

- Strictly avoid any hyperthermia

- Follow American Heart Association (AHA) Post-Cardiac Arrest Care (PCAC) guidelines for prevention and management of multi-organ dysfunction

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asphyxial encephalopathy. N Engl J Med, 361 (2009), pp. 1349–1358

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PICU QuizDr. Nameet Jerath MD

Sr Consultant Pediatric Intensivist, IP Apollo Hospital, New Delhi


Critical Thinking

1. Which of the following statements is true about blood pressure measurements in the PICU:

a. Oscillometric measurements are more likely to overestimate the systolic and underestimate the diastolic blood pressure.

b. Arterial pressure waveforms show increased systolic pressure moving from central to peripheral artery because of reduced dampening.

c. Pressure wave travels about 10 times faster than flow wave in an artery.

d. The phenomenon of systolic amplification is augmented in states of vasodilatory shock.

2. A 2-year-old child, known case of Spinal Muscular Atrophy presents with altered sensorium over last week. An arterial blood gas in room air shows PaO2 40 mmHg, PaCO2 80 mmHg, and pH of 7.29. Which of the following would explain her hypoxemia?

a. Ventilation–perfusion mismatch

b. Intracardiac shunting

c. Intrapulmonary shunting

d. Alveolar hypoventilation

3. A 15-year-old girl presents to the emergency department 1 h after alleged ingestion of many phenobarbitone tablets and is found to have SpO2- 82%. An ABG taken in room air shows PaO2 - 58, PaCO2 - 48, and pH -7.32. The patient is placed on a 100% face mask and some time later the SpO2 is 88%. Which of the following would explain her hypoxemia?

a. Ventilation–perfusion mismatch

b. Intracardiac shunting

c. Intrapulmonary shunting

d. Alveolar hypoventilation

4. A man has a pulmonary embolism that completely blocks blood flow to his left lung. As a result, which of the following will occur?

a. Ventilation/perfusion (V/Q) ratio in the left lung will be zero

b. Systemic arterial PO2 will be elevated

c. V/Q ratio in the left lung will be lower than in the right lung

d. Alveolar PO2 in the left lung will be approximately equal to the PO2 in inspired air

e. Alveolar PO2 in the right lung will be approximately equal to the PO2 in venous blood

5. A 12-year-old boy has a severe asthmatic attack with wheezing. He worsens and becomes cyanotic. His ABG PO2 – 60, and his PCO2 - 30.

Which of the following statements is most likely to be true?

a. Forced expiratory volume/forced vital capacity (FEV1/FVC) is increased

b. Ventilation/perfusion (V/Q) ratio is increased in the affected areas of his lungs

c. His arterial PCO2 is higher than normal because of inadequate gas exchange

d. His arterial PCO2 is lower than normal

CRITICAL THINKING PICU Quiz


because hypoxemia is causing him to hyperventilate

e. His residual volume (RV) is decreased

6. A 3 year old boy (14 kg) is admitted to the PICU with respiratory distress and a

right upper lobe infiltrate. The next day, he develops diffuse infiltrates on chest

radiograph and is intubated for impending respiratory failure. Blood cultures grow Streptococcus pneumoniae. Conventional ventilator settings are: SIMV/PS, set rate 30 breaths per minute, PIP 28 cm H2O, PEEP 8 cm H2O, and delivered tidal volume 100 ml. What is this patient's respiratory elastance?

a. 0.15 cmH2O/ml

b. 0.20 cmH2O/ml

c. 0.32 ml/cmH2O

d. 2.0 ml/cmH2O

e. 5.0 ml/cmH2O

7. A 9-year-old boy sustained extensive injury to his lower extremity in a motorvehicle crash, no other head or abdominal injury. He required multiple blood transfusions in the emergency department and in the OT. On return to PICU after surgery on the lower limb there is no obvious bleeding from catheter sites or from the surgical wound. His laboratory values are as follows: platelets, 45,000/mm3; fibrinogen, 120 mg/dL; activated partial thromboplastin time, 27 seconds; and hemoglobin, 9.0 g/dL. HR is 96/min, BP is 114/58 mm Hg, RR is 24/min, and temperature is 35°C (95°F).

