Download Journal of Pediatric Critical Care

Intensive Care Chapter
Indian Academy of Pediatrics
ISSN : 2349-6592
Website : www.journalofpediatriccriticalcare.com
Journal of
Pediatric Critical Care
Official Journal of IAP Intensive Care Chapter
CONTENTS
From Editors Desk
Original Articles
“ISCCM Criticare 2015 Hansraj Memorial Award Paper”
“Critical care without walls”- impact of a“pediatric emergency team” on picu admissions from
the wards and overall mortality -Nitika Agrawal; et al
Late Hemorrhagic Disease of the Newborn-Need for a Second Dose of Vitamin K ? -Sridhar M; et al
Special Article
Probiotics in critical illness – Is there a Role in Intensive care? -Hema kumar; et al
Review Articles
Management of Status Asthmaticus in the Pediatric Intensive Care Unit: Review of Literature
-Sandeep Tripathi; et al
Acute Bronchiolitis: A Review -Anand Bhutada; et al
Acute Encephalitis: Beyond Infection -Sangeetha Yoganathan; et al
Antibiotic Stewardship – Rational use of Antibiotics & Antifungal Agents -Meera Ramakrishnan
Technology and Equipment Update
High Flow Nasal Cannula: The New Mode of NIV in Pediatrics -Sanjay Perkar; et al
Drug review
Dexmedetomidine -Sanjay Perkar; et al
Critical Review
Journal Scan
Nameet Jerath; et al
Case Reports
Dengue Encephalitis Presenting As Febrile Status Epilepticus – A Case Report
-VSV Prasad; et al
Vol.2 No.2
April-June 2015
Catastrophic neurologic manifestations of a common Immunodeficiency Syndrome
-Nitika Agrawal; et al
Critical Thinking
Vol. 2; No. 2; April - June 2015
PICU Quiz -Nameet Jerath
a
JOURNAL OF PEDIATRIC CRITICAL CARE
Manual of Basic Pediatric Intensive Care Course
(BPICC Manual)
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BPIC
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Some upcoming
Basic Pediatric Intensive Care Course (BPICC)
Courses:
Cuttak, Orrisa
- May, 2015
NCPCC 2015
- 26th & 27th Nov, 2015
PEDICON 2016, Hyderabad
Criticare 2016, Agra
To Organize a BPICC in your area, please contact:
Dr Rajiv Uttam
National Co Convener, BPICC
M: 9810055670 • Email: [email protected]
Dr Anil Sachdev
Chairperson, IAP Intensive Care Chapter
M: 9810098360 • Email: [email protected]
Dr Madhu Otiv
Past Chairperson, IAP Intensice Care Chapter
M: 09822040950 • Email: [email protected]
Regional Conveners:
Dr Vikas Taneja (Gurgaon)
Dr Anjul Dayal (Hyderabad)
Dr Gnanam (Bengaluru)
Dr Parthsarathi Bhattacharya (Kolkotta)
Dr Vinay Joshi (Mumbai)
Dr Praveen Khilnani
Vol. 2; No. 2; April - June 2015
Founder Conveners:
Dr Rajiv Uttam
b
Dr Krishan Chugh
JOURNAL OF PEDIATRIC CRITICAL CARE
Contents
From Editors Desk
3
JPCC Editorial Board
4
IAP Intensive Care Chapter EB 2015
5
Author Instructions
6
Original Articles
“ISCCM Criticare 2015 Hansraj Memorial Award Paper”
“Critical Care without walls”- impact of a “Pediatric Emergency Team” on picu
Admissions from the Wards and Overall Mortality
11
Nitika Agrawal, Gnanam Ram, Shiv Kumar
Department of Pediatric Intensive Care Unit Manipal Hospital, Bangalore
Late Hemorrhagic Disease of the Newborn - Need for a Second Dose of Vitamin K ?
Sridhar M, V S V Prasad
17
Lotus Hospitals for Women & Children, Lakdikapul, Hyderabad
Special Article
Probiotics in Critical Illness – Is There A Role in Intensive Care?
Hema Kumar, Rakshay Shetty
18
Rainbow Children’s Hospital, Vijayawada, India
Review Articles
Management of Status Asthmaticus in the Pediatric Intensive Care Unit: Review
of Literature
23
Sandeep Tripathi, Gina Cassel, James R. Phillips
Division of Pediatric Critical Care Medicine, Mayo Clinic, Rochester, MN and Division of Pediatric Critical
Care, Montefiore Medical Center, Bronx, NY
Acute Bronchiolitis: A Review
33
Anand Bhutada, Satish Deopujari, Yusuf Parvez
Central India’s Child Hospital & Research Centre, Dhantoli, Nagpur and Dubai Hospital, Dubai
Acute Encephalitis: Beyond Infection
41
Sangeetha Yoganathan, Ebor Jacob James
Pediatric Intensive Care Unit, Christian Medical College Vellore-
Antibiotic Stewardship – Rational use of Antibiotics & Antifungal Agents
Meera Ramakrishnan
50
Manipal Hospital Bengaluru
Technology and Equipment Update
High Flow Nasal Cannula :The New Mode of NIV in Pediatrics
Sanjay Perkar, Nilesh Manya, Ankur Ohri, Ankur Chawla, Rachna Sharma, Praveen Khilnani
59
Pediatric Intensive Care Unit, BLK Superspeciality Hospital, New Delhi
Vol. 2; No. 2; April - June 2015
1
JOURNAL OF PEDIATRIC CRITICAL CARE
Drug Review
Dexmedetomidine
Sanjay Perkar, Nilesh Maniya, Ankur Ohri, Ankur Chawla, Rachna Sharma, Praveen Khilnani
63
Pediatric Intensive Care Unit, BLK Superspeciality Hospital, New Delhi
Critical Review
Journal Scan
67
Nameet Jerath, Anubhav Jain
Senior Consultant Pediatric Intensive Care, Senior Resident Pediatric Intensive Care , Indraprastha Apollo
Hopsital, New Delhi
Case Report
Dengue Encephalitis Presenting as Febrile Status Epilepticus – A Case Report
VSV Prasad
72
Pediatric Intensive Care Unit, Lotus childrens Hospital, Hyderabad
Catastrophic Neurologic Manifestations of a Common Immunodeficiency
Syndrome
75
Nitika Agrawal, Gnanam Ram, Shiv Kumar, Bidisha Banarjee
Department of Pediatric Intensive Care Unit, Department of Pediatric Neurology Manipal Hospital, Bangalore,
India
Critical Thinking
PICU Quiz
78
Dr Nameet Jerath
Senior Consultant Pediatric Intensivist and Pulmonologist, IP Apollo Hospital, New Delhi
Vol. 2; No. 2; April - June 2015
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JOURNAL OF PEDIATRIC CRITICAL CARE
From Editors Desk
Dear Colleagues,
April-june 2015 issue of JPCC has two original studies from Indian institutions regarding the feasibility of
Pediatric Emergency response team and use of vitamin K, respectively. During Criticare 2015, the annual
conference of ISCCM (Indian society of critical care medicine), the paper from Manipal hospital by Nitika
Aggarwal et al was awarded best paper “Hansraj memorial award”. This should be a trigger factor for all
the young and enthusiastic fellows and faculty persuing the carrier of Pediatric critical care medicine, to
systematically study, collate, analyse and publish many important issues that deserve due attention with
evidence based backing rather than empiric practice.
Publishing articles from all over the world, JPCC is growing at a rapid pace. Articles for peer review and
possible publication may be submitted on line or at [email protected]. Face book page is also growing
at rapid pace. Many interesting reviews and case reports are published in this issue.
NCPCC 2015 (Annual conference of IAP Pediatric intensive care chapter) is to be held in Jaipur this year
26-29th November: Contact Dr Manish Sharma : 09829300541. Email: [email protected] or visit
Website: www.ncpcc2015.com
Some upcoming issues have symposia planned on PICU Infections: Guest Editor: Soonu Udani and
Neurocritical care: Guest editors: Sunit singhi and Jayshree M.
At JPCC our editorial team stands committed to publishing quality articles of relevance to the practicing
Pediatric intensivist (critical care specialist) as well as the academically oriented fellows and faculty at
Institutions.
Happy reading !
Dr Praveen Khilnani MD, FAAP, FSICCM, FICCM, FCCM (USA)
Editor in Chief JPCC
Vice President ISCCM
Director Pediatric Critical Care and Pulmonology Services
BLK Superspeciality Hospital, New Delhi
[email protected]
www.journalofpediatriccriticalcare.com
Vol. 2; No. 2; April - June 2015
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JOURNAL OF PEDIATRIC CRITICAL CARE
Journal of Pediatric Critical Care (JPCC)
Editorial Board
Editor-In-Chief:
Dr Praveen Khilnani
Associate Editors:
Dr Nameet Jarath
Dr Kundan Mittal
Dr Rakshay Shetty
Dr Basavaraj
Dr Gnanam
Dr Sandeep Kanwal
Senior Editors and Reviewers:
Dr (Prof) Sunit Singhi
Dr K Chugh
Dr S Udani
Dr S Ranjit
Dr Rajiv Uttam
Dr Anil Sachdev
Executive Editor:
Dr V S V Prasad
Dr Madhu Otiv
Dr S Deopujari
Managing Editor:
Dr Dhiren Gupta
Dr Bala Ramachandran
Dr S Soans
Executive Members:
Dr Arun Bansal
International Advisory Board:
Biostatistics:
Dr M Jayshree
Dr Niranjan Kissoon
Dr Banani Poddar
Dr Jhuma Sankar
Dr Jerry Zimmerman
Dr Ebor Jacob
Dr Arun Baranwal
Dr Joseph Carcillo
Dr Lokesh Tiwari
Dr Partha Bhattacharya
Dr Prabhat Maheshwari
Dr Dinesh Chirla
Dr Deveraj Raichur
Dr Karunakara
Dr Mritunjay Pao
Dr Deepika Gandhi
Dr Bhaskar Saikia
Dr Shipra Gulati
Dr Vikas Taneja
Dr Ashok Sarnaik
Ethics:
Dr Urmila Jhamb
Dr Rakesh Lodha
Dr Meera Ramakrishnan
Dr Vinay Joshi
Website:
Dr Peter Cox
Dr Shekhar Venkataraman
Dr Vinay Nadkarni
Dr Mohan Mysore
Dr Utpal Bhalala
Dr Suneel Pooboni
Dr Maninder Dhaliwal
Dr Rahul Bhatia
Dr Vinayak Patki
Dr Ravi Samraj
Dr Anjul Dayal
Publication:
National Advisors:
Dr Y Amdekar
Dr Indira Jayakumar
Dr Rachna Sharma
Dr S C Arya
Dr Sanjay Bafna
Dr Pradeep Sharma
Dr R N Srivastava
Dr Sanjay Ghorpade
Dr Sanjeev Kumar
Dr C P Bansal
Dr Sagar Lad
Dr V Yewale
Dr M P Jain
Vol. 2; No. 2; April - June 2015
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JOURNAL OF PEDIATRIC CRITICAL CARE
IAP Intensive Care Chapter
Executive Committee 2015
Dr Anil Sachdev
Chairperson
Delhi
Ex Officio Chairperson
Pune
Dr Madhu Otiv
Dr Vishram Buche
Dr Kundan Mittal
Dr Karunakara BP
Dr Praveen Khilnani
Dr Vikas Taneja
Dr Dayanand Nakate
Honorary Secretary
Bangaluru
Dr Bakul Parekh
West Zone
Chairperson Elect
Nagpur
Editor JPCC
Delhi
Dr Basavaraja GV
South Zone
Joint Secretary
Delhi
Dr Arun Baranwal
East Zone
Dr Dinesh Chirla
Central Zone
Vice Chairperson
Rohtak
Treasurer
Solapur
Dr Punit Pooni
North Zone
Executive Members
Vol. 2; No. 2; April - June 2015
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JOURNAL OF PEDIATRIC CRITICAL CARE
Author Instructions
For JPCC (Journal of Pediatric Critical Care) Manuscript Submission
Manuscript submission using online submission system is now functional. All authors need to register and
then log in to submit articles. Alternatively submissions may also be made by e-mail: Khilnanip@hotmail.
com.
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
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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
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INTENSIVE CARE include the following:
Editorials
Editorials will present the opinions of leaders in pediatric intensive care
Vol. 2; No. 2; April - June 2015
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JOURNAL OF PEDIATRIC CRITICAL CARE
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Original clinical or laboratory investigation of clinical subjects should be reported. The material should be
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Vol. 2; No. 2; April - June 2015
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JOURNAL OF PEDIATRIC CRITICAL CARE
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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
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Vol. 2; No. 2; April - June 2015
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JOURNAL OF PEDIATRIC CRITICAL CARE
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Vol. 2; No. 2; April - June 2015
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JOURNAL OF PEDIATRIC CRITICAL CARE
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
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Vol. 2; No. 2; April - June 2015
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JOURNAL OF PEDIATRIC CRITICAL CARE
Original Article
“Critical Care without Walls”- Impact of a “Pediatric Emergency Team”
on Picu Admissions from the Wards and Overall Mortality
Nitika Agrawal*, Gnanam Ram**, Shiv Kumar***
*Deptt. of Pediatric Intensive Care Unit, **HOD and Consultant Pediatric Intensivist, Consultant Pediatric Intensivist
Manipal Hospital, Bangalore, India
ABSTRACT
A high index of suspicion is needed in pediatric patients with neurological symptoms being the sole presenting
manifestation, to diagnose infection with the Human Immunodeficiency Virus (HIV). This is a write up of two
such cases who were admitted to the pediatric intensive care unit with neurological manifestations.
A 6 year old previously healthy child, who initially presented with intermittent drowsiness and fluctuation
in blood pressure, later during hospital stay, developed progressive motor, cognitive, visual and language
difficulties. Investigations revealed the child to be HIV positive and magnetic resonance imaging (MRI)
findings were consistent with progressive multifocal leucoencephalopathy.
A 12 yr old child had stroke initially (for which extensive work up had been done) and later, after 8 months
presented with the same complaints along with severe pneumonia. He succumbed to severe opportunistic
infections. That he was HIV positive, had not been detected during the first admission as left sided weakness
was the only presenting manifestation.
Key words: Pediatrics, rapid response team, pediatric emergency team, medical emergency response team
Introduction
Cardiopulmonary arrest in children is often a
gradual process, preceded by a critical period of
physiologic instability, during which life saving
interventions can decrease the mortality and
improve outcomes in sick children, admitted to the
hospital1-3. Inhospital cardiopulmonary arrests have
a very poor outcome,with a one year survival rate
of only 15 to 34 percent4. The recognition that,sick
patients have warning signs and symptoms prior to
cardiopulmonary arrest, has led to the introduction
of Rapid Response Teams-Medical Emergency
Teams (MET), when they are physician led or Rapid
Response Teams (RRT), when they are nurse led.
They are meant to be called before a patient has a
cardiopulmonary arrest, in hopes of improving
outcomes. Studies in Western countries have shown
reduction in cardiopulmonary arrests and hospital
mortality after introduction of medical emergency
teams (in adults)7.
There are very few studies on the implementation of
such Rapid Response Teams in children and there
are no standard RRT criteria available to recognize
children as sick, as different age groups have different
physiologic variables.In a first such study from india,
we are reporting successfull implementation of a
Pediatric emergency team (PET) concept and its
effectiveness in an Indian setting in reducing overall
mortality.
Methods
This study was conducted at Manipal hospital,
Bangalore. Manipal Hospital is a 620 bedded tertiary
care hospital with approximately 400 Pediatric
admissions per month. We do not have a dedicated
Pediatric ward; neither do we have a Pediatric
High Dependency Unit (HDU). Pediatric patients
are admitted across all wards, from the 4th to the
11th floors. The hospital has a 10 bedded Pediatric
Intensive Care Unit with close to 600 admissions
annually. Along with general Pediatric services, most
of the pediatric medical subspecialty (cardiology,
neurology, haemato-oncology, metabolic-genetics,
infectious diseases, etc) and surgical subspecialty
(general pediatric surgery, pediatric cardiothoracic
Correspondence:
Dr. Gnanam Ram, MD, DNB, FIAP
Head Pediatric intensive care unit Manipal Hospital,
Bangalore, India
E-mail: [email protected]
Vol. 2; No. 2; April - June 2015
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JOURNAL OF PEDIATRIC CRITICAL CARE
Original Research Article
“Critical Care without Walls”- Impact of a “Pediatric Emergency Team” on Picu Admissions
from the Wards and Overall Mortality
surgery, neurosurgery, orthopaedics and urology)
services are available at Manipal Hospital.
This study is a retrospective audit, before and after
implementation of the Pediatric Emergency Team
(PET) concept in Pediatric wards. All children admitted
to Pediatric wards were considered participants. The
pre-intervention period was between October 2011 and
March 2013 (phase-1) and post-implementation period
was between April 2013 and October 2014 (phase-2).
It was hypothesized that implementation of the PET
concept would prevent subsequent cardio pulmonary
arrests in the wards, reduce the number of admissions
to the PICU from the wards and the overall mortality.
There are no standard Medical Emergency Team (MET)
criteria available to recognize deterioration in children
admitted to the wards. A Pediatric Emergency Team
Chart highlighting the warning signs and symptoms
of various illnesses was prepared. (Annexure 1).
PLACARDS indicating these warning signs and
symptoms were made and displayed prominently in
every ward. A pocket sized Pediatric Ready Reckoner
card was also prepared for nurses, across all floors,
highlighting the normal values of vital parameters and
what needs to be done in an emergency.
All nursing staff across the hospital were trained (bimonthly classes) on recognition of early warning
signs and symptoms in children. They were also
made to undergo the Nurses PALS. We Selected 2 of
our senior nurses, with PICU experience of more than
2 years as PET (Pediatric Emergency Team) Nurses.
They were PALS trained as well. They worked in
two shifts- from 8am to 4pm and from 12 noon to
8 pm. At any given point of time, there are around
60-70 Pediatric patients admitted to the wards in
Manipal Hospital. Out of these admissions, the “AT
RISK” patients (around 15-20 on any given day),
were identified by the ER fellow, primary treating
Pediatrician or PICU fellow/Consultant.
admitting Pediatrician/staff is concerned about.
5) Sick/potentially sick haemato–oncology patients
6) Children undergoing dialysis in the nephrology unit.
7) Tracheostomized children in wards.
8) Neurosurgical and post surgical patients in the wards.
A key aspect of the system was that, any staff
member, irrespective of rank, may summon the PET
(on a mobile exclusively carried by the team) without
having to inform senior colleagues.
A List of these “AT RISK” patients was generated in
the morning by the PET nurse. These would include
some new patients and some patients carried forward
from the previous day’s list. Patients who had improved
considerably were removed from the list, after being
seen by the PICU consultant. Detailed rounds were
done three times a day- in the morning, evening and at
night, initially by the PET nurse and later by a PICU
fellow/Consultant. The potentially sick children
were seen more often, as required. At any point, if
the doctor or nurse felt that the child needed to be
shifted to the PICU, the same was done, after keeping
the primary treating Pediatrician informed. The PET
chart (annexure 1) had to be filled in for every patient
on the list. This was done by the nurses in the wards
and when warning signs/symptoms were noticed,
they would alert the Pediatric Emergency team on the
PET mobile number. (All these patients were anyway
seen by the PET). This ensured monitoring of the
child more closely than other patients.
The following variables were compared before and
after implementation of the PET concept- the number
of patients having cardiopulmonary arrest in the
ward, the number of patients transferred to the PICU
from the wards, the number needing intubation on
Day1 of transfer and the overall mortality of patients
transferred in.
Results
145 patients needed to be shifted to the PICU
because of worsening clinical status, out of a
total of 10,088(1.43%) admissions during phase
1(before introduction of PET), as against 103
out of 7737(1.33%) admissions during phase 2
(after introduction of PET). The age and gender
characteristics were evenly matched. The mean age
of patients transferred to PICU before and after
introduction of PET was 4.5 years and 3.2 years
respectively.
Criteria to include patients in the “AT RISK” Group
were:
1) All Patients shifted out of the PICU after relative
recovery.
2)Patients admitted directly from the Emergency
Room, who need frequent monitoring, but not sick
enough to be admitted to the PICU. This was left to
the discretion of the Pediatric ER fellow/consultant.
3) All patients admitted through the ER after midnight.
4)Any child in the ward about whom the primary
Vol. 2; No. 2; April - June 2015
12
JOURNAL OF PEDIATRIC CRITICAL CARE
“Critical Care without Walls”- Impact of a “Pediatric Emergency Team” on Picu Admissions
from the Wards and Overall Mortality
Original Research Article
Characteristics and Overall Outcome of Patients
in Wards before and after Starting Pet
Variable
Before Pet
After Pet
Total Admissions in Wards
10088
7737
Total Transfers to Picu
145
103
Intubation within 24 hours in PICU
26
6
Cardiopulmonary Arrest in Wards
1
0
Number of Deaths
9
0
Failure to rescue refers to the lack of caregivers’
ability to recognize early signs and symptoms of
deterioration in patient’s condition, or acting too
late to prevent a cardiac arrest. We started the PET
(Pediatric emergency team) concept in our hospital
after noticing a number of patients being transfered
to PICU in a critically ill condition,thereby
increasing their mortality. We hypothesised that,
early recognition of the warning signs and symptoms
of patients admitted to the wards and appropriate
intervention reduces their rate of transfer to the PICU
and their overall mortality-extending the “Golden
hour “ concept to ward patients as well!.. This is the
first study from India on the impact of the Pediatric
Rapid response Team (here Pediatric Emergency
Team) on pediatric in-patients transfer to the PICU
and their mortality.
We studied the impact of the Pediatric Emergency
Team (PET) on the incidence of cardiopulmonary
arests in the wards, number of patients transferred
to the PICU from the wards, the number of those
needing mechanical ventilation within 24 hours and
the overall mortality of the patients transferred in.
Cardiopulmonary arrest during the course of illness
in pediatric patients is a very late event, and in
hospitalised in-patients in the wards, it was almost
nonexistant in our hospital (1 in 10088). We hence
used the criteria of intubation and mechanical
ventillation within 24 hours of their transfer to the
PICU and the mortality in those patients to evaluate
the effectiveness of PET. We found a significant
reduction in the number of patients needing intubation
and mechanical ventillation within 24 hours after
their transfer to PICU, after starting PET (from
There was not a significant difference in the number
of patients transferred to the PICU between the two
phases, as the total number of admissions varied.
26 patients required intubation and mechanical
ventilation within 8 hours after their transfer to PICU
during Phase-1 (17.9%) and 6 during Phase-2 (5.8%)
(p value 0.012864, OR 0.2831,95% CI 0.1120 to
0.7156). All the six patients who needed intubation
during phase-2 underwent the same only 12-24 hours
after their transfer in. Other interventions like use of
inotropes, invasive arterial BP monitoring and fluid
boluses were not significantly different between
the two groups. All the patients transferred in to the
PICU after starting PET survived, whereas 9(6.2%)
patients died before starting PET (p value 0.0366).
Discussion
ICU-based Medical Emergency Team (MET) system
was first described by Lee and colleagues in 199510.
The formation of rapid response teams (RRTs)/
medical emergency teams(MET)/`patient-at-risk
team’ (PART), as these have been variously called
was based on the concept of “failure to rescue.”12.
Characteristics of Patients Transfered to PICU before and after Starting Pet
Variable
Before Pet n=145
After Pet n=103
0.68 (n=1)
0 (n=0)
P Value
OR (95%CI)
Interventions, %
CPR
Intubation within 24 hours
17.9 (n=26)
5.8 (n=6)
0.012864
0.28 (0.11 to 0.71)
Inotropes
37.2 (n=54)
38.8 (n=40)
0.864314
1.07.CI:0.63 to 1.79
Invasive Bp Monitoring
44.8 (n=65)
46.6 (n=48)
0.865873
1.074 CI:0.64 to1.78
Fluid Bolus
73.1 (n=106)
79.6 (n=82)
0.662694
1.43 CI:0.78 to 2.6276
Outcome,%
Died In PICU
6.2 (n=9)
0.0 (n=0)
0.0366
0
Suvival To Discharge
93.8 (n=136)
100 (n=103)
0.767496
6.7500 CI:0.8417 to 54.1315
Vol. 2; No. 2; April - June 2015
13
JOURNAL OF PEDIATRIC CRITICAL CARE
“Critical Care without Walls”- Impact of a “Pediatric Emergency Team” on Picu Admissions
from the Wards and Overall Mortality
Original Research Article
17.9% before starting PET to 5.8% after starting
PET) (p value 0.012864,OR 0.2831,95% CI 0.1120
to 0.7156.)
This is similiar to the first pediatric report published
by Tibballis et al, who found reduction in code rate
from 0.19 to 0.11 per 1000 admissions after starting
MET11. In the study by Richard J. Brilli et al8, the
code rate per 1,000 admissions decreased from 1.54
(baseline) to 0.62 (post-MET) (risk ratio, 0.41; 95%
confidence interval, 0–0.86; p value 0.02). In a recent
study in adult patients, the adjusted rate reduction for
IHCA (inhospital cardiac arrest) was 1.93 (ie, 3.72 −
1.79) patients per 1000 admissions (risk ratio [RR],
0.48; 95% CI, 0.42–0.55; P < 0.001)13.
Mortality in patients needing intubation and
mechanical ventillation within 24 hours after their
admission to the PICU in our study decreased from
6.2 % to 0% (p value 0.0366), after the implementation
of PET.This was similar to similiar to the study by
Tibbalis et al (0.12 to 0.06 per 1000 admissions)
after the implementation of MET at Royal Children’s
Hospital in Melbourne7. In the study by Richard
J. Brilli et al the pre-MET mortality rate was 0.12
per 1,000 days compared with the post-MET rate of
0.06 per 1000 days (risk ratio, 0.48; 95% confidence
interval, 0–1.4, p _ .13). The adjusted rate reduction
in IHCA (in hospital cardiac arrest)-related mortality
was1.49 (ie, 2.71 − 1.22) patients per 1000 admissions
(95% CI, 1.30–1.68) (RR,0.45; 95% CI, 0.38–0.52;
P < 0.001) in a recent study on adult patients13.
All the patients needing intubation within 24 hours
of shifting to the PICU survived (mortality-0%) after
the implementation of PET, whereas 9/26(34.6%)
needing intubation died, before starting PET. 7 out of
9 patients died within 24 hours of transfer in and the
other 2 died within 48 hours. The number of patients
needing interventions in the form of arterial blood
pressure monitoring and inotropes was more before
starting PET, but the difference was not significant.
Diagnosis of Patients Intubated on D1 of Shifting to PICU
Before Pet
Diagnosis
Expired
No.
After Pet
Diagnosis
HEMATO-ONCOLOGY
Expired
No.
HEMATO-ONCOLOGY
ALL
3
3
ALL
1
Hodgkin’s lymphoma
2
2
Post BMT(Thalessemia)
1
HLH
1
Wilms tumour
1
Undifferentiated mass
1
AML
1
1
NEUROLOGICAL
NEUROLOGICAL
Status Epilepticus
3
GBS
1
Congenital Myopathy
1
1
Hereditary motor neuropathy
1
1
RESPIRATORY
4
RESPIRATORY
Laryngomalacia
2
Laryngo-tracheal cleft
Pneumonia
1
Bronchiolitis
1
RENAL
3
HUS
2
ESRD
1
MISCELANEOUS
6
Septic Shock
3
DSS
2
PCM poisoning
1
Vol. 2; No. 2; April - June 2015
Glioblastoma
1
1
1
14
JOURNAL OF PEDIATRIC CRITICAL CARE
Original Research Article
“Critical Care without Walls”- Impact of a “Pediatric Emergency Team” on Picu Admissions
from the Wards and Overall Mortality
There were 145 patients who needed to be shifted to
PICU because of worsening clinical status for a total
of 10088(1.43%) admissions,before introduction of
PET against 103 for 7737(1.33%) admissions, after
introduction of PET. Goldhill, D.R. et al reported
decrease in the number of unnecessary transfers to a
higher level of care by a mean of 30%9. In our study,
the total number of patients monitored by PET was
987, out of a total 7737 admissions (12.75%).89.56%
of the patients kept under PET were managed in the
wards and did not need tranfer to the PICU, because of
our proactive approach in identifying patients at risk
of clinical deterioration during ward stay. Warning
signs and symptoms were recognized early and
they were appropriately managed in the wards-fluid
boluses, administration of oxygen and nebulisations,
adinistratio of the first dose of antibiotic, seizure
control etc.
Although more such studies may be needed
in the Indian subcontinent, it may be said that
implementation of a Pediatric Emergency Team
concept (Pediatric RRT) will reduce the incidence
of respiratory and cardiopulmonary arrests or sudden
deteriorations outside of the critical care areas,
thereby reducing overall mortality. The Institute
for Healthcare Improvement’s Saving 100,000
Lives Campaign has advocated the deployment
of in hospital medical emergency teams (METs)
as a means to rescue patients and reduce hospital
mortality rates, and has already been adopted with
good results in many hospitals worldwide (for adult
patients)5-6.. There are very few exclusive Pediatric
hospitals in the Indian subcontinent and nurses
taking care of adult patients are not trained to pick
up subtle warning signs/symptoms in children. By
the time it is recognized that the child is sick and is
then transferred to the PICU, it may be too late. We
hence recommend implementation of the Pediatric
Emergency Team (RRT) concept in all tertiary
care hospitals, in an attempt to reduce in-hospital
cardiopulmonary arrests and overall mortality in
Pediatric patients.
After successful implementation of this concept, we
now have an exclusive 5 bedded Pediatric HDU,
Vol. 2; No. 2; April - June 2015
where the potentially sick children are admitted .We
are also in the process of procuring a ward (an entire
floor) which is exclusive for Pediatrics.
References
1. Buist MD, Jarmolowski E, Burton PR, et al. Recognising
clinical instability in hospital patients before cardiac arrest
or unplanned admission to intensive care. Med J Aust 1999;
171: 22-25.
2. Franklin C, Mathew J. Developing strategies to prevent inhospital cardiac arrest: analyzing responses of physicians and
nurses in the hours before the event. Crit Care Med 1994; 22:
244-247.
3. Shein RMH, Hazday N, Pena M, et al. Clinical antecedents to
in-hospital cardiopulmonary arrest.Chest 1990; 98: 1388-1392.
4. Reis AG Nadkarni V Perondi MB Grisi S Berg RA A prospective investigation into the epidemiology of inhospital pediatric cardiopulmonary resuscitation using the
international Utstein reporting style. Pediatrics 2002;109 (2)
200- 209
5. Berwick DM, Calkins DR, McCannon CJ, Hackbarth AD.
The 100,000 lives campaign: setting a goal and a deadline for
improving health care quality. JAMA 2006; 295: 324-327.
6. Institute of Health Care Improvement (IHI) 2006. How to
guide pediatric supplement Rapid Response Team; http://
www.ihi.org. Accessed on 10 February 2009
7. James Tibballs, MB, BS, MD, BMedSc, MEd, MBA, MH lth
& Med Law, Grad Dip Arts, FANZCA, FJFICM, FACLM;
Sharon Kinney, RN, MN, PhD Reduction of hospital
mortality and of preventable cardiac arrest and death on
introduction of a pediatric medical emergency team. Pediatr
Crit Care Med 2009; 10:306 –312).
8. Brilli RJ Gibson R Luria JW et al. Implementation of
a medical emergency team in a large pediatric teaching
hospital prevents respiratory and cardiopulmonary arrests
outside the intensive care unit. Pediatr Crit Care Med 2007;8
(3) 236- 247.
9. Goldhill, D.R. et al. The patient-at-risk team: identifying and
managing seriously ill ward patients.Anesthesia 1999;54:853860.
10.Lee A, Bishop G, Hillman KM, Daffurn K: The Medical
Emergency Team. Anaesth Intensive Care 1995, 23:183-186
11.Tibballs J, Kinney S, Duke T, et al: Reduction of paediatric
in-patient cardiac arrest and death with a medical emergency
team: Preliminary results. Arch Dis Child 2005; 90: 1148–
1152
12.D. R. Goldhill et al. Identifying and managing seriously ill
ward patients. Anaesthesia, 1999, 54, pages 853±860
13.Jack Chen et al, Cardiopulmonary arrest and mortality trends,
and their association with rapid response system expansion.
MJA 2014; 201: 167-170.
15
JOURNAL OF PEDIATRIC CRITICAL CARE
Original Research Article
“Critical Care without Walls”- Impact of a “Pediatric Emergency Team” on Picu Admissions
from the Wards and Overall Mortality
Annexure 1
Pediatric Emergency Team (Pet) Chart
Instructions for Use:
Patient Name:
• Record vital parameters as usual
• Enter into appropriate column
Age: Sex:
Hospital Number :
Inpatient Number:
Diagnosis:
Red Alert (Warning) Symptoms/Signs
Respiratory systems:
RR/min
<1 years
1-5 years
> 5 years
>60
>40
>30
WOB:
Moderate/severe
Presence of noisy breathing
(+)
SaO2<92% on nasal prongs (2L/min)
(+)
Circulatory System:
Sleeping Heart Rate
<1 year
1-5 years
>5 years
(per min)
>130
>120
>110
CFT:
>3 sec
Urine output:
Not passed urine for >8 hours
<1 years
1-5 years
> 5 years
<70
<86
<90
BP (Systolic mmHg)
Neurologic System:
AVPU:
V/P/U
Presence of seizures/posturing
(+)
Presence of unequal pupils
(+)
Staff concerned about the child
(+)
Date
Time
RR/min
WOB
Noisy Breathing
SaO2/O2 required
Functioning IV line
HR/min
CFT
UO
BP
AVPU
Seizures/Posturing
Pupils
Plan of action
Dr Signature
Vol. 2; No. 2; April - June 2015
PET Nurse Signature
16
JOURNAL OF PEDIATRIC CRITICAL CARE
Original Article
Late Hemorrhagic Disease of the Newborn - Need for a Second Dose of
Vitamin K ?
Sridhar M*, V.S.V.Prasad**
*Consultant intensivist, **Director and CEO Division of Pediatric Critical Care, Lotus Children’s Hospitals.
Lotus Hospitals for Women & Children, Lakdikapul, Hyderabad-50004, Telangana.
(66.6%). The common clinical finding was pallor in 6
babies (66.6%), followed by bulging fontanelle in 5
(55.5%) and features of herniation in 3 (33.3%). All
infants had altered vitamin K dependent coagulation
profile which was corrected with Injectable vitamin
K. CT Scans of the Brain revealed intracranial
hemorrhages in all the babies (100%). Eight infants
(88.8%) required anticonvulsants, five (55.5%)
required mechanical ventilator support. Surgical
intervention was required in 4 cases (44.4%). Out of 9
infants 5 recovered (55.5%), 3 babies expired (33.3%)
and one baby was discharged against medical advice.
Introduction
Hemorrhagic disease of the newborn is one of the most
common causes of acquired haemostatic disorder of
infancy, especially in those who have not received
vitamin K immediately after birth. It is classified
into early, classic and late depending on the time
of manifestation. Late hemorrhagic disease usually
manifests between 2-12 weeks. One of the common
manifestations is intracranial hemorrhage. In our
study we present a case series of 9 infants who were
admitted in our institute with intracranial hemorrhage
and diagnosed to have late Hemorrhagic disease of the
newborn, despite being delivered in institutions where
a standard dose of intramuscular Vitamin K was
being administered to all infants soon after birth. The
occurrence of intracranial hemorrhage in these infants
raises the question of the need for a second dose, and
the optimal timing of its administration.
Conclusion
Intracranial hemorrhage is a common devastating
manifestation of Late hemorrhagic disease. It can
also occur in babies who received vitamin K at birth.
Mortality is high depending on the severity and
intracranial location of the hemorrhage. Whether this
preventable complication warrants a second dose of
Vitamin K needs to be addressed and studied further.
The subset of infants who develop this complication
needs identification and clues and markers to this
effect needs delineation.
Methods
This is a prospective observational study conducted at
our tertiary pediatric centre located in Lakdikapul,
during the period of Dec 2009 to Aug 2011.
Results
There were 9 infants aged > 1 month and less than 12
months. included in our study. All were term babies,
delivered in hospital and had received one dose of
1 mg vitamin K at birth intramuscularly which was
documented. Of these, the majority were male infants
6 (66.6%). Six babies (66.6%) were exclusively breast
fed, 2 were formula fed (22.2%) and 1 was fed with
both breast fed and formula fed (11.1%). Majority
of the babies presented with seizures and lethargy 6
References
1. Isarangkura PB, Pintadit P, Tejavej A, Siripoonya
P. Chulajata C, Green GM. Vitamin K prophylaxis
in the neonate by oral route and its significance
in reducing infant mortality and morbidity. J Med
Assoc Thai 1986; 69: 56-61.
2. Bor O, Akgun N, Yakut A, Sarbus F, Kose S. Late
Hemorrhagic disease of the newborn. Pediatrics
Int 2000; 42: 64-66.
3. Heron P, Cull A. Avoidable hazard to New Zealand
children: case reports of hemorrhagic disease of the
newborn. New Zealand Med 1998; 101: 507-508.
4. Zipursky A. Prevention of vitamin K deficiency
bleeding in newborn. Brit J Hematol 1999; 104:
430-437.
Correspondence:
Dr V. S. V. Prasad
Consultant and CEO
Lotus Hospitals for Women & Children, Lakdikapul,
Hyderabad-50004
Mobile: +919849067373
E-mail: [email protected]
Vol. 2; No. 2; April - June 2015
17
JOURNAL OF PEDIATRIC CRITICAL CARE
Special Article
Probiotics in Critical Illness – Is There a Role in Intensive Care?
Hema Kumar, DNB*, Rakshay Shetty, MD**
*Pediatric Critical Care Fellow, **Consultant Pediatric Intensivist, Rainbow Children’s Hospital, Vijayawada, India.
ABSTRACT
Probiotics are living microbes, when adequately ingested confer benefits to the host which include shortened
duration of infection or decreased susceptibility to pathogens. Probiotics improve gut barrier function,
restore non-pathogenic digestive flora, prevent colonization by pathogenic bacteria and have role in
immunomodulation. In the era of increasing antibacterial resistance and fewer new antibiotics in the research
pipeline, non-antibiotic approaches like use of probiotics offer a ray of hope to clinician in the prevention of
nosocomial infections in critical ill patients. Till to date, trials conducted on the role of probiotics in critically
ill patients have shown significant heterogenicity in clinical outcomes, type of strain studied, dose and
duration of therapy. Hence, the current data does not offer sufficient evidence to draw a conclusion regarding
clinical indications of probiotics in critically ill. Well designed clinical trials are needed to validate the effects
of particular probiotics given at specific dosages and for specific treatment durations. Although probiotics
are generally safe in critically ill, more information is needed on safety profile of probiotics particularly in
immunocompromised patients.
Key words: Probiotics, Critically ill, Nosocomial infections, Multiorgan dysfunction
intensive care patients3. The proposed benefits
include either a shortened duration of infections or
decreased susceptibility to pathogens4. Thus, the
therapeutic concept with probiotics is an effort to
reduce or eliminate potential pathogens and toxins,
to release nutrients, antioxidants, growth factors
and coagulation factors, to stimulate gut motility
and to modulate innate and adaptive immune
defence mechanisms via the normalization of
altered gut flora5.
Probiotics are defined by FAO/WHO (Food
and agricultural organization/World Health
Organization) as “live bacteria which when
administered in adequate amounts confer a health
benefit to the host”. These bacteria do not contain
any virulence properties or antibiotic resistance
cassettes1.
During the last few years a number of scientific
papers have studied utility of probiotics in some
specific groups of critically ill patients. During
critical illness, alterations in gut microflora
are due to several factors that include changes
in circulating stress hormones, gut ischemia,
immunosuppression, the use of antibiotics and
other drugs, possible bacterial translocation
and lack of nutrients2. Lot of interest has been
generated in utilizing probiotics as colonizers to
prevent the cycle of colonization with pathogens
and ultimately prevent nosocomial infections in
Mechanisms of probiotics function
Commonly used probiotics available in commercial
preparations are listed below.
• Lactobacillus species – L.sporogenes, L.acidophilus,
L.rhamnosus, L.lactis
• Bifidobacterium species – B.longum, B.infantis,
B.bifidum
• Saccharomyces boulardii
• S. cerevisiae
• Streptococcus thermophilus
• Bacillus clausi
Probiotics can exert their beneficial effect by
multiple mechanisms. These are summarised in
Table 1.
Correspondence:
Dr. Rakshay Shetty
Pediatric Intensivist, Rainbow Children’s Hospital, Opp.NTR
Health University, Currency Nagar, Vijayawada, Andhra
Pradesh -520008
E-mail: [email protected]
Vol. 2; No. 2; April - June 2015
18
JOURNAL OF PEDIATRIC CRITICAL CARE
Special Article
Probiotics in Critical Illness – Is There a Role in Intensive Care?
study with 208 ICU patients and showed delayed
occurrence of Pseudomonas aeruginosa respiratory
colonization and or infection in the probiotic group.
Giamarellos-Bourboulis et al18 in a trial of 72 patients
with severe multiple injuries showed that 15-day
administration of Synbiotic 2000 FORTE significantly
decreased the occurrence of VAP by Acenitobacter.
baumannii.
Lactobacillus rhamnosus holds a lot of promise in
prevention of VAP and decreasing hospital stay in
high risk patients. However more studies are needed
to confirm the probiotic strain and dosage which
provides maximum effect.
Table 1: Proposed mechanisms of action of Probiotics
Mechanism of Action
Description
Carrier function
Increased mucin
production6,7
Anti apoptotic effect8,9
Anti inflammatory effect9
Production of Antimicrobial
substance
Enhances the production of
defensins and bacteriocins10
Competition for adherence
Compete with invading
pathogens for epithelial
binding sites11
Immune modulation
Regulation of cytokine
expression12
Effects on phagocytosis
Augment IgA production13
Interference with quorum
sensing signalling
Interferes with cell-to-cell
signalling mechanism of
microbes that facilitates
colonization and infection14
Effect on other Nosocomial Infections and
Multiorgan Dysfunction Syndrome (MODS)
Impaired intestinal barrier function is implicated in
pathogenesis of MODS in patients with decreased gut
perfusion resulting from surgery, trauma and shock.
Probiotic bacteria have been shown to modulate
intestinal barrier and immune function.
In a randomixed control trial (RCT) conducted by
Alberda et al19 on 28 critically ill patients, probiotics
showed significant improvement in the systemic
concentrations of IgA and IgG with decreased intestinal
permeability after 7 days. A trial of 65 critically
ill, mechanical ventilated, polytrauma patients by
Kotzampassi et al20 showed that Synbiotic Forte for
15 days significantly reduced rate of infections, SIRS,
severe sepsis and mortality. ICU stay and duration of
mechanical ventilation were also significantly reduced
in relation to placebo. However a study on perioperative
administration of Lactobacillus plantarum 299v to
patients undergoing elective major abdominal surgery
did not confer any advantage with respect to the
prevention of Bacterial translocation, colonization of
the upper gastrointestinal tract, or septic morbidity and
mortality during post operative period.
In view of conflicting reports on beneficial effects and
lack of details about the dose and strain, probiotics
cannot be recommended currently for prevention of
MODS and nosocomial infections other than VAP.
Clinical applications in Intensive care unit–
Effect of probiotics on VAP (Ventilator Associated
Pneumonia)
Meta-analysis of five randomized controlled trials
showed that the administration of probiotics,
compared with control, was beneficial in terms of
incidence of ventilator-associated pneumonia, length
of intensive care unit stay and colonization of the
respiratory tract with Pseudomonas aeruginosa15.
However, no statistically significant difference was
found between the groups regarding in-hospital
mortality, intensive care unit mortality, duration of
hospital stay or duration of ICU stay.
Marrow et al16 conducted a prospective, randomized,
double-blind, placebo-controlled trial of 146
mechanically ventilated patients at high risk of
developing VAP treated with Lactobacillus rhamnosus
GG at a dose of 2×109 CFU were significantly less
likely to develop microbiologically confirmed VAP
compared with patients treated with placebo. Patients
treated with probiotics had fewer days of antibiotics
prescribed for VAP and for C. difficile-associated
diarrhea. No adverse events related to probiotic
administration were identified.
Forestier and colleagues17 conducted a prospective,
randomized, double-blind, placebo controlled
Vol. 2; No. 2; April - June 2015
Effect on Antibiotic Associated Diarrhea (AAD)
Frequent use of broad spectrum antibiotics causes
19
JOURNAL OF PEDIATRIC CRITICAL CARE
Special Article
Probiotics in Critical Illness – Is There a Role in Intensive Care?
antibiotic associated diarrhea with reported incidence
of 5-30% in critically ill patients21. Though any
antibiotic group can cause AAD but greatest risk
is seen with clavulinic acid, cephalosporins and
clindamycin22.
In nine trials, the probiotics were given in combination
with antibiotics. The meta-analysis suggests that S
boulardii and Lactobacilli are beneficial in prevention
of antibiotic associated diarrhea23. However, their
efficiency in treating antibiotic associated diarrhea
still remains to be proven. But it has to be noted that
these studies have not been conducted in critical care
setting and hence large well designed studies are
needed to look into cost of and need for routine use
probiotics in AAD in critically ill.
has been heavily criticized for its faulty design and
2 other RCT’S done subsequently didn’t show any
harmful effects after probiotic administration for
acute pancreatitis 34,35 .
Severe Traumatic Brain Injury
2 small RCT conducted in traumatic brain injury
patients demonstrated reduced rate of nosocomial
infections. Tan et al.36 conducted a RCT on 26
severe traumatic brain injury patients (GCS 5-8)
to look for cytokine profile and clinical outcomes
after administration of multispecies probiotic for 3
weeks. It showed significantly decreased nosocomial
infection rate and a decrease in IL-4 and IL-10 levels.
Other small RCT was done in 20 brain injured
(GCS 5-12) patients also showed that probiotics and
glutamine given for 5- 14 days reduced the incidence
of infection rate, ICU stay and ventilation days.
Effect on Clostridium Diarrhea
Probiotics have been studied in the prevention and/
or treatment of primary and recurrent Clostridium
diarrhea in non-critically ill and they heve been
proven to be beneficial in prevention and recurrence
of Clostridium diarrhea24-31. One RCT has studied
the efficacy of S. boulardii when added to low dose
vancomycin, high dose vancomycin or metronidazole
in patients with established Closteridium associated
diarrhea (CCAD). Patients treated with high dose
vancomycin and probiotic had significantly decreased
recurrent Closteridium deficile infection ( CDI ) rates
compared with vancomycin and placebo.
As of now, role of probiotics in management of
Clostridium diarrhea in ICU is not well supported by
studies and cannot be recommended.
Hepatic Encephalopathy
Interest in the role of probiotics in the management of
hepatic encephalopathy arose from studies showing
that they can reduce serum ammonia levels. A metaanalysis of studies in minimal hepatic encephalopathy
found that probiotics and synbiotics were effective in
reducing encephalopathy but these agents were less
effective than prebiotic lactulose monotherapy37.
Safety of Probiotics
Probiotics so far used in clinical trials can be generally
considered as safe. However, Probiotics have
theoretical risks of transferring antibiotic resistance
genes and translocating to other areas of the body.