Which of the following is the most appropriate next course of action?

a. Prophylactic transfusion of platelets due to his postoperative state

b. Transfusion of packed red blood cells to

maintain hemoglobin level greater than 10 g/dL

c. Rewarming the patient

d. Transfusion of cryoprecipitate to maintain fibrinogen level above 140 mg/dL

e. Administration of fresh frozen plasma for factor replacement

8. An 18-month-old child has been in the PICU with 75% burns for almost a month with multiple trips to the operating theatres for skin grafting. He has been on Morphine infusion for this duration. As his condition is now improved you wean off the Morphine over 48 hours but have problems with increased irritability, diaphoresis and diarrhea. Which of the following is an appropriate management strategy?

a. Double the dose of IV Morphine and continue till discharge

b. Restart IV Morphine and IV Fentanyl, wean off Morphine after 2 days

c. Start oral Morphine at 1.5 times the IV dose

d. Restart IV Morphine and add Clonidine

e. Start an SSRI for acute stress disorder.

9. Which of the following does not apply to this mode of ventilation:

a. Tlow is usually <1.5 sec

b. Plow should not be zero

c. Is an extreme form of inverse ratio ventilation

d. Can be used in spont breathing or apneic patients

e. Patients contribution to MV is 10-40%



10. The O2 dissociation curves of a patient change from A to B as below. Which of

the following is TRUE regarding the patient's condition?

a. The child is hyperventilating

b. Child receives fresh whole blood transfusion

c. Child receives old (42 days) stored packed red cell transfusion

d. Child has bled with a drop in Hb

e. Child develops sudden cerebral edema with CO2 retention

1.Answer: a

Explanation: Automated Oscillometric blood pressure measurements are most commonly used in the PICUs. They are known to overestimate systolic and underestimate diastolic pressures (while mean blood pressure continues to correlate).

The increase in systolic pressures moving towards periphery is because of amplification from reflected waves from the peripheries. This phenomenon is augmented in vasoconstrictive shock (option d).

Pressure wave travels about 20 times faster than the flow wave (10m/sec vs 0.5m/sec).

2. Answer: d

Explanation: The story is convincingly consistent with hypoventilation, which is correct. It is always a wise idea to do the A-a difference calculations to confirm the seemingly obvious hunch, (check the next question). The A-a gradient here is normal (around 10).

3. Answer: c

The story here too seems to suggest hypoventilation. The A-a gradient here is around 35, wide. The

PICU Quiz answers and explanation



causes of wide A-a gradient are shunts- intrapulmonary or intracardiac and V/Q mismatch. Failure of improvement of hypoxemia to 100% oxygen makes V/Q mismatch unlikely. In an acute setting with no prior history of cardiac disease, intrapulmonary shunting (aspiration, pneumonia) is the most likely.

4. Answer: d

Explanation: The V/Q in left lung with no perfusion

would be ∞ , with lowering of PO2. Alveolar PO2

would equilibrate with alveolar PO2 without any improvement in systemic PO2 because of absence of any perfusion.

5. Answer: d

Explanation: Hypoxia induces a strong respiratory drive mediated by the carotid and aortic body chemoreceptors. This induces respiratory alkalosis untill the drive is able to compensate.

6. Answer: b

Explanation: Elastance is the reciprocal of compliance. Compliance can be calculated from the given data, C= dV/ dP, 100/20=5 ml/cmH20. The elastance of the respiratory system is 1/C= 0.2 cmH20/ml.

7. Answer: c

Explanation: The child is hemodynamically stable without any active bleed in the PICU. Platelet counts and coagulation profile are reasonable for a child with no active bleed. Hypothermia along with acidosis and tissue hypoperfusion can worsen

coagulopathy in a post-traumatic bleeding child. Hypothermia should be corrected now.

8. Answer: d

Explanation: The situation of withdrawal after prolonged opioid and/or benzodiazepine use in ICUs is neither unknown nor uncommon. There are many ways of dealing with withdrawal mostly including restarting of opioid with very gradual tapering. Clonidine with its central alpha2 agonist activity is often added to this regime. Oral morphine when started needs to be about 4-5 times the intravenous dose. Switching from Morphine to Fentanyl offers no advantage. Amongst the options provided “d” is the most logical.

9. Answer: b

Explanation: The graphic is representative of APRV, Airway Pressure Release Ventilation. This is an extreme form of inverse ratio ventilation and allows patient to breathe spontaneously while delivering mandated “release” breaths. The release is kept short, a low Tlow. The Plow can be set at zero ensuring the flow doesnot go down to zero, by using a shorter Tlow. Patients can contribute upto 40% of MV.

10. Answer: d

Explanation: The graph is of PaO2 vs CaO2 the oxygen content (1.34 x Hb x SaO2 + 0.003 x PaO2). A drop on content from A to B can be easily explained by a drop in hemoglobin, bleeding.

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