Bacteremia and fungemia has been reported with the
use L. rhamnosus GG and S. boulardii respectively
in critically ill immunocompromised patients38,39.
Due to relative immunosuppression and the frequent
need of devices in ICU patients those bypass normal
host defences, it is important to follow universal
precautions and strict hand hygiene practices when
handling Probiotics.40
Other indications
Acute Pancreatitis
A Meta-analysis and systemic analysis of 6 trials32
addressing the role of probiotics in severe acute
pancreatitis didn’t find a beneficial outcome
with regards to pancreatic infection rate, overall
infections, operation rate, hospital stay or mortality.
PROPATRIA trial33 done by Dutch Acute Pancreatitis
Study Group reported higher incidence of
complications in probiotic arm like bowel ischemia,
multiorgan failures and mortality rate. This study
Vol. 2; No. 2; April - June 2015
Conclusion
In an era of increasing antibiotic resistance among
20
JOURNAL OF PEDIATRIC CRITICAL CARE
Special Article
Probiotics in Critical Illness – Is There a Role in Intensive Care?
pathogens and limited new antibiotics in the offering,
probiotics offer enormous promise. However,
design limitations of existing studies (different
strains, dosages, and durations of treatment) and
small sample sizes limit widespread usage in ICU.
Although data suggest that probiotics are potentially
effective in various critically ill populations, current
evidence also indicates that probiotic effects are strain
specific, dose dependent, and may vary by disease
state. As such, the optimal probiotic prescription for
critically ill patients remains unknown. Although
the data with probiotics are far from conclusive,
this is a fascinating, inexpensive, and non-antibiotic
approach to nosocomial infections that merits further
investigation.
Lactobacillus helveticus inhibit enterohaemorrhagic
Escherichia coli O157:H7 adhesion to epithelial cells. Cell
Microbiol 2007, 9: 356-367.
12.Tien MT, Girardin SE, Regnault B, Le Bourhis L, Dillies
MA, et al. Anti-inflammatory effect of Lactobacillus casei
on Shigella-infected human intestinal epithelial cells. J
Immunol 2006, 176: 1228-1237.
13.Galdeano CM, Perdigón G The probiotic bacterium
Lactobacillus casei induces activation of the gut mucosal
immune system through innate immunity. Clin Vaccine
Immunol 2006, 13: 219-226.
14.Medellin-Peña MJ, Wang H, Johnson R, Anand S, Griffiths
MW Probiotics affect virulence-related gene expression in
Escherichia coli O157:H7. Appl Environ Microbiol 2007,
73: 4259-4267.
15.Giamarellos-Bourboulis EJ, Bengmark S, Kanellakopoulou
K, Kotzampassi K. Pro and synbiotics to control
inflammation and infection in patients with multiple
injuries. J Trauma. 2009; 67(4):815-821.
16.Morrow LE, Kollef MH, Casale TB. Probiotic prophylaxis
of
ventilator-associated
pneumonia:
a
blinded,
randomized, controlled trial. Am J Respir Crit Care
Med. 2010;182(8):1058-1064
17.Forestier C, Guelon D, Cluytens V, Gillart T, Sirot J, De
Champs C. Oral probiotic and prevention ofPseudomonas
aeruginosainfections: a randomized, double-blind, placebocontrolled pilot study in intensive care unit patients. Crit
Care. 2008;12(3):R69
18.Siempos II, Ntaidou TK, Falagas ME. Impact of the
administration of probiotics on the incidence of ventilatorassociated pneumonia: a meta-analysis of randomized
controlled trials. Crit Care Med. 2010; 38(3):954-962.
19.Alberda C, Gramlich L, Meddings J, Field C, McCargar L,
Kutsogiannis D, Fedorak R, Madsen K: Effects of probiotic
therapy in critically ill patients: a randomized, double-blind,
placebo-controlled trial. Am J Clin Nutr 2007, 85:816-23.
20.Kotzampassi K, Giamarellos-Bourboulis EJ, Voudouris A,
Kazamias P, Eleftheriadis E: Benefits of a synbiotic formula
(Synbiotic 2000Forte) in critically Ill trauma patients: early
results of a randomized controlled trial. World J Surg 2006,
30:1848-55.
21.Besselink MG, van Santvoort HC, Buskens E, et al., the
Dutch Acute Pancreatitis Study Group: Probiotic prophylaxis
in predicted severe acute pancreatitis: a randomised, doubleblind, placebo-controlled trial. Lancet 2008, 371:651–659
22.Shanmiao Gou, Zhiyong Yang, Tao Liu et al., Use of
probiotics in the treatment of severe acute pancreatitis:
a systematic review and meta-analysis of randomized
controlled trials Critical Care 2014, 18:R57
23.Oláh A, Belágyi T, Issekutz A,etal., Randomized clinical
trial of specific Lactobacillus and fibre supplement to early
enteral nutrition in patients with acute pancreatitis. Br J Surg
2002, 89:1103–1107.
24.Oláh A, Belágyi T, Pótó L, Romics L Jr, Bengmark S:
Synbiotic control of inflammation and infection in severe
acute pancreatitis: a prospective, randomized, double blind
study. Hepatogastroenterology 2007, 54:590–594.
References
1.Food and Agriculture Organization and World Health
Organization Expert Consultation. Evaluation of health
and nutritional properties of powder milk and live lactic
acid bacteria. Cordoba, Argentina: Food and Agriculture
Organization of the United Nations and World Health
Organisation;2001
2. Alverdy JC, Laughlin RS, Wu L: Influence of the critically ill
state on host-pathogen interactions within the intestine: gutderived sepsis redefined. Crit Care Med 2003, 31:598-607.
3. McNabb B, Isakow W: Probiotics for the prevention of
nosocomial pneumonia: current evidence and opinions.
Curr Opin Pulm Med 2008, 14: 168 -75
4. Antoine JM: Probiotics: beneficial factors of the defence
system. Proc Nutr Soc 2010, 69: 429-433.
5. Singhi SC, Baranwal A: Probiotic use in the critically ill.
Indian J Pediatr 2008, 75:621-7.
6. Mack DR, Ahrne S, Hyde L, Wei S, Hollingsworth MA
Extracellular MUC3 mucin secretion follows adherence of
Lactobacillus strains to intestinal epithelial cells in vitro. Gut
2003, 52: 827-833.
7. Mattar AF, Teitelbaum DH, Drongowski RA, Yongyi F,
Harmon CM, et al. Probiotics up-regulate MUC-2 mucin
gene expression in a Caco-2 cell-culture model. Pediatr Surg
Int 2002, 18: 586-590.
8. Yan F, Polk DB Probiotics as functional food in the treatment
of diarrhea. Curr Opin Clin Nutr Metab Care 2006, 9: 717-721.
9. Gaudier E, Michel C, Segain JP, Cherbut C, Hoebler C The
VSL# 3 probiotic mixture modifies microflora but does not heal
chronic dextran-sodium sulfate-induced colitis or reinforce the
mucus barrier in mice. J Nutr 2005, 135: 2753- 2761.
10.Penner R, Fedorak RN, Madsen KL Probiotics and
nutraceuticals: non-medicinal treatments of gastrointestinal
diseases. Curr Opin Pharmacol 2005, 5: 596- 603.
11.Johnson-Henry KC, Hagen KE, Gordonpour M, Tompkins
TA, Sherman PM Surface-layer protein extracts from
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Probiotics in Critical Illness – Is There a Role in Intensive Care?
33.Kotowska M, Albrecht P, Szajewska H et al., Saccharomyces
boulardii in the prevention of antibiotic-associated diarrhea
in children: a randomized double-blind placebo-controlled
trial. Alimentary Pharmacology and Therapeutics 2005;21
(5):583–90.
34.Hickson, M, D’Souza, AL, Muthu, N, et al.,Use of probiotic
Lactobacillus preparation to prevent diarrhoea associated
with antibiotics: randomised double blind placebo controlled
trial. BMJ 2007; 335(7610):80.
35.Surawicz CM, Elmer GW, Speelman P,etal., Prevention of
antibiotic-associated diarrhea by Saccharomyces boulardii: a
prospective study. Gastroenterology 1989; 96(4):981 8.
36.Ef Min Tan, Jing-Ci Zhu, Jiang Du etal., Effects of probiotics
on serum levels of Th1/Th2 cytokine and clinical outcomes
in severe traumatic brain-injured patients: a prospective
randomized pilot study Critical Care 2011, 15:R290
37.Sharma P, Sharma BC, Agarwal A, et al. Primary Prophylaxis
of overt hepatic encephalopathy in patients with cirrhosis: an
open labelled randomized controlled trial of lactulose versus
no lactulose. J Gastroenterol Hepatol 2012;27:1329-1335
38.Elaheh Vahabnezhad, MD, Albert Brian Mochon et al.,
Lactobacillus Bacteremia Associated With Probiotic Use in a
Pediatric Patient With Ulcerative Colitis (J Clin Gastroenterol
2013;47:437–439)
39.F.Lestin, A.Pertschy, D.Rimek et al., Fungemia after oral
treatment with Saccharomyces boulardii in a patient with
multiple co-morbidities Dtsch med Wochenschr 2003;
128(48): 2531-2533
40.Doron SI, Hibbered PL, Gorbach SL. Probiotics for
prevention of antibiotic associated diarrhea. J Clin
Gastroenterol.2008:42: S58-S63.
25.Szymsński H, Pejcz J, Jawień M et al.,Treatment of acute
infectious diarrhea in infants and children with a mixture
of three Lactobacillus rhamnosus strains--a randomized,
double-blind, placebo-controlled trial. Aliment Pharmcol
Ther. 2006 Jan 15; 23(2):247-53.
26.Szajewska H, Ruszczynski M, Radzikowski A.Probiotics in
the prevention of antibiotic-associated diarrhea in children a
meta-analysis of randomized controlled trials J pediatr 2006
Sep;149(3):367-372.
27.Aloysius L D’Souza, Chakravarthi Rajkumar etal.,Probiotics
in prevention of antibiotic associated diarrhoea: metaanalysis BMJ 2002;324:1361
28.McFarland LV, Surawicz CM, Greenberg RN et al. Prevention
of beta-lactam associated diarrhea by Saccharomyces
boulardii compared with placebo. American Journal of
Gastroenterology 1995;90 (3):439–48
29.
Plummer S, Weaver MA, Harris JC, Dee P, Hunter
J.Clostridium difficile pilot study: effects of probiotic
supplementation on the incidence of C. difficile diarrhoea.
International Microbiology 2004;7(1):59–62.
30.Thomas MR, Litin SC, Osmon DR etal., Lack of effect
of Lactobacillus GG on antibiotic associated diarrhea: a
randomized, placebo-controlled trial. Mayo Clin Proc. 2001
Sep;76(9):883-9.
31.M Can M, Be irbellioglu BA, Avci IY et al., Prophylactic
Saccharomyces boulardii in the prevention of antibioticassociated diarrhea: a prospective study. Medical Science
Monitor 2006;12(4):Pi19–22
32.Lewis SJ, Potts LF, Barry RE. The lack of therapeutic
effect of Saccharomyces boulardii in the prevention of
antibioticrelated diarrhoea in elderly patients. Journal of
Infection 1998;36(2):171–4
Journal of Pediatric Critical Care
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Vol. 2; No. 2; April - June 2015
22
JOURNAL OF PEDIATRIC CRITICAL CARE
Review Article
Management of Status Asthmaticus in the Pediatric Intensive Care
Unit: Review of Literature
Sandeep Tripathi, Gina Cassel, James R. Phillips
*Division of Pediatric Critical Care Medicine, Mayo Clinic, Rochester, MN and #Division of Pediatric Critical Care,
Montefiore Medical Center, Bronx, NY
ABSTRACT
Asthma continues to be a chronic illness affecting millions of children worldwide. In spite of very good
controller medications now available, Status Asthmaticus is one of the most common diagnosis among
children admitted to the Pediatric Intensive Care Units. There are also a very wide variety of therapeutic
options available to the intensivist for treating an asthma exacerbation. Although in conditions of extremes,
probably it is worth to utilize all the therapies possible, more often than not, a practitioner has to choose one
vs the other. In view of potential side effects of all the therapies, it is valuable to understand the evidence
behind them. In this brief review we have tried to summarize the options and the research behind them.
Key words- Pediatrics, Status Asthmaticus, Asthma, Evidence-Based Medicine.
Acute severe asthma or Status Asthmaticus
(SA) is an acute exacerbation of asthma that is
unresponsive to initial standard treatment with
short acting bronchodilators, anticholinergic drug,
and corticosteroids. Approximately 25.9 million
Americans (including 7.1 million children) had
asthma in 2011; a rate of 84.8 per 1,000 population.
The highest prevalence rate was seen in those
5-17 years of age (105.5 per 1,000 population)1.
Status asthmaticus is one of the leading causes of
hospitalization among children younger than 15
years in the United States. Asthma accounts for
29% of total pediatric hospital discharges, and in
2009, 157 deaths of patients younger than 15 years
were attributed to asthma2. Morbidity and mortality
from asthma are decreasing as a result of the
multiple modalities for intervention available in the
emergency department, general pediatric floor, and
intensive care unit. Because asthma has the highest
morbidity rate of all pediatric diseases, it has been
widely studied around the world. However, as with
most diseases in modern medicine, some dogmas
and therapies are unsubstantiated by any evidencebased research. Exemplifying the large variations
in asthma management is a multicenter study by
Bratton et al3 that took place over 3 years and
included 7,125 children: rates of invasive mechanical
ventilation (MV) use in patients with SA varied
Vol. 2; No. 2; April - June 2015
from 6% for those admitted to a pediatric intensive
care unit (PICU) in the Pacific region to 27% in the
East North Central region. Therapeutic intervention
varied widely by census region, with 26% receiving
systemic β-agonists, 59% inhaled anticholinergics,
21% magnesium sulfate, 6% methylxanthines, 10%
inhaled helium-oxygen gas mixtures, and 14%
endotracheal intubation and MV.
In this review article, we aimed to identify the
evidence for various therapeutic options available
to treat SA in children, from the emergency room
to the intensive care unit. Independent literature
searches (using PubMed and Google Scholar)
were conducted by 2 of the authors (S.T. and G.C.)
to identify studies regarding various therapeutic
options for severe asthma. Recently published metaanalyses and systematic reviews were also included
in the search. Studies that were deemed relevant by
both investigators were included in this review. We
did not attempt to conduct a systematic review or a
meta-analysis of published studies, but this review
represents a compilation of prior research pertinent
to clinicians caring for children with acute severe SA.
Each type of therapy is discussed in the following
sections followed by the practice followed by our
standard practice (in italics) and a decision support
algorithm (Figure 1).
23
JOURNAL OF PEDIATRIC CRITICAL CARE
Review Article
Management of Status Asthmaticus in the Pediatric Intensive Care Unit: Review of Literature
(Score range 1-12, with higher score for more severe
asthma), was 90% in the MDI group vs 71% in the
nebulizer group (P=.01) after the first hour.
The MDI/valved holding chamber may be better
tolerated and achieve similar if not better drug
delivery then compared with nebulization.
Sympathomimetic (b2-Agonist) Therapy
Bronchodilation by β2-agonist therapy has been
the cornerstone of acute asthma therapy for both
outpatients and inpatients. Although its effectiveness
is not debated, some unresolved questions remain
related to the different agents, doses, and routes of
administration.
Levalbuterol
Levalbuterol (Xopenex, Sunovion Pharmaceuticals
Inc), an orally inhaled racemic albuterol, has the
theoretical advantage of causing less tachycardia.
It is therefore widely prescribed in small children.
However, independent clinical trials have mostly
been unremarkable. A 2009 double-blind, randomized
controlled trial (RCT) of high-dose continuous
albuterol vs racemic albuterol in 81 children aged
6 to 18 years showed similar time requirements for
both therapies, as well as similar changes in heart
rate7. A study measuring changes in clinical asthma
scores and forced expiratory volume in 1 second
(FEV1) changes also showed no difference 8.
Levo-albuterol is significantly more expensive than
racemic albuterol and may offer no advantage during
the initial asthma exacerbation treatment.
Continuous Albuterol
Nebulized albuterol 2.5 mg every 1 to 2 hours is
effective in decreasing asthma symptoms rapidly.
Continuous delivery of nebulized albuterol is
routinely used in emergency departments and
intensive care units. There is some evidence in favor
of using continuous therapy vs hourly therapy in
severe asthma. In a randomized study of 17 pediatric
asthma patients, with 1 group receiving 0.3 mg/kg
per hour of continuous albuterol and the other group
receiving 0.3 mg/kg over 20 minutes every hour,
Papo et al4 found that the patients in the continuous
albuterol group improved quicker and had a shorter
duration of hospital stay.
Continuous albuterol in doses ranging from 5 mg/
hour to 20 mg/hour is routinely used as a first line
agent.
Subcutaneous Adrenergic Agents
Epinephrine is a nonselective adrenergic agent, but
α action predominates at higher doses and β1/β2 at
lower doses. Sub cutaneous or intra muscular use of
epinephrine has been used for management of acute
severe asthma. Studies, however, have not shown
a conclusive difference in outcomes comparing
subcutaneous epinephrine with nebulized albuterol9.
Terbutaline is a β-selective adrenergic agent, although
it loses its β2-selective property when administered
subcutaneously, and offers no advantage over
epinephrine.10 However, 1 double-blind crossover
study comparing 0.25 mg of epinephrine with 0.5
mg of terbutaline showed a more pronounced effect
with regard to forced vital capacity, FEV1, maximal
expiratory flow rate, and maximal midexpiratory
flow rate in the group who had received terbutaline11.
Single administration of I.M terbutaline in the
emergency department and in the PICU is utilized
for impending respiratory failure to potentially
Metered-Dose Inhaler
A metered-dose inhaler (MDI) is an effective and
efficient mode of delivering aerosolized medication
to the respiratory tract. MDI with a valved holding
chamber works very well even in small children, who
can have increased anxiety with nebulizations. The
MDI/valved holding chamber drug delivery system
offers a shorter treatment time, does not require
electricity, and is more effective than use of a nebulizer
in young children in the emergency department
setting5. The widespread perception that nebulization
is somewhat more effective is not supported with
evidence. In a single-blind, prospective randomized
trial6, patients aged 1 to 24 months with moderate to
severe wheezing were randomly assigned to receive
either MDI with a spacer (2 puffs, 100 mcg each,
every 10 minutes for 5 doses) or nebulizer treatment
(0.25 mg/kg every 13 minutes for 3 doses). Treatment
success, as defined by a clinical score of less than 5
Vol. 2; No. 2; April - June 2015
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JOURNAL OF PEDIATRIC CRITICAL CARE
Review Article
Management of Status Asthmaticus in the Pediatric Intensive Care Unit: Review of Literature
Ipratropium given in combination with albuterol
(Combi-nebs) is used frequently in the E.D setting,
however due to limited data on efficacy in PICU
patients not used routinely in the PICU.
avoid intubation and to allow steroids and nebulized
albuterol to take effect.
Continuous Terbutaline Infusion
A severe asthma exacerbation leads to impaired
delivery of nebulized medications to the
tracheobronchial tree, with resulting limited
therapeutic effect. A b-selective bronchodilator given
systematically has a potential advantage in such
circumstances, with intravenous (IV) terbutaline
infusions being the preferred agent by most
emergency department physicians and intensivists.
The clinical benefit of continuous terbutaline and its
safety profile has been shown to be favorable in small
nonrandomized trials12 and retrospective studies13.
However, a prospective, randomized, double-blind
trial failed to show clinical benefit after adding IV
terbutaline to the treatment regimen of children aged
2 to 17 years who were already receiving continuous
high-dose albuterol. Specifically, no difference was
observed in clinical asthma severity scores, number
of hours on continuous albuterol, or PICU length of
stay between the group receiving IV terbutaline plus
albuterol vs albuterol alone14.
Terbutaline infusion is the preferred second line
agent for failure to respond to nebulized albuterol/
steroids.
Corticosteroids
Corticosteroids, along with nebulized albuterol, are
considered the standard initial therapy for asthma.
Multiple trials have documented the efficacy of
corticosteroids, but variations in agents, doses, and
routes of administration persist. Many studies have
shown equal efficacy of oral vs IV corticosteroids18.
A Cochrane review in 2000 identified 7 trials with
a total of 426 children treated with IV/oral or
nebulized corticosteroids19. The authors concluded
that some forms of systemic corticosteroids
(oral or IV) decreased hospital length of stay, and
these patients were less likely to have a relapse
within 3 months. Inhaled corticosteroids were not
found to be equivalent to systemic corticosteroids
for treatment of acute asthma exacerbations in this
review19. Other trials have shown no benefit in
outcomes using high-dose corticosteroids compared
with “standard” doses16, 17 In fact, a single dose of
intramuscular dexamethasone has been found to
be equally efficacious to a 3-day oral prednisolone
course when comparing clinical improvement and
prevention of further emergency department visits20.
Dexamethasone 0.6 mg/kg (max 15 mg) I.M. x 1 dose
is preferred agent for children 18 mo-7 yr with acute
asthma seen in the ED. For children admitted to the
PICU, methylprednisolone at 1 mg/kg/dose q6 is
started I.V and tapered to 1 mg/kg/dose q12 hours
(I.V or P.O) by day 2-3.
Anticholinergic Agents
Ipratropium bromide (Ipravent; Cipla) is an
anticholinergic agent that acts by inhibiting
parasympathetic-mediated bronchospasm. Used
alone or in combination with albuterol, it is a popular
first-line therapy for management of asthma in
children in the emergency department. The clinical
studies regarding its usage have been equivocal.
RCTs by Craven et al15 and Goggin et al16 have
shown no benefit of adding ipratropium bromide to
a standard regimen of albuterol and corticosteroids,
as measured by asthma score, hospital length of stay,
or changes in FEV1. However, in a larger trial of 434
children by Qureshi et al17 the subset of patients with
more severe asthma had significantly decreased need
for hospitalization with the addition of ipratropium
bromide.
Vol. 2; No. 2; April - June 2015
Magnesium Sulfate
Magnesium sulfate 25 mg/kg over 20 minutes during
the first hour of an asthma exacerbation is a secondline agent that has been shown to significantly
decrease the need for mechanical ventilation in
pediatric patients, 2-15 years old21. Magnesium
sulfate produces bronchodilation by relaxing smooth
muscles. However, its bronchodilation efficacy is
variable. Some patients show vigorous response
to magnesium sulfate, and others are virtually
25
JOURNAL OF PEDIATRIC CRITICAL CARE
Review Article
Management of Status Asthmaticus in the Pediatric Intensive Care Unit: Review of Literature
Education and Prevention Program (NAEPP) does
not recommend methylxanthines in the emergency
care or hospital setting28.
Due to safer alternative agents, no significant
improvement in symptoms, no decrease in LOS, and
limited supply, methylxanthines are not recommended
in the PICU setting.
unresponsive. This may be due to variations in the
severity of asthma. Studies have been equivocal,
although more data support the use of magnesium.
Noppen et al22 in 1990 showed significant
improvement in pulmonary function tests and clinical
status with use of IV magnesium in a small group
of 12 patients with severe asthma. Another RCT in
1996 showed a greater percentage of improvement in
FEV1 with use of IV magnesium infusion compared
with placebo23. However, in a subsequent RCT, a
single dose of 75 mg/kg of magnesium sulfate did
not show any advantage as a treatment adjunct24.
Magnesium should be employed during the first hour
of asthma exacerbation treatment in patients who
demonstrate poor improvement in SpO2, cyanosis,
use of accessory muscles, expiratory wheezes, and
level of consciousness.
Heliox
Substitution of nitrogen with helium in the inspired
air (heliox) decreases the density of gas, which in
turn makes the flow of gas through a circular tube
(ie, tracheobronchial tree) easier. Heliox produces
a marked response in children with upper airway
obstruction and croup. Its use in asthma, however,
has only been studied in small trials and has had
conflicting results. One prospective trial in 11
children aged 5 to 18 years showed no significant
difference in clinical score or spirometry at baseline
and 15 minutes after initiation of a 70% helium/30%
oxygen gas mixture29. However, Kudukis et al30
showed lower peak flow and lower dyspnea index in
an RCT of 18 patients aged 16 months to 16 years
with longer use of heliox gas mixture.
Another study reported the successful use of heliox
to improve ventilation in 28 intubated children with
asthma.31 However, a rather large RCT involving
the use of heliox in 42 children aged 2 to 21 years
with moderate to severe asthma failed to show
any difference in clinical asthma score or PICU or
hospital length of stay32.
Not routinely used. Occasionally tried in refractory
patients who do not have oxygen requirement.
Methylxanthines
Theophylline was once the standard pharmaceutical
agent for treatment of acute asthma. However, with
its narrow therapeutic index and availability of safer
agents, its use has declined in developed countries.
Theoretically, with careful monitoring of drug levels,
aminophylline may be as safe as any b-agonist. An
RCT from 1998 by Yung and South25 showed greater
improvement in spirometry at 6 hours, higher oxygen
saturations in 30 hours, and a significant decrease
in intubation rates using theophylline combined
with terbutaline compared with terbutaline alone.
This study included 40 children aged 3 to 15 years
with impending respiratory failure. Similar results
were observed by Wheeler et al26 in a more recent
trial, which also showed decreased length of stay
and incidence of adverse events with aminophylline
compared with terbutaline. A Cochrane review27
failed to show a decrease in symptoms, number of
nebulization treatments, or length of stay (LOS) with
aminophylline. However, that review also showed
that the addition of aminophylline to standard therapy
with β2-agonist and corticosteroids significantly
improved FEV1 after 6 to 8 hours and peak expiratory
flow rate at 12 to 18 hours. Although aminophylline
was well tolerated, the treatment group had a
significantly increased incidence of vomiting. An
expert panel commissioned by the National Asthma
Vol. 2; No. 2; April - June 2015
Antibiotics
Asthma is a mechanical event, triggered by the
hypersensitivity of the musculature in the bronchial
wall. It has been proposed that infections may
exacerbate such acute episodes. There are strong
arguments in favor of an association between atypical
bacteria (Mycoplasma or Chlamydia) and asthma in
school-aged children33, which has generated interest
in the use of azithromycin in acute asthma episodes.
The anti-inflammatory properties of azithromycin are
also believed to help control asthma exacerbations34.
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Management of Status Asthmaticus in the Pediatric Intensive Care Unit: Review of Literature
its effect. In a hyperinflated chest, CPT may be
harmful by increasing the risk of pneumothorax. The
only instance in which it may be helpful is in small
children with clear segmental or lobar atelectasis. The
argument can be made that CPT is helpful in infants
with bronchiolitis, but evidence for its utility in
bronchiolitis is not very strong. In fact, a recent metaanalysis of 3 RCTs found no benefit of using CPT
with vibration or percussion techniques in children
younger than 24 months38. A small percentage of
patients with asthma on MV may require and can
benefit from selective suction of mucus plugs/casts
or thick secretions by bronchoscopy39. For most
exacerbations, chest physiotherapy is not beneficial
and is unnecessarily stressful for the breathless
asthma patient28.
Chest physical therapy is not generally recommended.
There are no large studies documenting the efficacy
of azithromycin in children, but some evidence in
the adult literature supports the efficacy of macrolide
antibiotics. In an RCT in 278 adults with asthma34,
patients randomly assigned to receive telithromycin
within 24 hours of an acute exacerbation had a
significantly greater decrease in asthma symptoms
than patients assigned to receive placebo. This study
also showed that identification of M pneumonia
and C pneumonia by polymerase chain reaction in
asthmatic patients best identifies the macrolideresponsive phenotype. Similar use of amoxicillin in
an RCT among adult patients with asthma did not
show a beneficial effect 35.
The decision to start antibiotics for comorbid
conditions based on the intensivists judgment.
Ketamine
Ketamine is a synthetic derivative of phencyclidine
and is often recommended as the induction agent
of choice for the asthma patient because of its
bronchodilatory properties and sedative effects.
Ketamine has been administered as a continuous
infusion for sedation in patients receiving invasive or
noninvasive positive pressure ventilation for asthma.
It is also used to break refractory bronchospasm in
intubated patients. Some prospective trials and case
reports suggest that it may be a useful adjuvant
to standard therapy in children with impending
respiratory failure36. In a prospective observational
study in the emergency department, Petrillo and
colleagues37 administered ketamine as an infusion
to 10 nonintubated patients who were unresponsive
to standard therapy for asthma. They showed a
significant improvement in asthma scores and oxygen
saturations.
Ketamine is used for, a) Induction for intubation, b)
Sedation for intubated asthmatics, c) Light sedation
for small children who do not tolerate CPAP/BiPAP.
Oxygen
All patients with asthma have ventilation-perfusion
ratio mismatch and require some supplemental
oxygen. It is important to remember that albuterol
induces bronchodilation and, as a result, decreases
hypoxic vasoconstriction and worsens hypoxemia,
therefore increasing ventilation-perfusion ratio
mismatch. Because of the potential for hypoxia, the
recommended driving gas for albuterol nebulization
is oxygen. In a randomized crossover study that
included 27 episodes of acute asthma exacerbation,
the effect of oxygen as a driving gas was noted to be
transient40. In adult patients with chronic obstructive
pulmonary disease, there is a concern for suppression
of hypoxic respiratory drive with supplemental
oxygen; this phenomenon is not seen in otherwise
healthy children with asthma. In adult patients with
asthma, 100% oxygen administration has also been
found to adversely affect gas exchange. In a trial of
37 adult patients with asthma, Chien et al41 observed
an increase in PaCO2 between 1 and 10 mm Hg within
25 minutes of 100% oxygen administration. No such
trial has been conducted in pediatric patients.
Utilized as needed to maintain saturations above
90% and less than 98%.
Chest Physiotherapy and Airway Clearance
Chest physiotherapy (CPT) can theoretically augment
airway clearance and encourage resolution of mucus
plugging. Some clinicians recommend CPT for
asthma, although no clinical studies have evaluated
Vol. 2; No. 2; April - June 2015
Fluids
Most asthmatic children are dehydrated at initial
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Management of Status Asthmaticus in the Pediatric Intensive Care Unit: Review of Literature
been associated with a greater likelihood of hospital
admission in children aged 6 years or older46.
If not obtained in the E.D, all asthmatics requiring
admission to the PICU should have a CXR acquired
to assess for pneumothorax, pneumomediastinum,
pneumonia, or atelectasis.
evaluation (poor fluid intake, vomiting, increased
insensible fluid losses from the respiratory tract).
Dehydration produces thicker, more tenacious
bronchial secretions, thereby leading to worsening
bronchial mucus plugging. Fluid replacement and
maintenance of euvolemic state are necessary to
minimize thickening of secretions. It is common for
children admitted for severe asthma to receive fluid
boluses and to be started on maintenance IV fluids.
However, caution is advised regarding fluid therapy
in asthmatic patients because of the risk of SIADH
(syndrome of inappropriate antidiuretic hormone)
and consequent hyponatremia and fluid overload42.
SA is associated with high negative transpulmonary
pressures; this facilitates fluid accumulation around
respiratory bronchioles and thus leads to pulmonary
edema and decreased respiratory status43. No studies
have evaluated a conservative vs liberal fluid strategy
in the management of asthma. Corrections of fluid
status should be guided by serial assessment of urine
output, urine specific gravity, mucus membrane
moisture, and serum electrolytes.
Intravenous fluids (0.45 NS) should be given at a
rate to ensure an acceptable fluid status in children
who are not able to tolerate oral rehydration. Serum
electrolytes should be obtained on admission.
Noninvasive Ventilation
The presence of air trapping in acute asthma
exacerbation leads to auto–positive end expiratory
pressure, which requires the patient to generate
higher negative inspiratory pressures to overcome
it. The use of continuous positive airway pressure
allows for equilibration of pressure between the
mouth and alveoli and can facilitate better gas
exchange and decreased work of breathing. The
use of noninvasive ventilation (NIV)—continuous
positive airway pressure and biphasic positive
airway pressure (BiPAP)—has gained acceptance in
managing difficult-to-control asthma, especially as
a temporalizing measure while awaiting therapeutic
benefit of pharmacotherapy. The safety and efficacy
of BiPAP in asthma has been demonstrated by
many retrospective studies in the PICU47 and in the
emergency department48-50. Thrill et al51 conducted
a prospective study with a crossover design in 20
children. They placed children on BiPAP for 2 hours,
followed by conventional treatment for 2 hours, or
vice versa. They found significant decreases in both
respiratory rate and clinical asthma score at the end
of the 2 hours on BiPAP. A 2012 prospective RCT
that randomly assigned 20 patients to either NIV or
standard therapy showed significant improvement in
clinical asthma scores at 2 hours, 4 to 8 hours, 12
to 16 hours, and 24 hours after initiation of BiPAP
(P< .01)52. No major adverse events related to NIV
occurred.
Commonly used as a second line agent for children
who can tolerate. May need to use sedation (ketamine
or dexmedetomidine).
Chest Radiography
Chest radiography (CXR) is frequently performed
for children with asthma exacerbation. Children
with persistent hypoxemia despite therapy are at
higher risk for abnormalities on CXR. Tsai et al44
prospectively compared CXR findings in hypoxemic
vs nonhypoxemic children aged 1 to 17 years.
They found both small and large lung volumes,
extravascular fluid, and atelectasis to be more common
in radiographs from hypoxemic asthmatic patients.
However, they found no correlation between CXR
findings and duration of hypoxemia, hospital stay,
or PICU admission. Significant findings on CXR are
relatively rare, as shown by Brooks et al45, who found
significant abnormalities in only 7 of 128 children
with acute asthma. The CXR findings commonly
observed are lung hyperinflation, hypoinflation, or
atelectasis. Lung hypoinflation is considered a sign
of respiratory fatigue and poor prognosis and has
Vol. 2; No. 2; April - June 2015
Invasive Mechanical Ventilation
The indications to intubate patients with asthma
include hypoxemia despite high concentration of
oxygen on NIV, severely increased work of breathing,
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Management of Status Asthmaticus in the Pediatric Intensive Care Unit: Review of Literature
group at lower airway and intrathoracic pressures
than those receiving standard MV. If obstacles to
clinical implementation of TGI can be overcome, it
may lead to the development of commercial systems
with widespread TGI application.
Not routinely used.
altered mental state, or cardiac arrest. Hypercarbia
alone is not an indication for intubation, although
progressively increasing PaCO2 despite maximal
therapy warrants intubation53. Managing asthma in
children on MV is very challenging. Despite decades
of experience, an optimal strategy has not been
established. In 1984, Darioli and Perett54 introduced
the concept of permissive hypercarbia in adult
asthma and showed that an MV protocol to manage
hypoxemia, without attempting to restore adequate
alveolar ventilation, is safe. In addition, the risks
of barotrauma and circulatory failure, which are
frequently reported as fatal complications, appear
to be significantly decreased with this strategy.
Successful management of asthma with PaCO2
up to 269 mm Hg has been described55. Trials of
different modes of MV in the pediatric population
are scarce. To ensure minute ventilation, volume
control ventilation is considered standard. Sarnaik
and colleagues56, however, published a retrospective
review of 40 children who were successfully
ventilated with a pressure-control mode using an
inspiratory-to-expiratory time ratio of 1:4 with the
pressure adjusted to target an exhaled tidal volume
of 10 to 12 mL/kg. The pressure-control mode can
be a safe and effective mode of MV in acute asthma.
Intubation is avoided if possible.
No one mode has been shown to be better than the
other. Ventilator settings (PEEP, I:E ratio, Rate and
Tidal volume) need fine adjustment to meet individual
patient requirements. Permissive hypercapnia
practiced if pH can be maintained above 7.2.
Anesthetic Gases
Inhalational anesthetics (halothane, isoflurane, and
sevoflurane) are potent bronchodilators. Although
the mechanism of action of inhalational anesthetics is
unknown, their use in animal models and case reports
of patients with respiratory acidosis has resulted in
improved ventilation. Practical limitations to the
use of inhalational anesthetics include the abrupt
return of bronchoconstriction after discontinuation
and the need for delivery via an anesthesia machine,
with proper scavenging of the anesthetic gases.
Nevertheless, their use has been tried as a rescue
maneuver in children with acute severe asthma
exacerbation with persistent ventilatory failure
despite appropriate MV and aggressive medical
therapy. The largest pediatric case series on the use
of isoflurane for SA reported on 6 children aged 14
months to 15 years in whom conventional treatments
had failed58. A standard protocol was used for
management in all patients (initiation with 1%-2%
isoflurane, increased by 0.1% every 15 minutes until
therapeutic effect), which resulted in statistically
significant improvements in PaCO2, peak inspiratory
pressure, and pH. All 6 patients were successfully
treated and discharged from the hospital without
sequela.
Utilized in refractory conditions. Anesthesia machine
needs to be brought in the PICU and managed in
conjunction with the anesthesia.
Tracheal Gas Insufflation
Tracheal gas insufflation (TGI) as an adjuvant to
MV delivers fresh gas into the central airways
continuously or in a phasic manner to improve
efficiency of alveolar ventilation or to minimize
ventilator pressure requirements. Recently, TGI has
received attention as an ideal lung-protective strategy
for MV. Human studies on TGI are lacking, although
animal experiments are promising. Eckmann57, in
2000, published a prospective trial on the use of chest
wall vibration along with TGI during experimental
bronchoconstriction in 6 anesthetized dogs. He
showed that gas exchange was achieved in the TGI
Vol. 2; No. 2; April - June 2015
High-Frequency Oscillatory Ventilation
High-frequency oscillatory ventilation is an accepted
management technique for pediatric respiratory
failure. It is generally contraindicated in obstructive
airway disease, however, because of the risk of air
trapping. As opposed to conventional ventilation,
high-frequency oscillatory ventilation has an active
expiratory phase, which may account for reports
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extracorporeal support for refractory hypercapnia.
of its successful use in children with asthma59. It is
essential to apply sufficient mean airway pressure to
open and stent the airways and to use lower frequency
to overcome the greater attenuation of the oscillatory
waves in the narrowed airways. As in conventional
ventilation, permissive hypercapnia is a desirable
strategy.
Reserved for refractory cases who may not be suitable
candidates for extra corporial support.
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Despite an elaborate arsenal available, management
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Excellent best practice recommendations have been
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Acute Bronchiolitis: A Review
Anand Bhutada *, Satish Deopujari **, Yusuf Parvez***
Pediatric & Neonatal Intensivist *, Senior Consultant Pediatrician **, Pediatric Intensivist***, Central India’s Child
Hospital & Research Centre, Dhantoli, Nagpur; Specialists Pediatrics, Dubai Hospital, Dubai
ABSTRACT
Acute bronchiolitis is the most common lower respiratory tract infection (LRTI) in infants and children
less than two years of age. It is broadly defined as a clinical syndrome characterized by upper respiratory
symptoms followed by lower respiratory infection and inflammation, resulting in wheeze and crackles.
Supportive care with focus on oxygenation and hydration remains the main stay of therapy. Several recent
evidence-based reviews reveal that bronchodilators or corticosteroids should not be routinely used in
bronchiolitis. This review presents the current status of recent therapies such as nebulized hypertonic saline,
heliox, continuous positive airway pressure (CPAP), montelukast, surfactant, and inhaled furosemide, etc.
Key words- Acute bronchiolitis, hypertonic saline, heliox, CPAP
Risk factors for bronchiolitis are male gender,
prematurity, young age, being born in relation
to the RSV season, preexisting disease such as
bronchodysplasia, underlying chronic lung disease,
neuromuscular disease, congenital heart disease,
exposure to environmental tobacco smoke, high
parity, young maternal age, short duration/no breast
feeding, maternal asthma and poor socioeconomic
status.6-8 These are also risk factors for more severe
form of bronchioloitis. Some specific genetic
polymorphisms are also known to be risk factors for
more severe disease.9
Introduction
Bronchiolitis is the most common cause of
hospitalization due to acute lower respiratory
tract infection in infants. A substantial proportion
of children will experience at least one episode
with bronchiolitis, and as much as 2-3% of all
children will be hospitalized with bronchiolitis
during their first year of life. There is a trend
towards increasing incidence of bronchiolitis in
recent years. Bronchiolitis is generally seasonal
appearing most commonly as epidemics during
winter. In India, outbreaks occur from September to
March.1-3 Bronchiolitis is a disease with high
morbidity, but low mortality. Death from respiratory
failure in bronchiolitis is rare and range from 2.9 (UK)
to 5.3 (USA) deaths per 100 000 children below 12
months of age. In UK mortality rate for bronchiolitis
in children below 12 months has declined from
21.5 to 1.8 per 100000 children from 1979 to
2000 reflecting improvement in pediatric intensive
care.4, 5 However, considerably higher mortality rates
have been observed for children with cardiopulmonary
abnormalities and in immunosuppressed patients.
Etiology
Broncholitis is caused by various viruses. Respiratory
syncitial virus (RSV) is the most common
(60-70% in less than 1 year) followed by Rhinovirus
(14-30%), human bocavirus (14–15%), human
metapneumovirus (3-12%), entero-, adeno-, corona
and influenza viruses (1–8%). Dual infections are
reported in 20–30% of children.6, 10-12
Pathology
Pathologic changes in lungs include detachment and
necrosis of epithelium, airway wall edema, infiltration
of airway wall and of the interstitium with leucocytes
(predominantly macrophages and lymphocytes), and
Correspondence:
Dr. Satish Deopujari
Shree Child Clinics, Near Suretech Hospital, Dhantoli,
Nagpur- 440012
Email: [email protected]
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JOURNAL OF PEDIATRIC CRITICAL CARE
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Acute Bronchiolitis: A Review
plugging of airway with mucus and cellular debris.
The complete and partial plugging of airways leads to
localized atelectasis and overdistension respectively.
There is no evidence of smooth muscle hypertrophy
in bronchiolitis.13, 14
Table 1: Bronchiolitis scoring system
Immunology
Passively acquired maternal immunoglobulins
protect newborn from RSV infection during first two
months of life. The immunoglobulin levels gradually
decrease, leaving most infants unprotected against
RSV. Epithelial cells and alveolar macrophages
activate cellular immunity by releasing multiple
chemical substances including interleukins (IL1,6,8),
TNF alpha, MIP 1alpha, RANTES. Children are
more likely to wheeze or develop asthma, if RSV
infection induces peripheral blood eosinophilia.15
1-mild
2-moderate
3- severe
RR
<40
40-50
50-60
>60
Color O2
sat in RA
Capillary
refill
Normal Normal
>97 <2 94-96 <2
sec
sec
Normal 90- Dusky / mottled
93 Normal <90 Normal on
on O2 @1L O2@ >1L
Retractions/
Work of
breathing
None
Subcostal
Supraclavicular
Intercostals
Sternal
& subcostal
Paradoxical
when quite
respiration
Clear
Good air
entry
End exp
wheeze +
rales
Fair air
entry
Inspiratory
&
expiratory
wheeze +
rales
Air entry
Wheezing
Level of
Alert
conciousness
Clinical Features
Children with bronchiolitis typically present with an
acute viral upper respiratory prodrome comprising
of rhinorrhea, cough, and on occasion, a low grade
fever. Within 1-2 days of these prodromal symptoms,
the cough worsens and child may also develop
rapid respiration, chest retractions, and wheezing.
The infant may show irritability, poor feeding, and
vomiting. Though, in majority of the cases, the
disease remains mild and recovery starts in 3-5 days,
some of these children may continue to worsen.
On examination, most children have tachycardia
and tachypnea. Pulse oximetry helps us in deciding
about the need for supplemental oxygen. The chest
may appear hyper-expanded and may be hyper
resonant to percussion. Wheezes and fine crackles
may be heard throughout the lungs. Severe cases
may have grunting, marked retractions, cyanosis,
impaired perfusion and apnea. Examination should
include assessment for hydration status (respiratory
distress often prevents adequate oral fluid intake and
causes dehydration) and co morbidities (chronic lung
disease, congenital heart disease, immunosuppressed
states).14, 16
Vol. 2; No. 2; April - June 2015
0
normal
Restless
Mild
when
irritability
disturbed
Poor
Grunting,
Inspiratory
& expiratory
wheeze + rales
Lethargic/ hard
to arouse
Differential Diagnosis
Bronchiolitis is so common over the winter months that
it can be easy to forget that there are other diagnostic
possibilities of respiratory failure in infants. The
differential diagnosis includes bronchopneumonia,
foreign body, gastroesophageal reflux, congenital
heart diseases (Total anomalous pulmonary venous
connection), cystic fibrosis, immunodeficiency etc.
Table 2: Predictors of severe bronchiolitis17
A. Host Related Risk Factors
• Prematurity
• Low birth weight
• Age less than 6 to 12 weeks
• Chronic pulmonary disease
• Hemodynamically significant congenital
heart disease (eg, moderate to severe
pulmonary hypertension, cyanotic heart
disease, or congenital heart disease that
requires medication to control heart failure)
• Immunodeficiency
B. Environmental Risk Factors
• Having older siblings
• Passive smoke
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Acute Bronchiolitis: A Review
Clinician should carefully asses ability of child to
accept orally and small frequent feeds should be
encouraged. Orogastic or nasogastric tube feeding
is an alternative to oral feeds. IV fluids should be
given to those with severe illness13. A close watch is
warranted as these kids are prone for Syndrome of
inappropriate antidiuretic hormone16-22. Nasal block
can be relieved by frequent instillation of saline
drops in nostrils and gentle suctioning23. A prone
position may improve oxygenation and is suggested
for infants if they are carefully observed13, 24.
Humidified oxygen should be administered to
hypoxemic infants by any technique familiar to the
nursing personnel (nasal cannula, face mask, or
head box). Pulse oximetry is the most commonly
used tool to decide about oxygen supplementation.
Supplemental oxygen is indicated if SpO2 falls
persistently below 90% in previously healthy infants.
Oxygen may be discontinued if SpO2 is at or above
90% and the infant is feeding well and has minimal
respiratory distress16.
In severe bronchiolitis early intervention in the
form of CPAP has been used to prevent mechanical
ventilation. CPAP helps in recruitment of collapsed
alveoli by opening terminal bronchioles. Airway
resistance in terminal airways is reduced with CPAP
and also there is decreased air trapping, hyperinflation
and work of breathing. However routine use of CPAP
in bronchiolitis requires further studies25.
In a prospective cohort study done in children
admitted with RSV LRTI, approximately 9% of
patients required mechanical ventilation. Indications
for intubation and mechanical ventilation are
worsening respiratory distress (hypoxemia despite
oxygen supplementation), listlessness, poor
perfusion, apnea, bradycardia, or hypercarbia26.
• Household crowding
• Child care attendance
C. Clinical Predictors
• Toxic or ill appearance
• Oxygen saturation <95 percent by pulse
oximetry while breathing room air
• Respiratory rate ≥70 breaths per minute
• Moderate/Severe chest retractions
• Atelectasis on chest radiograph
Investigations
The diagnosis of bronchiolitis and the assessment
of disease severity should be based on history and
physical examination. Chest X ray is not a routine,
but when indicated usually reveals hyperinflation,
peribronchial thickening and patchy atelectasis. The
indications for chest X ray are when the diagnosis
is in doubt, co-morbidity like chronic lung disease
or heart disease is suspected, or if the child is
severely ill. Similarly, routine laboratory tests are
not required16. Arterial blood gas may be required
in few kids at risk for respiratory failure for CO2
monitoring. Measurement of lactate dehydrogenase
(LDH) concentration in the nasal-wash fluid has been
proposed as an objective indicator of bronchiolitis
severity; increased values (suggestive of a robust
antiviral response) have been shown to be associated
with decreased risk of hospitalization18. Virological
studies may not help in treatment or outcome as
most viruses present similarly. But positive result
can avoid unnecessary antibiotic use in hospital
setting. The available tools for etiologic diagnosis
include Antigen detection, Immunofluorescence,
Polymerase Chain Reaction (PCR), and culture of
respiratory secretions obtained by nasal wash or nasal
aspirate (19-21).
Inhaled Saline
Inhaled normal saline (0.9%) is commonly used for
children with bronchiolitis to increase clearing of
mucous. Inhaled hypertonic saline (3%) has shown
to increase mucociliary clearance possibly through
induction of an osmotic flow of water to the mucus
layer and by breaking ionic bonds within the mucus
gel. Recent metaanalyses including more than
1000 infants with mild to moderate bronchiolitis
Therapy
Acute bronchiolitis is mostly a mild and self limiting
disease which can be managed on outpatient basis
with supportive care, adequate feeding and parental
education.
Children with bronchiolitis are at an increased risk of
dehydration because of their increased needs (related
to fever and tachypnea) and reduced oral acceptance.
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Acute Bronchiolitis: A Review
history of atopy or asthma; if present, salbutamol
inhalation may be given. In absence of it, a trial of
epinephrine inhalation may be given. Further doses
of either medication may be continued only on
documentation of improvement. There is no role of
oral bronchodilators34.
concluded that the use of hypertonic saline (3-5%)
may reduce the length of hospital stay and the rate
of hospitalization. However, due to the possible
side effect of bronchospasm, all but few patients
received a combination with a bronchodilator13, 2729
. A Cochrane review of seven trials involving
581 infants (282 inpatients, 65 outpatients and
234 emergency department patients) with acute
bronchiolitis found that nebulisation with 3% saline
results in a significantly shorter length of hospital
stay as well as a lower clinical score as compared to
nebulisation with 0.9% saline30. A recent randomized
controlled trial reported that high volume normal
saline was as effective as 3% saline in children
with mild bronchiolitis31. Its routine use cannot be
recommended till one gets an answer regarding its
optimal volume, concentration of saline, frequency
of administration and effective device.
Steroids
There is no evidence for use of inhaled corticosteroids
(ICS) to prevent or reduce postbronchiolitis
wheezing after RSV bronchiolitis. A systematic
review of 5 studies involving 374 infants did not
demonstrate an effect of ICS, given during the acute
phase of bronchiolitis, in the prevention of recurrent
wheezing following bronchiolitis35. An additional
RCT involving 243 infants with RSV-related LRTI
did not find any effect of inhaled corticosteroids on
recurrent wheeze36.
A meta-analysis evaluating the use of systemic
glucocorticoids (oral, intramuscular, or intravenous)
and inhaled glucocorticoids for acute bronchiolitis in
children (0 to 24 months of age) included 17 trials
with 2596 patients. In pooled analyses, no significant
differences were found in hospital admission rate,
length of stay, clinical score after 12 hours, or
hospital readmission rate37. Another meta-analysis
(of 3 studies) studied the role of systemic steroids in
critically ill children with bronchiolitis It was found
that systemic corticosteroid showed no overall effect
on duration of mechanical ventilation38. Hence, it is
recommended not to use glucocorticoids in healthy
infants and young children with a first episode of
bronchiolitis.
In a multicentre trial, there was a reduction in
hospitalization rates in the group that received
dexamethasone and 2 doses of epinephrine by
nebulizer as compared with those who were treated
with placebo (17.1% vs 26.4%). Number needed to
prevent one admission was 139. This study suggests
a possible synergy between epinephrine and steroids
but need further evaluation to include in any
guidelines.
Bronchodilators
Routine use of inhaled bronchodilators in
management of bronchiolitis is questionable. In
a meta-analysis of 28 trials (1912 participants)
comparing bronchodilators other than epinephrine
(included salbutamol, terbutaline, ipratopium) with
placebo, there were no significant differences in
improvement in oxygenation, hospitalization rate, or
duration of hospitalization. A modest improvement in
clinical scores was noted in the treated outpatients32.
Another meta-analysis of 19 trials (2256 participants)
compared nebulized epinephrine with placebo or
other bronchodilators33. Epinephrine versus placebo
among outpatients showed a significant reduction in
admissions at Day 1 but not at Day 7 postemergency
department visit. Epinephrine versus salbutamol
showed no differences among outpatients for
admissions at Day 1 or 7. Although epinephrine was
associated with decreased length of stay compared
with salbutamol, epinephrine did not decrease length
of stay when compared with placebo.
It is difficult to distinguish bronchiolitis from viral
infection associated wheezing or asthma. In the
latter condition, broncho-dilators may improve
clinical outcome. Therefore, we consider a trial of
bronchodilator with careful monitoring. Choice of
bronchodilator may be based on personal or family
Vol. 2; No. 2; April - June 2015
Antibiotics
Routine use of antibiotics is not recommended in
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Acute Bronchiolitis: A Review
obstruction including acute bronchiolitis by
decreasing airway turbulence. A meta-analysis of
four clinical trials (84 participants), using heliox
demonstrated improved respiratory distress scores in
first hour in children with moderate to severe acute
bronchiolitis. However, heliox inhalation did not
affect need for intubation and mechanical ventilation
and length of stay in pediatric intensive care unit49.
Present heterogeneity of various available studies
suggests a need to evaluate its role further.
acute bronchiolitis as it will increase the cost of
treatment, and lead to adverse reactions as well as
development of bacterial resistance. Its use should
be restricted to specific population with concurrent
bacterial infection16, 40. Clinical setting in presence
of consolidation (not just atelectasis or infiltrates)
on X ray may indicate bacterial infection in acute
bronchiolitis.
Antivirals
A systematic review of 10 RCTs (320 participants)
reported no improvement in clinical outcome
of acute bronchiolitis after ribavirin use(16).
Ribavirin may be considered in high risk infants
(immunocompromised and/or hemodynamically
significant cardiopulmonary disease) and in
infants requiring mechanical ventilation16, 38. Role
of fusion inhibitors (TMC353121, CL387626,
RFI-641, JNJ-2408068 etc)41, 42 and leflunomide
(immunosuppressant with antiviral activity against
RSV) is under trial43.
Surfactant
A meta-analysis (included three RCTs with total
79 participants) evaluated the effect of exogenous
surfactant in infants and children with bronchiolitis
requiring mechanical ventilation. The duration of
mechanical ventilation and duration of ICU stay were
significantly lower in the surfactant group compared
to the control group. Use of surfactant had favorable
effects on oxygenation and CO2 elimination. No
adverse effects and no complications were observed50.
Current evidence suggests that surfactant therapy
may have potential use in acute severe bronchiolitis
requiring mechanical ventilation.
Inhaled Furosemide
Furosemide inhalation in acute bronchiolitis may
improve outcome by acting on airway smooth muscle,
airway vessels, electrolytes and fluid transport
across respiratory mucosa, and reducing airway
inflammation. One RCT (32 participants) studied the
effect of inhaled furosemide in hospitalized infants
with bronchiolitis, and recorded no significant
clinical effects in these infants44. Presently there is
no evidence for use of inhaled furosemide in the
management of bronchiolitis.
Prevention
It is important to avoid nosocomial spread of RSV
and other respiratory viruses from children with
bronchiolitis. RSV can survive up to seven hours on
surfaces and is transmitted directly or indirectly by
touch. Air sampling in subjects infected with RSV
has detected RSV RNA up to 700 cm from head of
the patient’s bed51, 52. General measures like hand
decontamination and barrier nursing are important to
prevent nosocomial infections16, 51
Passive immunoprophylaxis using polyclonal or
monoclonal antibodies to high risk infants before RSV
season has been documented to reduce admission
rates in these infants with acute bronchiolitis. The
potential disadvantages associated with polyclonal
antibodies include need for intravenous access; risk
of transmission of blood-borne infections, possible
interference with antibody response to routine
immunization specifically live vaccines53, 54.
Palivizumab is a humanized mouse IgG1 monoclonal
Leukotriene Receptor Antagonists (Montelukast)
Montelukast is currently not recommended for
treatment of bronchiolitis or for prevention of airway
reactivity after bronchiolitis as most RCTs had
conflicting results45-48.
Heliox
Heliox (mixture of helium and oxygen) may reduce
work of breathing and improve oxygenation in
respiratory illness with moderate to severe airway
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antibody directed against site A and F glycoprotein
of RSV. Palivizumab blocks the fusion of the
virus to the host epithelial cells. It reduces RSV
infection associated hospitalization in high risk
infants but does not reduce mortality rates16. Present
recommendations for use of palivizumab54 are
1.Children younger than 24 months of age with
chronic lung disease (CLD) of prematurity who
have required medical therapy for CLD within 6
months before the start of the RSV season.
2.Infants born at 28 weeks of gestation or earlier
who are younger than 12 months of age at the start
of the RSV season.
3. Infants born at 29 to 32 weeks of gestation who
are younger than 6 months of age at the start of the
RSV season.
4. Infants born between 32 and 35 weeks of gestation,
who are younger than 6 months of age at the
start of the RSV season and have 2 or more of
the following risk factors: child care attendance,
school-aged siblings, exposure to environmental
air pollutants, congenital abnormalities of the
airways, or severe neuromuscular disease.
Palivizumab is administered intramuscularly at a
dose of 15 mg/kg monthly (every 30 days) during
the RSV season. A maximum of 5 doses is generally
sufficient prophylaxis during one season55. Other
monoclonal antibody (mAb) variants derived from
palivizumab are being evaluated in clinical trials
for immunoprophylaxis includes Motavizumab, a
second-generation mAb, and Numax- YTE, a thirdgeneration mAb53.
In summary, bronchiolitis remains the most common
cause of hospitalization in infants especially in
winter. Although, it is mostly self-limiting requiring
only supportive treatment, in selected high risk cases
judicious use of newer therapies may be beneficial.
Further robust clinical studies are necessary
especially to reduce the hospital burden and save
lives from severe form of bronchiolitis.
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S. Paulo, 50(1): 37-40, 2008.
22.van Steensel-Moll HA, Hazelzet JA, van der Voort E, Neijens
HJ, Hackeng WH. Excessive secretion of antidiuretic
hormone in infections with respiratory syncytial virus. Arch
Dis Child. 1990;65:1237-9.
23.Steiner RWP. Treating acute bronchiolitis associated with
RSV. Am Family Physician. 2004;69:325-30.
24.Gillies D, Wells D, Bhandari AP: Positioning for acute respiratory distress in hospitalised infants and children. Cochrane
Database Syst Rev 2012, 7, CD003645.
25.Donlan M, Fontela PS, Puligandla PS. Use of continuous
positive airway pressure (CPAP) in acute viral bronchiolitis:
A systematic review. Pediatr Pulmonol. 2011;46:736-46
26.Wang EE, Law BJ, Stephens D. Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) prospective study of risk factors and outcomes in patients hospitalized with respiratory syncytial viral lower respiratory tract
infection. J Pediatr. 1995;126:212-9.
27.Mandelberg A, Amirav I: Hypertonic saline or high volume
normal saline for viral bronchiolitis: mechanisms and rationale. Pediatr Pulmonol 2010, 45:36–40.
28.Zhang L, Mendoza-Sassi RA, Wainwright C, Klassen TP:
Nebulised hypertonic saline solution for acute bronchiolitis
in infants. Cochrane Database Syst Rev 2013, 7, CD006458.
29.Chen YJ, Lee WL, Wang CM, Chou HH: Nebulized hypertonic saline treatment reduces both rate and duration of
hospitalization for acute bronchiolitis in infants: an updated
meta-analysis. Pediatr Neonatol 2014. doi: 10.1016/j.pedneo.2013.09.013.
30.Zhang L, Mendoza-Sassi RA, Wainwright C, Klassen TP.
Nebulized hypertonic saline solution for acute bronchiolitis
in infants. Cochrane Database Syst Rev. 2008;4:CD006458.
54. Luo Z, Liu E, Luo J, Li S, Zeng F, Yang X, et al.
31.Nebulized hypertonic saline/salbutamol solution treatment
in hospitalized children with mild to moderate bronchiolitis.
Pediatr Int. 2010;52:199-202.
32.Gadomski AM, Brower M. Bronchodilators for bronchiolitis.
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2010;156:749-54.
48.Bisgaard H, Flores-Nunez A, Goh A, Azimi P, Halkas A,
Malice MP, et al. Study of montelukast for the treatment
of respiratory symptoms of post-respiratory syncytial virus bronchiolitis in children. Am J Respir Crit Care Med.
2008;178:854-60.
49.Liet JM, Ducruet T, Gupta V, Cambonie G. Heliox inhalation
therapy for bronchiolitis in infants. Cochrane Database Syst
Rev. 2010;4:CD006915.
50.Jat KR, Chawla D. Surfactant therapy for bronchiolitis in critically ill infants. Cochrane Database Syst Rev.
2012;9:CD009194.
51.Harris JA, Huskins WC, Langley JM, Siegel JD, Pediatric
Special Interest Group of the Society for Healthcare Epidemiology of A: Health care epidemiology perspective on the
October 2006 recommendations of the Subcommittee on Diagnosis and Management of Bronchiolitis. Pediatrics 2007,
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120:890–892.
52.Hall CB, Douglas RG Jr, Geiman JM: Possible transmission
by fomites of respiratory syncytial virus. J Infect Dis 1980,
141:98–102.
53.Mejías A, Ramilo O. Review of palivizumab in the prophylaxis of respiratory syncytial virus (RSV) in high risk infants.
Biologics. 2008;2:433-9.
54.American Academy of Pediatrics. Red Book: 2006 Report of
the Committee on Infectious Diseases. 27th ed. Elk Grove
Village, IL: American Academy of Pediatrics; 2006.
55.American Academy of Pediatrics Committee on Infectious
Diseases and Committee on Fetus and Newborn. 2003. Revised indications for the use of palivizumab and respiratory
syncytial virus immune globulin intravenous for the prevention of respiratory syncytial virus infections. Pediatrics.
2003;112:1442-6.
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JOURNAL OF PEDIATRIC CRITICAL CARE
Review Article
Acute Encephalitis: Beyond Infection
Sangeetha Yoganathan*, Ebor Jacob James**
Assistant Professor*, Department of Neurological Sciences, Professor
Pediatric Intensive Care Unit**, Christian Medical College Vellore-
ABSTRACT
Acute encephalitis is one of the common neurological illnesses requiring admission of children in the
intensive care unit. In developing countries, acute encephalitic presentation in children often results from
various infections including viral, bacterial, fungal and protozoal. With the advent of better diagnostic
modalities and advances in critical care management, more cases of encephalitis beyond infection have
been identified. Autoimmune encephalitis, acute disseminated encephalomyelitis, vasculitis, paraneoplastic,
toxin mediated and metabolic disorders are the non-infectious causes that attribute for encephalitis and
encephalopathy in children. Early identification and treatment of these disorders can lead better neurological
outcome. In this review, the various common etiologies for non-infectious encephalitis, diagnosis and
management of these disorders are discussed briefly.
Key words- Acute, encephalitis, autoimmune, children, PICU, CNS infections, meningoencephalitis
Table 1: Diagnostic criteria for confirmed or probable and
possible encephalitis
Introduction
Acute encephalitis is a devastating neurological
syndrome in children with heterogeneous
etiologies. Depending on the site of neuroaxis
involvement, infection of the central nervous
system can result in meningitis, encephalitis,
rhombencephalitis, myelitis and radiculitis.
Encephalitis is a pathological diagnosis
which means an underlying inflammation of
brain parenchyma.1 However in most setting,
the diagnosis of inflammation is based not
on biopsy findings but based on the clinical
evidence of neurological dysfunction with
supportive laboratory and imaging findings.
Diagnostic criteria for patients with confirmed
or probable and possible encephalitis is given
in Table 1.2
Correspondence:
Dr. Ebor Jacob James
Professor
Pediatric ICU
Christian Medical College, Vellore-632004
E-mail: [email protected], [email protected]
Vol. 2; No. 2; April - June 2015
Major criteria
Minor criteria
Altered mental status
(decreased or altered level of
consciousness, lethargy or
personality change) lasting
≥24 h and no other causes
identified.
Time period more than
24 hours was selected to
exclude postictal state
1. Fever ≥38° C (100.4°F)
within the 72 h before or
after presentation
2. Generalized or partial
seizures with no preexisting epilepsy
3. Focal neurologic findings
which is of recent onset
4. CSF pleocytosis≥5 cells/
cu.mm
5. Neuroimaging preferably
MRI revealing new onset
changes compared to
previous imaging or acute
inflammation in brain
parenchyma
6.Electroencephalography
showing non specific
slowing or specific
patterns (periodic
lateralized epileptiform
discharges or periodic
complexes)
MRI- Magnetic resonance imaging, CSF- Cerebrospinal fluid
Presence of 2 criteria is required for possible diagnosis
and 3 or more is required for probable or confirmed
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Acute Encephalitis: Beyond Infection
diagnosis of encephalitis and encephalopathy of
presumed infectious or autoimmune etiology2.
decarboxylase; ANNA- Anti neuronal nuclear
antibody; PCA – Purkinje cell antibody
Epidemiology
Even after extensive evaluation, the etiology of
encephalitis was not established in more than half
of the cases.2 California encephalitis project had
analyzed the etiology of encephalitis in children and
young adults less than 30 years and it was identified
that autoimmune encephalitis had surpassed the
viral etiologies in this cohort.3 Acute disseminated
encephalomyelitis (ADEM) is the most common
immune mediated cause for encephalitis followed
by anti N methyl D aspartate receptor (NMDAR)
encephalitis. Encephalitis with autoimmune
association can be broadly categorized into 3 groups
namely paraneoplastic, non paraneoplastic and
central nervous system vasculitis which could be
primary or secondary due to an underlying systemic
autoimmune disease or systemic vasculitis. Causes
of immune mediated encephalitis are categorized and
summarized in Table 2.4
Immune Mediated Encephalitis
Acute disseminated encephalitis
Definition
International Pediatric multiple sclerosis study
group defined ADEM as “an acute or sub acute onset
clinical event with polysymptomatic presentation
and involvement of multifocal areas of CNS”.5
Manifestation of ADEM includes encephalopathy,
which may be either behavioral change or altered
level of consciousness with multifocal deficits.
Etiopathogenesis
ADEM is an immune mediated disorder of the CNS
affecting predominantly the white matter of brain
and spinal cord. It can also affect the cortical gray
matter, basal ganglia and thalamus. Histological
examination revealed infiltration of T cells and
macrophages around the venules with perivenular
inflammation and myelin disruption.6
Table 2:
Causes for immune mediated encephalitis or
encephalopathy
Paraneoplastic
or non
paraneoplastic
antibody
associated
Systemic vasculitis
Systemic
autoimmune
diseases
1.VGKC
(LG1,
CASPR2)
2.NMDAR
3. GAD 65
4.AMPAR
5.GABA B
6.ANNA-1
7.ANNA-2
8.ANNA-3
9.AGNA
10.PCA-2
11.Amphiphysin
12.Anti Ma
1.Polyarteritis
nodosa
2.Wegener
granulomatosis
3.Microscopic
polyangitis
4. Churg strauss
syndrome
5.Cryoglobulinemia
6. Takayasu arteritis
7. Giant cell arteritis
1. Systemic lupus
erythematosus
2.Anti
phospholipid
antibody
syndrome
3.Systemic
sclerosis
4.Behcets
disease
Clinical presentation
ADEM more commonly occurs in children than
adults and the mean age at presentation varies from
5 to 8 years.7 Clinical presentation sets in within 48
hours to 4 weeks of antigenic challenge following an
infection or vaccination. ADEM has been reported
to occur following viral (measles, mumps, rubella,
influenza, hepatitis A, hepatitis B, Epstein Barr
virus, herpes simplex virus, human herpes virus
6, dengue virus, human immunodeficiency virus,,
coxsackie B and coronavirus infection), bacterial
(streptococci, leptospirosis, salmonella, legionella),
mycoplasma and rickettsial infection or following
vaccination (Rabies neural, Hepatitis B, Diphtheria,
Pertussis, Tetanus, Japanese B encephalitis,
Measles and Influenza vaccines).6 In most cases,
an initial prodromal phase of fever, headache,
malaise and vomiting occurs followed by seizures,
encephalopathy, meningeal signs and/or focal
neurological deficits.
VGKC- Voltage gated potassium channel, NMDARN methyl D aspartate receptor, GAD- Glutamic acid
decarboxylase, AMPAR- alpha amino3-hydroxy-5methyl-4-isoxazolepropionic acid receptor; GABAGamma amino butyric acid; GAD- Glutamic acid
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Diagnostic evaluation
Diagnosis is based on the history, neurological
examination and neuroimaging findings. Magnetic
resonance imaging (MRI) brain and spinal cord with
gadolinium is used to describe the demyelinating
lesion and establish the diagnosis. MRI reveals
patchy, ill-defined multifocal areas of hyperintensities
involving white matter of cerebral hemispheres,
cerebellum, brainstem, spinal cord, thalami and basal
ganglia with usual sparing of corpus callosum. Post
contrast images can show enhancement in the pattern
of incomplete or complete ring, nodular, gyral or
spotty. Magnetic resonance spectroscopy (MRS) in
acute phase can show reduction of N acetyl aspartate
(NAA) and elevation of lactate.7 MRI brain and spine
findings in a child diagnosed with ADEM are shown
in figure 1. CSF analysis might show lymphoytic
pleocytosis with elevation of protein and oligoclonal
bands. Electroencephalography (EEG) may be
normal or can reveal non-specific findings, focal
or generalized slowing or epileptiform discharges.
Electrophysiological studies including nerve
conduction parameters, visual evoked potential and
somatosensory evoked potentials must be done to
look for other sites of neuroaxis involvement.
Fig. 1 B
Figure 1 B : MRI spine T2 saggital images showing hyperintense
signal changes from T3 to conus
How can viral encephalitis be differentiated from
ADEM ?
It is imperative to distinguish ADEM from acute
infectious encephalitis. While the diagnosis may
not be very clear initially, ADEM usually occurs
in children following infection or immunization
with a prodromal phase, encephalopathy and
multifocal neurological symptoms/signs involving
brain with or without spinal cord signs. Whereas
infectious encephalitis usually is preceded by fever
in most cases and manifest with altered sensorium,
seizures, pyramidal or extrapyramidal involvement.
CSF analysis in most cases of ADEM and viral
encephalitis show lymphocytic pleocytosis, elevated
protein and normal sugar; elevated oligoclonal bands
is found in ADEM and polymerase chain reaction for
viruses may be positive in viral encephalitis.
Treatment
Therapy includes administration of high dose
intravenous steroids after excluding underlying
infection,
intravenous
immunoglobulin
or
plasma exchange.7 Intravenous pulsing of
methylprednisolone 30 mg/kg for 5 days followed
by tapering schedule of oral steroids 1-2 mg/kg for
Fig. 1 A
Figure 1 A: MRI brain T2 FLAIR axial images showing
hyperintense signal changes involving bilateral posterior limb of
internal capsule
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Acute Encephalitis: Beyond Infection
4-6 weeks is commonly used in practice. In cases
of parainfectious ADEM or incomplete response
with steroids, intravenous immunoglobulin can
be used in the dosage of 2gm/kg over 5 days. If
there is no clinical response, 5-8 plasma exchanges
over 10 days is preferred. Need for specialized
equipment and trained personnel, central venous
access, risk of infection, need for multiple sessions,
thrombocytopenia related to heparin, anemia and
hypotension makes plasma exchange a less preferred
therapy as first choice. There are no randomized trials
comparing the efficacy of one therapy over another
in ADEM.
encephalopathies are onconeural antibodies directed
against the intracellular antigens or neuronal surface
antibodies. Onconeural neural antibodies such as
Hu, CV2, amphiphysin, Ri, Yo, Ma2, GAD are
often associated with tumors and neuronal surface
antibodies with or without tumor association include
VGKC, CASPR2, LGI1, NMDAR, AMPAR and
GABAB.4 Various antibody mediated encephalitis
and their clinical presentation are summarized in
Table 3.9
Table 3: Clinical presentation of various antibody associated
encephalitis
Outcome
Complete recovery has been reported in 60-90% of
patients with ADEM.7 Mortality has been reported as
high as 5%. Time period of recovery varies from 1-6
months. Although ADEM is a monophasic illness,
recurrences can occur. Recurrent ADEM refers to a
new demyelinating event occurring 3 months after
the initial attack or 4 weeks after completing steroid
therapy showing the same clinical presentation
and same areas of involvement in neuroimaging
as the initial event. Multiphasic ADEM refers to
involvement of new areas of the CNS on MRI and
neurologic examination. Neurocognitive deficits have
been observed among the survivors. In children less
than 5 years of age, ADEM can result in significant
intellectual and behavioral problems.8
Autoimmune encephalitis (AE)
VGKC- Voltage gated potassium channel antibody;
LGI1- Leucine rich glioma inactivated 1; CASPR2Contactin associated protein 2; AMPAR- a-amino3hydroxy-5-methyl-4-isoxazolepropionic
acid
receptor; GABA-Gamma amino butyric acid;
GAD- Glutamic acid decarboxylase; Gly R- Glycine
receptor; PERM-Progressive encephalomyelitis,
rigidity and myoclonus
Autoimmune encephalitis refers to group of disorders
with diverse immunological association and clinical
manifestations. Diagnosis is based on the clinical
course, serological evidence for autoimmunity and
ongoing intrathecal inflammation in the cerebrospinal
fluid. Antibodies associated with immune mediated
Vol. 2; No. 2; April - June 2015
Type of antibody
Clinical phenotype Clinical symptoms
VGKC complex:
LGI1 antibody
Limbic
encephalitis
Seizures, amnesia,
psychiatric
symptoms,
faciobrachial
dystonic seizures
VGKC complex:
CASPR2 antibody
Morvan syndrome
Amnesia, sleep
disturbances,
autonomic
dysfunction,
neuromyotonia,
myokymia
AMPAR antibody
Limbic
encephalitis
Seizures, amnesia,
prominent
psychiatric
symptoms
GABAB antibody
Limbic
encephalitis
Prominent
seizures, amnesia
and psychosis
GAD antibody
Limbic
encephalitis
Seizures of
temporal lobe
semiology
Cognitive decline
Gly R antibody
PERM
Encephalopathy.
Seizures,
rigidity, stiffness,
hyperekplexia
Hu antibody, Ma2
antibody, CV2
antibody
Limbic
encephalitis
Seizures,
psychosis, memory
disturbances
Ri antibody
Brainstem
encephalitis
Anti NMDAR (N methyl D aspartate receptor)
encephalitis
Etiopathogenesis
Antibodies are directed against the NR1 subunit of
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Acute Encephalitis: Beyond Infection
NMDA receptor which plays a vital role in synaptic
transmission and plasticity. This leads to antibody
mediated capping of NMDAR and internalization
of these receptors resulting in reduction of surface
density. Reduction of NMDA receptors affects the
dopaminergic, noradrenergic and cholinergic system
resulting in autonomic instability; inactivation of
gamma amino butyric acid (GABA) ergic neurons
resulting in activation of excitatory pathways
leading to psychosis, catatonia and dystonia
and affects pontomedullary network resulting in
hypoventilation.10
testing is mandatory for diagnosis if there is a delay
in diagnosis or the patient had been treated with
intravenous immunoglobulin or plasma exchange,
as antibodies might be absent in serum from these
patients. Histological examination of brain biopsy
specimen identified perivascular infiltration of B cells,
sparse parenchymal T-cell infiltrates, or microglial
activation in these patients. In children with anti
NMDAR encephalitis, extensive tumor surveillance
for ovarian teratoma and testicular tumors and
screening for tumor markers in blood such as CA125,
β-HCG, α-fetoprotein, or testosterone is essential to
plan the management. Tumor association has been
found in less than 10% of girls aged <14 years and
over 50% of girls aged>14 years.11
Clinical presentation
Anti NMADR encephalitis has multistage
presentation and a prodromal stage with fever,
headache, and vomiting and upper respiratory
symptoms are seen in 50% cases. Prodromal stage
is followed by clinical syndrome with insomnia,
speech disturbances, psychiatric symptoms such
as agitation, psychosis, hallucination, and seizures
may or may not occur. Later phase of this disease,
children develop extrapyramidal symptoms
(dystonia, choreoathetosis, stereotypies), respiratory
failure and dysautonomia.
Treatment
Concurrent
administration
of
intravenous
methylprednisolone 30 mg/kg for 5 days and
intravenous immunoglobulins 2gm/kg over 5 days or
plasma exchange is the recommended treatment if the
tumor surveillance is negative.10 If tumor is identified,
tumor removal plus above therapy is recommended.
In refractory cases, first dose of cyclophosphamide
500mg/m2 and weekly doses of rituximab 375mg/
m2 for 4 weeks is recommended. Follow up
tumor surveillance and immunosuppression with
azathioprine or mycophenolate is recommended in
refractory cases.
Diagnostic evaluation
MRI brain was found to be normal in 50% cases. T2 or
FLAIR signal hyperintensity involving hippocampi,
cerebellar or cerebral cortex, frontobasal and insular
regions, basal ganglia, brainstem, and spinal cord
have been reported in patients with anti NMDAR
encephalitis.10 Post contrast images might show
subtle contrast enhancement in the affected areas and
meninges. EEG findings are abnormal in most of the
cases. EEG abnormalities reported were non-specific
slowing, epileptiform discharges and electrographic
seizures. CSF abnormalities were documented in 80100% of patients with anti NMDAR encephalitis.
CSF might show moderate lymphocytic pleocytosis,
normal or mildly increased protein concentration,
and elevated CSF specific oligoclonal bands in two
thirds of patients.
Both serum and CSF testing of NMDAR antibodies
is ideal. However, presence of serum anti NMDAR
antibodies itself is sufficient for diagnosis. CSF
Vol. 2; No. 2; April - June 2015
Outcome
Three fourth patients recover completely or with mild
sequelae and remaining have significant morbidity or
mortality.10 During the process of recovery, symptoms
tend to occur in the inverse order. Residual cognitive,
motor deficits and relapses were reported in 25%.
Hashimotos encephalitis/encephalopathy (HE)
This controversial entity was first described by
Hakaru Hashimoto in 1912.12 It is a rare disorder
with an estimated prevalence of 2.1/100,000 subjects
and comprises a group of neurological symptoms
associated with elevated thyroid antibodies.13
Etiopathogenesis
It is not clear whether thyroid anti bodies (anti
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Acute Encephalitis: Beyond Infection
of children with HE. Treatment of choice is
intravenous pulsing of methylprednisolone 30 mg/
kg for 5 days followed by administration of oral
prednisolone for a variable period. In refractory
cases, intravenous immunoglobulin and plasma
exchange can be tried. In patients requiring long
term steroids, immunmodulation with azathioprine,
cyclophosphamide, rituximab and methotrexate have
also been tried.15,17,18,19,20
microsomal or anti thyroglobulin) itself attribute
towards the immune pathogenic mechanism or
thyroid antibodies are produced as an epiphenomenon
in patients with autoimmune encephalopathy.
Patients with autoimmune diseases such systemic
lupus erythematosus, Sjogren’s disease, myasthenia
gravis, anti NMDAR encephalitis and paraneoplastic
syndromes can have autoantibodies to thyroid
and presentation with neurological syndrome
(encephalopathy or encephalitis). Hence it is
suggested that Hashimotos encephalopathy can
be renamed as steroid-responsive encephalopathy
associated with autoimmune thyroiditis (SREAT).
Outcome
Response to steroids is variable and few cases have
resolved spontaneously. In a Pediatric case series,
only half of the children with HE have responded
to steroids.21 Delay in diagnosis and treatment can
result in neurological and cognitive sequelae. Disease
relapses have been reported in treated patients. It is
essential to monitor the thyroid profile during and
after completion of treatment.
Clinical presentation
HE is more common among females and the mean
age of onset is 45-55 years. However, cases have been
reported in Pediatric population and the youngest age
reported in literature is 2 years.14. Nearly one third
of patients with HE have an underlying autoimmune
disorder. Neurological spectrum includes relapsing
and remitting encephalopathy, seizures, cognitive
dysfunction, stroke like episodes, psychosis, mood
changes, sleep disorder, myoclonus or tremor, gait
disturbances, ataxia and cerebellar signs.15
Bickerstaff brainstem encephalitis (BBE)
Encephalitic presentation
History & clinical
examination
Diagnostic evaluation
HE is diagnosed based on the presence of antithyroid
peroxidase (usual titre more than 200 U/ml) and
antithyroglobulin antibodies. Thyroid profile may
show euthyroidism, hypo or hyperthyroidism.15 CSF
shows lymphocytic pleocytosis and mild elevation
of protein. Computerized tomography (CT) brain
findings are normal in half of the cases. CT and MRI
brain in patients with HE might show generalized
atrophy, periventricular white matter, subcortical
white matter changes and dural enhancement.15 EEG
usually shows non specific changes or may show
epileptiform discharges or non convulsive status
epilepticus. Nerve conduction studies should be done
to exclude involvement of peripheral nervous system
(PNS) as there is a report of an adolescent with HE
and PNS involvement.16 Screening for underlying
autoimmune diseases is also mandatory.
MRI brain with gadolinium
CSF- cell count, protein, sugar,
culture, multiplex PCR
EEG
Negative for
infection
Psychiatric
symptoms
Seizures
Extrapyramidal
symptoms
Dysautonomia
Autoimmune
encephalitis
antibody panel
Vasculitis screen
Thyroid
antibodies
Metabolic
screening
Etiology identified
Treat as appropriate
Figure 2: Approach to a child with an encephalitic presentation
Bickerstaff encephalitis is a neurological
syndrome with ophthalmoplegia, ataxia and altered
consciousness. BBE is brainstem encephalitis with
or without limb weakness and forms a continuous
spectrum of Guillian Barre syndrome. Recognition
Treatment
There are no standard guidelines for the management
Vol. 2; No. 2; April - June 2015
Infectious cause identified
Treat as appropriate
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and genetic studies. Management of these disorders
are usually supportive; initiation of megavitamin
therapy for mitochondrial disorders; lysine/
tryptophan restricted diet and riboflavin for glutaric
aciduria and genetic counselling. Other metabolic
causes for encephalopathy include hyponatremia,
hypernatremia, hypoglycemia, hyperglycemia,
hepatic encephalopathy, uremic encephalopathy and
pancreatic failure.
of this syndrome is important as it has a favorable
clinical outcome with treatment. It is postulated
that following an antecedent infection, antibodies
are directed against the gangliosides namely GM1,
GD1a or GalNAc-GD1a of brainstem, cranial
nerves and motor nerves. Electrophysiological
studies reveal acute motor axonal neuropathy or
demyelination and albumino cytological dissociation
has to be looked for in CSF analysis. Serology testing
for antiganglioside antibodies is essential. But it may
be positive only in 60-70% of the cases. MRI brain
abnormalities including hyperintense signal changes
in upper mesencephalon, cerebellum, thalamus or
brainstem have been reported in patients with BBE.22
An approach to diagnosis and management of
children with acute encephalitic presentation is
shown in figure 2.
Principles of Acute Care Management in Children
with Non Traumatic Brain Injury
Airway, breathing and circulation are the priorities
of management in a critically ill child irrespective of
the etiology. Protection of the CNS in critically ill
children with neurologic disorders is of paramount
importance in limiting morbidity and mortality during
intensive care stay. There are well known general
strategies for neurological protection and to prevent
secondary brain injury. Strategies for neurological
protection in children with nontraumatic brain injury
patient are summarized in Table 4.25
Toxic and Metabolic Causes
Toxin exposure causes brain dysfunction resulting in
toxic encephalopathy and the clinical manifestation
depends on the affected brain regions.23 Toxic
encephalopathy presents as symmetrical neurological
syndrome with definite temporal association between
exposure and onset of symptoms. Neurological
symptoms depend on the dose and duration of toxin
exposure. Acute diffuse toxic encephalopathy is
caused by organic solvents, gases (carbon monoxide,
hydrogen sulphide and cyanide), organic metals
(methyl mercury, tetraethyl lead, organic tin) and
inorganic metals (mercury, lead and tin).24 Diagnosis
is based on the history of exposure, clinical
symptomatology, blood for heavy metal screening
and imaging findings. Treatment is supportive,
avoidance of further exposure and therapy with
antidotes/chelating agents.
Certain neurometabolic syndromes and white
matter disorders such as glutaric aciduria type 1,
biotin responsive basal ganglia disease, Leighs
disease, vanishing white matter disease and other
mitochondrial cytopathies can have an acute
encephalitic presentation. Diagnosis of these
disorders is based on the neuroimaging findings
(MRI brain and MRS), blood lactate, ammonia,
blood tandem mass spectrometry, urine gas
chromatography mass spectrometry, CSF lactate
Vol. 2; No. 2; April - June 2015
Table 4: Strategies for neuroprotection in a child with non
traumatic brain injury
1.
2.
3.
4.
5.
6.
7.
Avoid hypoxemia /hyperoxemia (PaO2 100-200 mmHg)
Avoid hypocarbia /hypercarbia (PaCO2 40-45 mmHg)
Avoid hypovolemia / hypotension
Avoid pyrexia Temp (36-37.5° C)
Avoid hyponatremia Sodium (140-159mEq/L)
Avoid hypomagnesemia
Avoid hypogylcemia/hypergycemia
CPP- targeted approach
Autoregulation maintains Cerebral Blood Flow
(CBF) over a range of cerebral perfusion pressure
(CPP) during normal physiological conditions. When
CPP falls below the lower limit of autoregulation,
the brain becomes vulnerable to ischemia. If CPP
is more than the upper limit of autoregulation,
brain is exposed to increased perfusion.25, 26 Many
conditions such as acute CNS infections, Traumatic
brain injury (TBI) and intracerebral hemorrhage
are all associated with impaired autoregulation.25
The recent randomized controlled trial in children
with acute CNS infection reported that the children
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managed with CPP- targeted approach had decreased
90 day mortality, higher GCS at all points and shorter
duration of mechanical ventilation and length of ICU
stay.27
treatment of seizures should be initiated immediately
after recognition. Metabolic stressors like fever and
seizures have to be treated with utmost importance to
limit secondary neurological injury.
Cerebral edema
Cerebral edema, brain tissue shifts, and herniation
are potential complications of encephalitis and
they occur as the result of numerous neurological
insults such as acute infection, ischemia and status
epilepticus. The cerebral edema can be categorized
as vasogenic or cytotoxic in origin. Maintenance
of adequate serum osmolality by keeping sodium
between 140-150mEq/L and sugar within normal
limits can prevent exacerbations of cerebral edema.
Osmolar therapy with mannitol or 3% hypertonic
saline is an effective therapy for increased intracranial
pressure (ICP) which is due to cerebral oedema.25
Conclusion
In children with acute encephalitis and work up for
infection being negative, an extensive evaluation
is needed to identify autoimmune encephalitis,
vasculitis and metabolic disorders. Autoimmune
encephalitis is a potentially treatable disorder with
favorable outcome if identified earlier. Aggressive
neuro-protective strategy in intensive care,
immunomodulation therapy and neurorehabilitation
facilitates good recovery in these children.
References
1. Tunkel. The management of encephalitis: clinical practice
guidelines by the Infectious Diseases Society of America.
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2. Venkatesan A, Tunkel AR, Bloch KC, Lauring AS, Sejvar
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3. Gable MS, Sheriff H, Dalmau J, Tilley DH, Glaser CA. The
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4.Prutt AA. Immune-mediated encephalopathies with an
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5.Krupp LB, Banwell B, Tenembaum S; International
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Neurology.2007;68:S7-12.
6. Noorbakhsh F, Johnson RT, Emery D, Power C. Acute
disseminated encephalomyelitis: clinical and pathogenesis
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7. Tenembaum S, Chitnis T, Ness J, Hahn JS; International
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8.Douglas JWB. Early hospital admissions and later
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10.Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld
MR, Balice-Gordon R. Clinical experience and laboratory
investigations in patients with anti-NMDAR encephalitis.
Cerebral vasospasm
Vasospasm has been described following
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meningitis.25 The timing of vasospasm in TBI
has been reported from 2 to 21 days post injury.28
Vasospasm classically presents with depressed level
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Doppler ultrasound (TCD) or continuous EEG can aid
in detecting vasospasm. Maintenance of euvolemia
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Society’s Consensus Conference and the American
Heart Association (AHA).29 In adults, drugs including
nimodipine, L-type voltage gated calcium channel
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such as nicardipine, verapamil and also milrinone,
phosphodiesterase -3 inhibitor have been used for the
treatment of vasospasm.30,31,32
Aggressive management of fever and seizures
Temperature control is an important factor as fever
contributes to neurological injury by increasing
the cerebral metabolic oxygen demand by 3 fold.33
Continuous EEG monitoring captured 16% to
44% of patients with subclinical seizure activity in
Pediatric intensive care unit.34 Prompt and aggressive
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Lancet Neurol. 2011;10:63-74.
11.Florance NR, Davis RL, Lam C, Szperka C, Zhou L, Ahmad
S, Campen CJ, Moss H, Peter N, Gleichman AJ, Glaser CA,
Lynch DR, Rosenfeld MR, Dalmau J. Anti-N-methyl-Daspartate receptor (NMDAR) encephalitis in children and
adolescents. Ann Neurol. 2009;66:11-8.
12.Hashimoto H. Zur Kenntnis der lymphomatosen Veranderung
der Schilddruse (Strumalymphomatosa). Arch. Klin. Chir.
(Berl).1912; 97: 219-248.
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Ferracci F, Bertiato G, Moretto G. Hashimoto’s
encephalopathy: epidemiologic data and pathogenetic
considerations. J Neurol Sci. 2004; 217: 165-8.
14.Olmez I, Moses H, Sriram S, Kirshner H, Lagrange AH,
Pawate S. Diagnostic and therapeutic aspects of Hashimoto’s
encephalopathy. J Neurol Sci. 2013 ;331:67-71
15.Mocellin R, Walterfang M, Velakoulis D. Hashimoto’s
encephalopathy:
epidemiology,
pathogenesis
and
management. CNS Drugs. 2007;21:799-811.
16.Salpietro V, Mankad K, Polizzi A, Sugawara Y, Granata
F, David E, Ferraù V, Gallizzi R, Tortorella G, Ruggieri
M. Pediatric Hashimoto’s encephalopathy with peripheral
nervous system involvement. Pediatr Int. 2014;56:413-6.
17.Shaw PJ, Walls TJ, Newman PK, et al. Hashimoto’s
encephalopathy: a steroid-responsive disorder associated
with high anti-thyroid antibody titers: report of 5 cases.
Neurology 1991; 41: 228-33
18.Fatemi S, Bedri J, Nicoloff JT. Encephalopathy associated
with Hashimoto’s thyroiditis: use of serum immunoglobulin
G as a marker of disease activity. Thyroid 2003; 13: 227-8
19.Singh H, Ray S, Agarwal S, Verma RP, Talapatra P, Gupta V.
Spectroscopic correlation and role of Azathioprine in longterm remission in patients of Hashimoto encephalopathy.
Ann Indian Acad Neurol. 2013;16:443-6.
20.Marshall GA, Doyle JJ.Long-term treatment of Hashimoto’s
encephalopathy. J Neuropsychiatry Clin Neurosci.2006
;18:14-20
21.Mamoudjy N, Korff C, Maurey H, Blanchard G, Steshenko
D, Loiseau-Corvez MN, et al. Hashimoto’s encephalopathy:
identification and long-term outcome in children. Eur J
Paediatr Neurol. 2013;17:280-7.
22.Odaka M, Yuki N, Yamada M, Koga M, Takemi T, Hirata
K, Kuwabara S. Bickerstaff’s brainstem encephalitis: clinical
features of 62 cases and a subgroup associated with GuillainBarré syndrome. Brain. 2003;126:2279-90.
23.Firestone JA, Longstrength WT Jr. Neurologic and psychiatric
disorders. In: Rosenstock L, Cullen M, Brodkin C, Redlich C,
editors. Textbook of clinical occupational and environmental
medicine. 4th ed. Philadelphia (PA): Saunders; 2004. p.645-60.
24.Kim Y, Kim JW. Toxic encephalopathy. Saf Health Work.
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2012;3:243-56
25.Buttram.SDW, Bell M J. Neurological protection in the
nontrauma pediatric patient. Ana Lia Graciano, David
Turner , editors. Current Concepts in Pediatric Critical Care.
Society of Critical Care Medicine,2015; p 1-12
26.Diedler J, Santos E, Poli S, Sykora M. Optimal cerebral
perfusion pressure in patients with intracerebral
haemmorhage: an observational case series. Crit care
2014;18:R51
27.Kumar R, Singhi S, Singhi P, Jayashree M, Bansal A, Bhatti
A. Randomised controlled trial comparing cerebral perfusion
pressure–targeted therapy versus intracranial pressure-targeted
therapy for raised intracranial pressure due to acute CNS
infections in children. Crit Care Med.2014;42:1775-1787
28.O’Brien NF, Reuter-Rice KE, Khanna S, Peterson BM,
Quinto KB. Vasospasm in children with traumatic brain
injury. Intensive Care Med.2010;36:680-687
29.Diringer MN, Bleck TP, Claude Hemphill J III , Menon
D, Shutter L, Vespa P et al. Critical Care management of
patients following aneurysmal subarachnoid haemorrhage:
recommendations from the Neurocritical care Society’s
Multidisciplinary Consensus Conference. Neurocrit
Care.2011;15:211-240
30.Connolly ES Jr, Rabinstein AA, CarhuapomaJR, Derdeyn
CP, Dion J, Higashida RT et al. Guidelines for the
management of aneurysmal subarachnoid haemorrhage: a
guideline for healthcare professionals from the American
Heart
Association/American
Stroke
Association.
Stroke.2012;43:1711-1737
31.Rinkel GJ, Feigin VL, Algra A, van den Bergh WM,
Vermeulen M, van Gijn J. Calcium antagonists for
aneurysmal subarachnoid haemorrhage. Cochrane Database
Syst Rev.2005;(1):CD000277
32.Lannes M, Teitelbaum J, del Pilar Cortés M, Cardoso M,
Angle M. Milrinone and homeostasis to treat cerebral
vasospasm associated with cerebral haemorrhage: the
Montreal Neurological Hospital protocol. Neurocrit
Care.2012;16:354-362
33.Ingvar M. Cerebral blood flow and metabolic rate during
seizures: relationship to epileptic brain damage. Ann N Y
Acad Sci.1986;462:194-206
34.Saengpattrachai M, Sharma R, Hunjan A, Shroff M, Ochi
A. Nonconvulsive seizures in the pediatric intensive
care unit: etiology, EEG, and brain imaging findings.
Epilepsia.2006;47:1510-1518
35.
Kennedy PG. Viral encephalitis: Causes, differential
diagnosis and management. J Neurol Neurosurg Psychiatry.
2004;75:i10-i15
49
JOURNAL OF PEDIATRIC CRITICAL CARE
Review Article
Antibiotic Stewardship – Rational use of Antibiotics and Antifungal
Agents
Meera Ramakrishnan
Incharge, Pediatric Emergency Services, Manipal Hospital Bengaluru
ABSTRACT
Antibiotics remain the single biggest weapon that we have in our fight against infections. Sepsis continues
to be one of the biggest problems faced by the critically ill children. They are either admitted to the ICU
with a new infection or later in their course of illness, acquire an infection termed as nosocomial infection
or a hospital acquired infection. There are not very many new antibiotics that are available to fight the
bacterial infection. At the same time the microbes are rapidly developing resistance against antibiotics of
all classes, seemingly winning this war against infections. Antibiotics are one class of drugs that have the
potential to affect the health of not only the patient but also of the entire society over a period of time. The
rise of multidrug resistant organisms is a global phenomenon. It is imperative that we cherish and protect
the drugs with the goal of preserving them for generations to come. We may be able to do this by exercising
Antibiotic stewardship. This refers to a set of coordinated strategies to improve the use of antimicrobial
medications with the goal of enhancing patient health outcomes, reducing resistance to antibiotics and
decreasing unnecessary costs. Antimicrobial stewardship is the responsibility of all physicians. We can
each make a difference by exercising discipline in the management of patients. It is imperative that we try
to protect the environment of appropriate handling of waste. Hand hygiene, appropriate isolation practices,
terminal cleaning are all essential practices to reduce the spread of resistance organism. Selecting the right
antimicrobial looks at various aspects of the patient and the drug pharmacokinetics and pharmacodynamics.
This article will examine this concept and antibiotic stewardship in general, that makes the difference
between success and failure in the treatment of infections and spread of multidrug reistance.
Key words: Multidrug resistance, nosocomial infections, antibiotic stewardship, Drug resistance, Pediatrics,
ICU, infections.
Abbreviations: MRSA: methicillin resistant staph aureus.MDR Multidrug resistance.ESBL Extended
spectrum Beta lactamase
Introduction
Antibiotic stewardship1 refers to a set of coordinated
strategies to improve the use of antimicrobial
medications with the goal of enhancing patient health
outcomes, reducing resistance to antibiotics and
decreasing unnecessary costs.
has been shown to improve outcomes2. The guidelines
for time to therapy are as follows Septic shock:
1 hour from the determination of hypotension3,
Meningitis:as soon as possible4 and Community
acquired pneumonia-4 Hours5. Prior to starting
antibiotic, however, it is important to confirm the
presence of infection. High index of suspicion and
good clinical judgement is needed in determining
the need for anti-infective treatment. Not all patients
with fever and elevated white count have infection,
similarly not all patients with infections will
necessarily have fever. All positive cultures need not
be labelled as infection, there may be colonisation.
Initiate antibiotic after obtaining all appropriate
microbiological specimens, including blood cultures,
and if required urine cultures. In case of meningitis
Empirical Antibiotic therapy
Empiric antibiotics are essential in the management
of critically ill patients. Early and adequate therapy
Correspondence:
Meera Ramakrishnan
Incharge, Pediatric emergency services, Manipal Hospital
Bengaluru
E mail: [email protected]
Vol. 2; No. 2; April - June 2015
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Antibiotic Stewardship – Rational use of Antibiotics & Antifungal Agents
empiric antibiotic should be started as soon as
possible. Lumbar puncture can be performed when
it is clinically appropriate. In presence of central
venous catheters one peripheral line along with a
central line culture is needed. (Some authorities
recommend drawing culture from each lumen of the
catheter. This may not be practical or economically
feasible). If the suspicion for central venous line
infection is strong, the device should be removed as
soon as feasible.
a)
Consider obtaining sepsis biomarkers like
procalcitonin & C-reactive protein. Obtain fungal
biomarkers if index of suspicion for disseminated
fungal infection is high. Early diagnosis and
treatment of fungal infection has also been shown
to improve outcomes6.
b)The optimal therapy for the patient should take
into account: Most likely pathogens that need to
be covered. Target tissue penetration (respiratory
tract, blood stream, CNS etc.). Community
versus hospital-associated infection. Recent
previous antibiotic prescription. Organisms and
its resistance pattern commonly present in the
patients community. Patients renal and hepatic
function.
c)Need for monotherapy versus combination
therapy.
d)Pharmacokinetics and pharmacodynamics of the
drug to be used.
Antibiotics are the single biggest weapon that we have
in our fight against infections. Sepsis continues to be
one of the biggest problems faced by the critically ill
patients. They are either admitted to the ICU with an
infection or later in their course of illness acquire an
infection. There are not very many new antibiotics
that are available to fight the bacterial infection. At
the same time the microbes are rapidly developing
resistance against antibiotics of all class, seemingly
winning this war against infections. Antibiotics are
one class of drugs that have the potential to affect the
health of not only the patient but also of the entire
society over a period of time. The rise of multidrug
resistant organisms is a global phenomenon. It is
imperative that we cherish & protect the drugs with
the goal of preserving them for generations to come.
We may be able to do this by exercising Antibiotic
stewardship1. This refers to a set of coordinated
Vol. 2; No. 2; April - June 2015
strategies to improve the use of antimicrobial
medications with the goal of enhancing patient
health outcomes, reducing resistance to antibiotics
and decreasing unnecessary costs. Antimicrobial
stewardship is the responsibility of all physicians. We
can each make a difference by exercising discipline
in the management of patients. It is imperative that
we try to protect the environment of appropriate
handling of waste. Hand hygiene, appropriate
isolation practices, terminal cleaning are all essential
practices to reduce the spread of resistance organism.
Selecting the right looks at various aspects of the
patient and the drug. This article will look at some
of this concept that makes the difference between
success and failure in the treatment of infection.
Empirical Antibiotic Therapy
Empiric antibiotics are essential in the management
of critically ill patients. Early and adequate therapy
has been shown to improve outcomes2. The guidelines
for time to therapy are septic shock 1 hour from the
determination of hypotension3, meningitis as soon
as possible4 and community acquired pneumonia-4
hours5. Prior to starting antibiotic however it is
important to confirm the presence of infection. High
index of suspicion and good clinical judgement is
needed in determining the need for anti-infective
treatment. Not all patients with fever and elevated
white count have infection, similarly not all patients
with infections need to have fever. All positive cultures
need not be infection, they may be colonisation.
Initiate antibiotic after obtaining all appropriate
microbiological specimens, including blood cultures,
and if required urine cultures. In case of meningitis
empiric antibiotic should be started as soon as possible.
Lumbar puncture can be completed when it is clinically
appropriate. In presence of central venous catheters one
peripheral along with a central line culture is needed.
(Some authorities recommend drawing culture from
each lumen of the catheter. This may not be practical
or economically feasible). If the indications for central
venous infection is strong, the device should be
removed as soon as feasible.
a)
Consider obtaining sepsis biomarkers like
procalcitonin and C-reactive protein. Obtain fungal
biomarkers if index of suspicion for disseminated
fungal infection is high. Early diagnosis and
51
JOURNAL OF PEDIATRIC CRITICAL CARE
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Antibiotic Stewardship – Rational use of Antibiotics & Antifungal Agents
treatment of fungal infection has also shown to
improve outcome6.
b)The optimal therapy for the patient should take
into account. Most likely pathogens that need to be
covered Target tissue penetration (respiratorytract,
blood stream, CNS etc.). Community versus
hospital-associated infection. Recent previous
antibiotic prescription. Organisms and its
resistance pattern commonly present in the patients
community Patients renal andhepatic function
c) Need for monotherapy versus combination therapy.
d)Pharmacokinetics and pharmacodynamics of the
drug to be used.
Suggestions For Empirical Antibiotic Therapy
Situation
Drug
Remark
Sepsis without focus-Immunocompetent
Third generation cephalosporin
Consider cefotaximeif liver abnormality
is present
Ceftazidime if pseudomonas is possible
Sepsis without focus-Immunosupressed
PiperacillinTazobactum +/_ Vancomycin
Carbapenem +/_ Vancomycin
Meropenem if CNS infection is suspected
Add vancomycinif MRSA is possible.
Intrabdominal sepsis
Ceftriaxone + a) Metronidazole+ /_
aminoglycoside b) Carbapenem +/vancomycin c) Piperacillin Tazobactum
+/_ vancomycin
Use carbapenem only if there is high
chance of ESBL gram negative
If chances of MDR gram negative is high
as in hospital acquired infections consider
adding Tigecycline
Antifungal if colon is the focus
Tigecycline also covers MRSA and
enterococcus
Community acquired pneumonia
2nd generation cephalosporin
Amoxycillin + clavulanic acid
Consider Oseltamivir if the influenza is
likely
Community acquired pneumonia with
shock
3rd generation cephalosporin +
Clindamycin or linezold
Consider azithromycin in intubated
patients for immunomodulation
A β-lactum agent is bactericidal but
does not inhibit the toxin production
clindamycin or linezolid although
bacteriostatic inhibits toxinproduction
and improves toxic shock. In situations of
treating MRSA infection it is important
to look for inducible resistance to
clindamycin ( D Test ). Some recommend
addition of clindamycin due to the Eagle
effect due to high inoculum.7
Ventilator associated pneumonia < 4
days, without hospitalization in 30 days
or antibiotics in 15 days
Ceftriaxone/amoxycillin + clavulanic ±
macrolide or ertapenem ± macrolide
Late onset VAP defined as ventilator
LOS > 4 days
Pseudomonas Acinetobacterspp,
Stenotrophomonas,
Klebsiellapneumoniae (ESBL+) MRSA
are the common org
Antipseudomonal cephalosporin /
carbapenem /beta-lactam/betalactamase inhibitor + Antipseudomonal/
fluoroquinolone/aminoglycoside +
Tigecycline + carbapenem+sulbactam or
Tigecycline + carbapenem + colistin +/_
linezolid or vancomycin
Central line associated blood stream
infection
Vancomycin + carbapenem + /echinocandin or fluconazole
Vol. 2; No. 2; April - June 2015
52
- Modify therapy to local antibiogram.
- De-escalate as soon as culture results
are back-ertapenem, tigecycline do not
cover pseudomonas.
- Ertapenem is as effective asmeropenem as long as the MIC of the
organism is < 2µcg/ml8
- Do not use tigecycline or colistin alone
- Cotrimoxazole is the drug of choice in
stenotrophomonas
- Colistin combination with rifampicin
useful in pan resistant acinetobacter9, 10.
Carbapenem may be replaced with any
appropriate antibiotic to cover gram
negative as per the local antibiogram.
Imperative to decide about the need for line
and remove the device as soon as feasible
JOURNAL OF PEDIATRIC CRITICAL CARE
REVIEW Article
Antibiotic Stewardship – Rational use of Antibiotics & Antifungal Agents
Pharmacodynamics PD describes the effect of a
drug on the patient or the pathogens.15 The effect of
the antibiotic depends on inoculum size, microbial
physiology, and resistance mechanisms. The
most important PD parameter to consider is the
minimal inhibitory concentration (MIC), which is
the lowest serum drug concentration that inhibits
bacterial growth. Dosing strategies manipulate
these parameters for the best antimicrobial activity.
The way the drug kills may be categorised in two
predominant ways time-dependent killing and
concentration-dependent killing.16
Carbapenems are drug of choice against ESBL
producing gram negative organisms. ESBL producers
often tend to have cross resistance to fluroquinolone
and aminoglycoside. Considering that gram negative
infections resistant to carbapenems is on the rise it is
important to look at other alternatives in an attempt
to conserve carbapenams. βeta lactam/βeta lactamase
inhibitor such as piperacillin–tazobactam are effective
for ESBL producers when susceptibility is proven,
especially in urinary and biliary tract infections or
when the bacterial inoculum or MIC is low11.
PK /PD and Tissue Penetration12
Critical to dose optimisation is an understanding of
the pharmacokinetics (PK) and pharmacodynamics
(PD) of available drugs.
PK describes the fate of the drug once administered
to a patient, including absorption, distribution,
metabolism, and excretion.
Volume of distribution (VD)13 is the theoretic volume in
which the total amount of drug needs to be distributed
uniformly to produce the desired concentration of a
drug. Hydrophilic antibiotics (e.g., aminoglycosides,
beta-lactams, glycopeptides, and colistin) are affected
by increased VD and altered drug clearance. Lipophilic
antibiotics (e.g., fluroquinolone, macrolides,
tigecycline) are less susceptible to alterations in VD
but may have altered drug clearance in critically ill
patients. Increased capillary permeability, increased
cardiac output, reduced serum albumin, augmented
renal blood flow and organ failure all influence the
volume of distribution (VD) and drug clearance
(Cl) potentially leading to inadequate drug levels
and therapeutic failure. Augmented kidney blood
flow may occur in many patients with burns, sepsis,
febrile neutropenia and hypoalbuminemia. This
increased blood flow resultsinincreased creatinine
clearance (CLCr), leading to an increased capacity
of the kidneys to eliminate hydrophilic molecules.
This is called ‘augmented renal clearance’ (ARC)14.
ARC is one of the reason why loading dose is needed
while using colistin in patients with MDR gram
negative infections. This is a phenomenon that is
being increasingly recognised as a reason for failure
to respond to treatment in the case of hydrophilic
molecules.
Vol. 2; No. 2; April - June 2015
Figure 1 Common pharmacodynamics values17, 18
In time-dependent killing, maximum bacterial
killing occurs when the drug 18concentration remains
above the minimal inhibitory concentration (MIC).
Examples of antibiotics that demonstrate timedependent killing include β-lactam antibiotics (i.e.,
penicillins, cephalosporins, carbapenems, and
monobactams) and vancomycin.
In concentration-dependent killing, maximum
bacterial killing occurs when the peak drug
concentration is approximately 10 times the MIC.
Examples of agents with concentration-dependent
killing are fluoroquinolones and aminoglycosides.
Microbial killing continues to occur even when
the drug levels in the serum are very low. This
phenomenon is called postantibiotic effect (PAE).
It is this phenomenon along with the concentration
dependent killing that constitutes the basis for oncedaily aminoglycoside therapy.
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Drug
Antibiotic Stewardship – Rational use of Antibiotics & Antifungal Agents
PD Propety
recommendation of the dose.
Tigecycline does not have any urinary excretion
hence should not be used in the management of UTI
even if there is in vitro sensitivity. Same holds for
colistin which has very minimal renal excretion. On
the contrary fluoroquinolone have excellent renal
excretion and can be used even if it is an ESBL
producing organism that is causing a UTI.
Tactic to enhance
killing
Carbapenems
Cephalosporins
Linezolid
Beta lactam
Time-dependent
Maximize duration
of exposure
with prolonged
or continuous
infusion
Aminoglycosides
Fluoroquinolones
Ketolides
Metronidazole
Polymixins
Concentrationdependent (with
PAE )achieve
Cmax:MIC) > 10
Maximize peak
concentration
Clindamycin
Macrolides
Vancomycin
Colistin
AUC:MIC 24h >125 Maximize drug
AUC:MIC 24h > 400 dosage while
for MDR pathogens
avoiding toxicity
Monotherapy Versus Combination Therapy
Combination therapy is used principally because
a) there is an increased likelihood that the infective
pathogen will be susceptible to at least one of the drugs
of combination therapy, thereby allowing appropriate
initial therapy; b) To prevent resistance especially in
organisms like pseudomonas c) possibility of synergy
between drugs and hence betterbacterial clearing. d)
To produce immunomodulatory effects as in the use
of macrolides in ventilated patients with pneumonia.
e) To work on a different aspect of the illness like
clindamycin or linezolid to reduce toxin production
in Toxic Shock Syndrome. Combination therapy has
been found to be effective mostly in enterococcus
where penicillin or ampicillin is combined with
gentamicin or streptomycin.22
Combination therapy is often used to improve
outcomes such as mortality and duration of ICU stay
in patients with MRSA infection. Despite numerous
in vitro and in vivo studies there is still confusion
regarding this practice. It is best to avoid combination
of linezolid plus vancomycin or linezolid plus
fluroquinolone because the combination at best is
associated with antibiotic indifference and at worst
associated with antagonism.22
β-lactam combination with aminoglycoside
combinations have been most studied. Metaanalysis of several studies has failed to show any
advantage in terms of mortality, bacterial clearance
or development of resistance when the combination
has been compared with β lactam monotherapy.
In addition the combination is associated with
nephrotoxicity.23 Despite the theoretical advantages,
combination therapies have not shown to improve
outcomes except in patients with septic shock.24
Even here it is best to use combinations only till
hemodynamic stability is achieved and then change
Tissue Penetration
The site of infection is an important aspect that has to be
taken into consideration prior to the prescription16. For
example MRSA is treated by vancomycin, linezolid
and daptomycin. The choice of agent depends on site
of infection and MIC of the organism. Vancomycin
has poor penetration into the alveolar epithelium.
This problem may be overcome by giving it every 6
hours as a 1 hour infusion or giving it as a continuous
infusion while treating a patient with severe MRSA
pneumonia. Linezolid has a better penetration into
the alveolar epithelium. In adults some studies show
better results with linezolid than vancomycin in the
treatment of MRSA pneumonia19. Pneumonia is best
not treated with daptomycin as it is inactivated by
surfactant. In bacteremia due to MRSA daptomycin
may be better than vancomycin as the latter is only
nominally bactericidal. In situations meningitis due to
resistant streptococcus pneumoniaea dose of 15mg/
Kg of vancomycin administered every six hours is
recommended to increase the area under the curve.
Colistin levels in bronchial secretions are extremely
low even when serum levels are adequate. This
makes it essential that appropriate alternative drug or
method of administration of colistin is needed while
treating ventilator associated pneumonia (VAP). In
order to reduce toxicity colistin is combined with
Carbapenem. Nebulized colistin has been tried to
increase levels of the drug in bronchial secretion.20, 21
Enough studies are not there to give firm
Vol. 2; No. 2; April - June 2015
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Antibiotic Stewardship – Rational use of Antibiotics & Antifungal Agents
over to monotherapy if cultures are negative.
Also combination therapy is not very useful when
using broad spectrum agents such as carbapenems,
βlactam/βlactamase inhibitor such as piperacillin–
tazobactam, and anti-pseudomonalcephalosporin.24
The potential disadvantages related to combination
therapy, such as increased risk for toxicity, higher
costs, possible antagonism between specific drug
combinations (penicillin and chloramphenicol,
linezolid and fluroquinolone), and selection of
resistant strains should always be kept in mind.
CandidaScore ≥3 discriminated between colonization
and invasive candidiasis in non-neutropenic ICU
patients colonized with candidaspp., with a minimum
length of ICU stay of 7 days. Colonization index” is a
score that is used to determine the risk of patients for
subsequent infections. It isdefinedas the ratio of the
number of body sites colonized with thesame strain
to the total number of sites cultured27.
Aspergillusis the other fungus that is increasing in
incidence due to increasing survival of patients
withmalignancy and increasing numbers of patients
who are on immunosuppressant therapy.
Empirical antifungal treatment is started in a high
risk individual after obtaining appropriate cultures
and if possible serum biomarkers. The agent that is
started will depend on the nature of patient’s illness,
local resistance pattern and the organ system that
may be affected of the patient.
Antifungal Agents
Invasive fungal infections are becoming common in
the ICU world over. They are generally associated
with patients who are on prolonged antibiotics, are
immunosuppressed or have had multiple intravascular
devices. Invasive fungal infections are associated with
greater mortality than bacterial infections25. Time is of
as much essence in their treatment as with bacterial
infections in critically ill. Increasing use of antifungals
is also led to on the rise because of use of. Certain
organisms are intrinsically resistant to different agents.
Empiric differentiation of fungal and bacterial infection
is difficult because clinical signs and symptoms are
similar.
In an attempt to enhance appropriate patient selection
for empiric antifungal therapy scores have been used.
There are often combined with biological marker
(β-D glucan, anti mannanantibody, galactomannan)
to determine the probability and type of fungal
infection. The type of fungus involved determines
the empiric coverage.
The most common fungus continues to be candida
however the number of non albicans species causing
infections have increased. In order to determine
the at risk patient for candidemia the colonization
index and candida score is commonly used. León
and colleagues developed the Candida score based
on four risk factors to which numeric values were
assigned as follows: total parentral nutrition-TPN (1
point), multifocal colonization sites (1 point), severe
sepsis (2 points), and surgery (1 point). Patients
with a score greater than 2.5 were more than 7
times as likely to have proven infection as patients
with a Candida Score up to 2.5.26 A prospective
multicenter observational study demonstrated that a
Vol. 2; No. 2; April - June 2015
General Guidelines
In general invasive fungal infection should be
suspected and treated early.
a)
Invasive candidiasis-Drug of choice is
echinocandin and narrow it to fluconazole as
soon as possible. Treatment is for 14 days from
negative blood cultures28
b)
Invasive Aspergillosis- Drug of choice is
voriconazole.30 Has hepatotoxicity. Several drugs
that are used in immunosuppressed ICU patients
can affect drug level.
c)Candiduria generally does not need treatment.
Fluconazole is the drug of choice if treatment is
needed. Bladder irrigation with amphotericin is
no longer recommended
d) Candida pneumonia is rare and diagnosis requires
invasive sampling. Most candida isolated from
sputum samples or tracheal aspirates often
represent upper respiratory tract flora and does not
require treatment28
d) Zygomycetes – Liposomal amphotericin is
recommended along with surgical debridement.
e)
Cryptococcus – Combination therapy is
recommended with amphotericin and flucytocine.
f) In vitro studies show antagonism with amphotericin
and azole. However variable results have been
obtained when voriconazole and amphotericin are
combined for invasive aspergillosis.
55
JOURNAL OF PEDIATRIC CRITICAL CARE
REVIEW Article
Antibiotic Stewardship – Rational use of Antibiotics & Antifungal Agents
comorbid conditions and the local antibiogram. Prior
to choosing an agent one also needs to consider the
pharmacodynamics and pharmacokinetics of the
drug. Combination therapy may be needed in patients
with septic shock and if MDR organisms is likely.
De-escalation is needed as soon as feasible. Utility of
de-escalation is difficult to prove. It can be practiced
by reducing the dose of the drug (when appropriate),
narrowing the spectrum of coverage and by reducing
the number of drugs used to treat the infection. Due
to emergence of resistant fungi, the guidelines to
treat invasive fungal infection should be diligently
followed to prevent further morbidity and mortality.
Summary
Antibiotic stewardship is a concept catching on fairly
rapidly with most health care institutions. Infection
control teams with infectious disease specialist,
microbiologist, infection control nurse are becoming
an essential tool in most NABH or JCI accredited
institution to monitor antimicrobial therapy and
to curb nosocomial infection rates as well as the
antimicrobial resistance. Empiric therapy is needed
with most appropriate drug for optimal outcome in
ICU patients. It is impractical to wait for culture results
befor starting treatment. Adequate coverage should
take into account the nature of the patients illness,
Drug
Fungus sensitive
Amphotericin B MostCandidaspp,
Cryptococcus
neoformans
Histoplasma
Blastomyces,
Mucorales,
Coccidioides,
Paracoccidioides,
Aspergillusspp,
Fusariumspp.
Sporothrixschenckii
Azole
Depends on the
Azole
Fluconazole
Most candida spp
cryptococcus
Voriconazole
Aspergillus
Candida krusei
Echinocandin
Candida spp
Aspergillus
Vol. 2; No. 2; April - June 2015
Resistant fungus
Remark
Trichosporon
C. lusitaniae,
C guilliermondii),
Zygomecetes,
Cryptococcus spp
Fungicidal. Binds to fungal cell membrane, causes leakage of cell
content.
No dose adjustment needed in renal or liver failure or for renal
replacement therapy
Inhibit the synthesis of erogosterol by the fungal cell membrane,
Three generation of azole are there. All azoles penetrate into CSF
and eye well.
All have good oral bioavailability, Cause varying extents if GI upset.
All inhibit the metabolism of cyclosporine and tacrolimus
increasing the drug level
Candida Krusei
C. glabrata–variably
Aspergillus
Zygomycetes
-Only azole with good urinary levels. Metabolized in liver
-Dose adjustment needed in renal failure. Useful mainly in
patients who are relatively stable.
-First line of treatment nonneutropenic patients at risk for
candidemia28 without previous exposure to azole.
-Do not use if there is history of use of azole in past 30 days.
-Significant drug interaction- rifampicin.benzodiazepine,
phenytoin decrease drug level.
No dose adjustment in renal failure.
when parenteral treatment used, carrier cyclodextrin gets accumulated
and would need dose reduction if creatinine clearance < 50ml/min28.
Reduction in dose needed in liver failure.Therapeutic drug
monitoring of voriconazole levels should be considered in patients
in whom aspergillosis is refractory to therapy or drug toxicity is
suspected. The recommended trough level of voriconazole is >1
and <5.5 mg/L.29
Cryptococcus
Caspofungin, Antidulafungin and Micafungin.
Inhibit β1,3-D glucan synthesis
Useful in patients with hemodynamic instability
No penetration in CSF, eye or urine.
No dose adjustment needed for renal failure
Caspofungin dose to be reduced in moderate liver failure
56
JOURNAL OF PEDIATRIC CRITICAL CARE
REVIEW Article
Antibiotic Stewardship – Rational use of Antibiotics & Antifungal Agents
augmented renal clearance. Crit Care 2011;15(3):R139.
14.Udy AA, Varghese JM, Altukroni M, et al: Subtherapeutic
initial β-lactam concentrations in select critically ill patients:
Association between augmented renal clearance and low
trough drug concentrations. Chest 2012;142(1):30-39.
15.Levison M.E.: Pharmacodynamics of antimicrobial drugs.
Infect Dis Clin North Am 2004; 18: pp. 451-465.
16.Quintiliani, Richard, MD, FACP; Quintiliani, Richard, MD.
Volume 24, Issue 2. Pages 335-348.© 2008.Pharmacokinetics/​
Pharmacodynamics for Critical Care Clinicians.Critical Care
Clinics.
17.
Lodise TP, Drusano GL Pharmacokinetics and
pharmacodynamics: optimal antimicrobial therapy in the
intensive care unit. - Crit Care Clin - January 1, 2011; 27 (1);
1-18.
18.
Ebert SC, Craig WA: Pharmacodynamic properties
of antibiotics: Application to drug monitoring and
dosage regimen design. Infect Control HospEpidemiol
1990;11(6):319-326.
19.Wunderink RG, Niederman MS, Kollef MH, et al. Linezolid
in methicillin-resistant Staphylococcus aureus nosocomial
pneumonia: a randomized, controlled study. Clin Infect Dis
2012;54(5):621–9.
20.Kofteridis DP, Alexopoulou C, Valachis A, et al. Aerosolized
plus intravenous colistin versus intravenous colistin alone for
the treatment of ventilator-associated pneumonia: a matched
case-control study. Clin Infect Dis. 2010;51(11):1238-1244. 21.Michalopoulos A, Fotakis D, Virtzili S, et al. Aerosolized
colistin as adjunctive treatment of ventilator-associated
pneumonia due to multidrug-resistant gram-negative bacteria:
a prospective study. Respir Med. 2008;102(3):407-412. 22.Principles Governing Antimicrobial Therapy in the Intensive
Care Unit Hollis O’Neal, Christopher B. Thomas and George
KaramCritical Care Medicine: Principles of Diagnosis and
Management in the Adult, 51, 870-885.e4
23.Ioannis A. Bliziotis1, George Samonis3, Konstantinos Z.
Vardakas1,etal Effect of Aminoglycoside and β-Lactam
Combination Therapy versus β-Lactam Monotherapy on the
Emergence of Antimicrobial Resistance: A Meta-analysis of
Randomized, Controlled TrialsClin Infect Dis.(2005) 41 (2):
149-158.
24.Kumar A, Safdar N, KethireddyS, et al. A survival benefit
ofcombination antibiotic therapy for serious infections
associated with sepsis and septic shock is contingent only on
the risk of death: a meta-analytic/meta-regression study. Crit
Care Med 2010;38:1651-64
25.Morrell M, Fraser VJ, Kollef MH. Delaying the empiric
treatment of Candida bloodstream infection until positive
blood culture results are obtained: a potential risk factor
for hospital mortality.AntimicrobAgentsChemother 2005;
49:3640-5.
26.LeonC, Ruiz-Santana S, Saavedra P, et al. A bedsides
coringsystem (“Candidascore”) for early anti fungal
treatment in non neutropenic critically ill patients with
Candidacolonization. CritCareMed.Mar2006;34(3):730-737
27.Pittet D, Monod M, Suter PM, et al. Candida colonization
and subsequent infections in critically ill surgical patients.
References
1. Dellit TH, Owens RC, McGowan JE, et al. Infectious
Diseases Society of America and the Society for Healthcare
Epidemiology of America guidelines for developing an
institutional program to enhance antimicrobial stewardship.
Clin Infect Dis 2007;44:159–77.
2. Kollef MH: Inadequate antimicrobial treatment: An important
determinant of outcome for hospitalized patients. Clin Infect
Dis 2000;31(Suppl 4):S131-S138
3. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension
before initiation of effective antimicrobial therapy is the
critical determinant of survival in human septic shock. Crit
Care Med 2006;34:1589–96.
4. Tunkel AR, Hartman BJ, Kaplan SL, et al: Practice guidelines
for the management of bacterial meningitis. Clin Infect Dis
2004;39(9):1267-1284.
5. Houck PM, Bratzler DW, Nsa W, et al: Timing of antibiotic
administration and outcomes for Medicare patients
hospitalized with community-acquired pneumonia. Arch
Intern Med 2004;164(6): 637-644
6.Disseminated Fungal Infections, publishedj 22013:
Themistoklis Kourkoumpetis MD and Eleftherios E.
Mylonakis MD, PhD, FIDSACritical Care Secrets, Chapter
35, 240-245.
7. Eagle H, and Musselman AD: The rate of bactericidal action
of penicillin in vitro as a function of its concentration, and its
paradoxically reduced activity at high concentrations against
certain organisms. J Exp Med 1948; 88: pp. 99-131
8. Comparison of in vitro efficacy of ertapenem, imipenem
and meropenem in the infections caused by the
Enterobacteriaceae strains family.Guzek A, Tomaszewski D,
Rybicki Z, Truszczyński A, Barański M, Korzeniewski K. Anaesthesiol Intensive Ther-April 1, 2013; 45 (2); 67-72
9. Li J, Rayner CR, Nation RL, Owen RJ, Spelman D, Tan
KE, et al. Heteroresistancetocolistin in multidrug-resistant
Acinetobacterbaumannii. Antimicrob Agents Chemother
2006; 50:2946–50.
10.
Combination antibiotic treatment versus monotherapy
for multidrug-resistant, extensively drug-resistant, and
pandrug-resistant Acinetobacter infections: a systematic
review.Poulikakos P, Tansarli GS, Falagas ME-Eur. J. Clin.
Microbiol. Infect. Dis. - October 1, 2014; 33 (10); 1675-85
11.β-Lactam/β-lactam inhibitor combinations for the treatment
of bacteremia due to extended-spectrumβ-lactamaseproducing Escherichia coli: a post hoc analysis of prospective
cohorts.AURodríguez-Baño J, Navarro MD, Retamar P,
Picón E, PascualÁ, Extended-Spectrum Beta-Lactamases–
Red Española de InvestigaciónenPatologíaInfecciosa/Grupo
de Estudio de InfecciónHospitalaria Group Clin Infect Dis.
2012;54(2):167
12.Using PK/PD to optimize antibiotic dosing for critically ill
patients.Roberts JA, Current Pharmaceutical Biotechnology
[Curr Pharm Biotechnol], ISSN: 1873-4316, 2011 Dec; Vol.
12 (12), pp. 2070-9
13.Baptista JP, Udy AA, Sousa E, et al: A comparison of
estimates of glomerular filtration in critically ill patients with
Vol. 2; No. 2; April - June 2015
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Antibiotic Stewardship – Rational use of Antibiotics & Antifungal Agents
Ann Surg1994;220:751-8.
28.Pappas PG, Kauffman CA, Andes D, et al. Clinical practice
guidelines for the management of candidiasis: 2009 update
by the Infectious Diseases Society of America. Clin Infect
Dis 2009;48:503-35.
29.Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti
O: Voriconazole therapeutic drug monitoring in patients with
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invasive mycoses improves efficacy and safety outcomes.
Clin Infect Dis 2008, 46(2):201-211
30.
Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R,
Kontoyiannis DP, Marr KA, et al. Treatment of aspergillosis:
clinical practice guidelines of the infectious diseases Society
of America. ClinInfec Dis 2008;46(3):327e60
58
JOURNAL OF PEDIATRIC CRITICAL CARE
Technology and Equipment Update
High Flow Nasal Cannula: The New Mode of NIV in Pediatrics : A
Working Protocol
Sanjay Perkar, Nilesh Maniya, Ankur Ohri, Ankur Chawla, Rachna Sharma, Praveen Khilnani
Pediatric Intensive Care Unit, BLK Superspeciality Hospital, New Delhi
˗ Apnea of prematurity.
High flow can be used if there is hypoxemia
(SpO2<90%) and signs of moderate to severe
respiratory distress despite standard flow oxygen.
Introduction
Humidified high flow nasal prong (cannula) oxygen
therapy is a method for providing oxygen and
continuous positive airway pressure (CPAP) to children
with respiratory distress. It is used for the same
indications as the traditional method of CPAP using
a nasopharyngeal tube. HFNC may reduce need for
NCPAP/intubation, or provide support post extubation.
At high flow of 2 litres per kg per min, using appropriate
nasal prongs, a positive distending pressure of 4-8 cm
H2O is achieved. This improves functional residual
capacity thereby reducing work of breathing. Because
flows used are high, heated water humidification is
necessary to avoid drying of respiratory secretions and
for maintaining nasal cilia function.
Contraindications
˗ Blocked nasal passages/choanal atresia
˗ Trauma/surgery to nasopharanyx
Management Equipment
˗ Oxygen and air source
˗ Blender
˗ Flow meter
• <7Kg use standard 0-15L/min flow meter
• >7Kg use high flow oxygen flow meter which
delivers up to 50L/min flow
Indications
HFNCs are used for the same indications as the
traditional method of CPAP using a nasopharyngeal
tube:
˗ Respiratory distress from bronchiolitis, pneumonia,
congestive heart failure.
˗ Respiratory support post extubation and mechanical
ventilation.
˗ Weaning therapy from mask CPAP or BIPAP
˗ Respiratory support to children with neuromuscular
disease.
˗ Humidifier (Fisher and Paykel® MR850)
˗ Circuit tubing to attach to humidifier
• Children <12.5kg: small volume circuit tubing
(RT 329)
• Children ≥12.5kg: adult oxygen therapy circuit
tubing (RT203) and 22mmF oxygen stem
connector (Intersurgical 1568)
˗ Nasal cannula (prongs) to attach to humidifier
circuit tubing (size to fit nares comfortably)
• Newborn: OPT312 Premature or OPT314
Neonatal (maximum flow 8L/min)
• Infants and children up to 10kg: OPT316 Infant
(max flow 20L/min) or up to 12.5kg: OPT318
Pediatric cannula (max flow 25L/min) (Table 1)
Correspondence:
Dr Praveen Khilnani MD FCCM (USA)
Head Pedicatric ICU, BLK Superspeciality Hospital
E-mail: [email protected]
Table 1: Guidelines for (High flow nasal HFNC) cannula sizes and recommended flow rates according to age and weight
Premature
Neonatal
Infant
Pediatric
Canula brand /spec (Fischer and Paykle)
opt312
opt314
opt316
opt318
Max flow Rate (l/Min)
8
8
20
25
Cannula Weight
9g
9g
13g
13g
Approximate age Range
(< 32 wk)
(27 wk - 6 mo)
(37 wk - 3.5yr)
(1 yr- 6 yr)
Approximate Weight Range
(< 2 kg)
(1-8 kg)
(3-15 kg)
(12-22 kg)
Vol. 2; No. 2; April - June 2015
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JOURNAL OF PEDIATRIC CRITICAL CARE
Technology and Equipment Update
High Flow Nasal Cannula: The New Mode of NIV in Pediatrics : A Working Protocol
• Children >10kg: Adult cannula size S OPT542,
size M OPT544, size L OPT546
• >10Kg 2 L per kg per minute for the first
10kg + 0.5L/kg/min for each kg above that
(max flow 50 L/min).
• i.e. 16kg= 20L (2 x first 10kg) + 3L (0.5
x 6kg) = 23L/min; 40kg = 20L (2 x first
10kg) + 15L (0.5 x 30kg) = 35L/min.
• Start off at 6L/min and increase up to
goal flow rate over a few minutes to
allow patient to adjust to high flow.
• high flow meter flow should be rounded
down to nearest available flow (only
certain flows available).
˗ Water bag for humidifier
˗ Nasogastric tube
Set Up of Equipment
˗ Select appropriate size nasal cannula and circuit
tubing for patient size.
˗ Connect nasal cannula to adaptor on circuit tubing,
and connect circuit tubing to humidifier.
˗ Attach air and oxygen hoses from blender to air
and oxygen supply.
˗ Connect oxygen tubing from blender to humidifier.
˗ Use 22 mmF Oxygen stem connector (Intersurgical
1568) to attach oxygen tubing to humidifier
chamber with adult circuit (RT203).
˗ Attach water bag to humidifier and turn on to 37ºC.
The water bag must run freely and be placed as
high as possible above the humidifier to achieve
flow of water into the humidifier chamber. The
system is then ready for use.
• FiO2
• Always use a blender, never use flow meter
off wall delivering FiO2 100%
• Start at 50-60% for bronchiolitis and
respiratory distress.
• Lower FiO2 (e.g. 21% - 25%) may be
needed for cyanotic congenital heart
disease with balanced circulation.
• Target range for SpO2 of 94%-98%
• 75-85% in cyanotic congenital heart
disease with balanced circulation.
• Humidification
• Because flows used are high, heated water
humidification is necessary to avoid drying
of respiratory secretions and for maintaining
nasal cilia function.
• Set humidifier on 37° C invasive setting
(length from temperature probe to nares will
result in temperature drop to comfortable
level whilst maintaining optimal humidity).
HFNC Setup Diagram
Patient Monitoring
˗ Monitor patient for response
• Respiratory rate
• Heart rate
• Degree of chest in-drawing
• SpO2
Patient Management
˗ Secure nasal cannula on patient using supplied
“wiggle pads™”, ensuring the prongs sit well into
the nares
• prongs should not totally occlude nares
˗ Within 2 hours it should be possible to reduce the
FiO2 and clinical stabilisation should be seen
• The FiO2 required to maintain SpO2 in the target
range (as above) should decrease to <40%
• The heart rate and respiratory rate should reduce
by 20%
˗ Start the high flow nasal cannula system at the
following settings:
• Flow rate
• ≤10Kg 2 L per kg per minute.
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JOURNAL OF PEDIATRIC CRITICAL CARE
Technology and Equipment Update
High Flow Nasal Cannula: The New Mode of NIV in Pediatrics : A Working Protocol
• Decreased work of breathing
• Normal or improved respiratory rate
• Return to normal cardiovascular parameters
• Chest in drawing and other signs of respiratory
distress should improve
˗ Seek medical review if any of the following occurs:
• The patient is not stabilizing as described above
• The degree of respiratory distress worsens
• Hypoxemia persists despite high gas flow
• Requirement for >50% oxygen
For infants <10Kg
• The first step is to wean the FiO2 to <40% (usually
within the first 1-2 hours, as above).
• Reduce flow to 5 L/min then change to standard
low flow 100% oxygen (1 to 2L/min) or cease
oxygen therapy if stable.
˗ Note that on high flow if high FiO2 is used, oxygen
saturation may be maintained in an infant despite
the development of hypercarbic respiratory failure
˗ If there is rapid deterioration of oxygen saturation
or marked increased work of breathing, a chest
x-ray should be done to exclude a pneumothorax
For children >10Kg
• Wean FiO2 to 40%
• Once the indication for using high flow has
resolved, and the patient is stable in 40% oxygen the
flow can be weaned to 1-2 L/min with unblended
(100%) oxygen via standard nasal prong therapy,
or oxygen therapy ceased. Generally there is no
need for a prolonged weaning process, better to
be on high flow, standard low flow or off oxygen
therapy.
Patient Nursing Care
˗ All infants on high flow should have a nasogastric
tube.
• Once stable on high flow, the infant should be
assessed as to whether they can feed. Some
infants can continue to breast feed, but most
require feeding via a nasogastric tube.
• Regularly aspirate the NG 2-4 hourly for air.
Complications
˗ Gastric distension
˗ Pressure areas
˗ Blocked HFNP due to secretions
˗ Pneumothorax
˗ Oral and nasal care must be performed 2-4 hourly
˗ Note nasal prongs are in correct position and no
pressure areas to nares
• Spare “wiggle pads™” available to change as
required to ensure prongs secure
• wiggle pad™ OPT010 for OPT312 Premature
nasal cannula
• wiggle pad™ OPT012 for OPT314 Neonatal,
OPT316 Infant or OPT318 Pediatric nasal
cannula
˗ Gentle suction as required to keep nares clear
˗ Check humidifier water level hourly
Summary:
High Flow nasal cannula (HFNC) technology is being
commonly used in neonatal and Pediatric ICU’s as
a mode of delivering CPAP (as an alternative to
intubation and mechanical ventilation in patients
with moderate respiratory distress and increased
work of breathing associated with Hypoxemia)
while recognizing the lack of precision regarding
measurement of exact delivered CPAP values.
Nevertheless It is a relatively safe technique. It is
recommended that a set up for invasive mechanical
ventilation should be ready as ausual protocol
followed with all non invasive ventilation modalities.
Gastric distension and pneumothorax as well as
blockage of cannula and pressure injuries should be
looked for and avoided by minimizing the duration
of use.
Documentation
˗ Document hourly on MR100 PICU observation
chart:
• Flow rate, FiO2 & humidifier temp
• Document RR, HR, SpO2 & WOB
Weaning of High Flow Nasal Cannula Oxygen
˗ When the child’s clinical condition is improving as
indicated by:
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JOURNAL OF PEDIATRIC CRITICAL CARE
Technology and Equipment Update
High Flow Nasal Cannula: The New Mode of NIV in Pediatrics : A Working Protocol
Disclosure and Acknowledgement:
Authors have no affiliation what so ever to any of
the company manufacturing the high flow cannulae,
equipment. The information is to be used for
educational purpose only.
References
1. Dysart K, Miller TL, Wolfson MR, Shaffer TH. Research
in high flow therapy: mechanisms of action. Respiratory
Medicine 2009.;103:1400-5.
2. Groves N & Tobin A. High flow nasal oxygen generates
positive airway pressure in adult volunteers. Australian
Critical Care.2007, 20, 126—131
3. Spentzas T, Minarik M, Patters AB, Vinson B, Stidham G.
Children with respiratory distress treated with high-flow
nasal cannula. J Intensive Care Med 2009;24:323-8.
4. Schibler, A., Pham, T., Dunster, K., Foster, K., Barlow, A.,
Gibbons, K., and Hough, J. Reduced intubation rates for
infants after introduction of high-flow nasal prong oxygen
delivery. Intensive Care Medicine. May;2011,37(5):847-52.
5. McKieman, C., Chua, L.C., Visintainer, P. and Allen, P. High
Flow Nasal Cannulae Therapy in Infants with Bronchiolitis.
Journal of Pediatrics 2010, 156:634-38
HFNC and humidification Equipment specifications
are described as Manufactured by Fisher and Paykle,
and Intersurgical.
The working protocol is an adaptation as per
current High flow nasal prongs protocol (originally
developed by John Kemp, Clinical Support Nurse
and group 2014-2015) in use at Melbourne women
and childrens hospital, Melbourne Australia.
Vol. 2; No. 2; April - June 2015
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JOURNAL OF PEDIATRIC CRITICAL CARE
Drug Review
Dexmedetomidine
Sanjay Perkar, Nilesh Maniya, Ankur Ohri, Ankur Chawla, Rachna Sharma, Praveen Khilnani
Pediatric Intensive Care Unit, BLK Superspeciality Hospital, New Delhi
Dexmedetomine was approved by the Food and Drug
Administration (FDA) on December 24, 1999 for the
sedation of adults receiving mechanical ventilation
in an intensive care setting. It provides sedation with
minimal effects on respiratory function, and may be
used prior to, during, and following extubation. In
clinical trials of adults, dexmedetomidine produced
the desired level of sedation in approximately 80%
of patients with no additional agents. Concomitant
use of dexmedetomidine also allowed for a reduction
in the dose of midazolam or morphine.1-3 Based
on its efficacy in adults, dexmedetomidine is now
being explored as a possible alternative or adjunct to
benzodiazepines and opioids in the pediatric intensive
care setting. We shall review the papers describing
the efficacy and adverse effects of dexmedetomidine
in children.
A number of case reports, series, and small
studies have been published describing the use of
dexmedetomidine in infants and children. The initial
reports of its utility in this population were published
by Tobias, Berkenbosch, and Russo in two case
series4,5. The first described their experience with using
dexmedetomidine during mechanical ventilation, in
the operative setting, and for procedural sedation.4
The second paper described dexmedetomidine use
in five spontaneously breathing children requiring
sedation.5 Three were given a loading dose of 0.5
mcg/kg over 10 minutes followed by an intravenous
(IV) infusion of 0.25 mcg/kg/hr, titrated to response.
The remaining two patients, were given a single 0.5
mcg/kg bolus dose. All patients achieved adequate
sedation and tolerated dexmedetomidine without
adverse effects.
In 2004, these clinicians conducted a prospective
randomized, open-label trial comparing midazolam
and dexmedetomidine in children requiring
mechanical ventilation.6 Thirty children were
randomized to either midazolam, with a 0.1 mg/
kg loading dose followed by 0.1 mg/kg/hr, or
dexmedetomidine low dose (0.25 mcg/kg loading
dose followed by an infusion of 0.25 mcg/kg/hr) or
Vol. 2; No. 2; April - June 2015
high dose (0.5 mcg/kg followed by an infusion of 0.5
mcg/kg/hr). All infusions were titrated to maintain
adequate sedation. No differences were noted in
sedation scores or Bispectral Index Monitor (BIS)
scores among the groups. The children in the high dose
dexmedetomidine group required significantly fewer
supplemental morphine doses than the children given
midazolam. The total morphine use was also lowest
in this group. The number of inadequately sedated
children was also lower in the two dexmedetomidine
groups than in the midazolam group. Based on their
Results, the authors suggest that dexmedetomidine
at a dose of 0.25 mcg/kg/hr was approximately
equivalent to midazolam given at a rate of 0.22 mg/
kg/hr, and that a higher infusion rate (0.5 mcg/kg/hr)
may be more effective.6
Additional evidence comes from a brief report
of dexmedetomidine use in 48 pediatric patients
treated at Phoenix Children’s Hospital.7 The
patients (10 months-19 years of age) were given
dexmedetomidine in an intensive care unit, for a
variety of diagnoses, using a loading dose of 0.5 mcg/
kg given over 15 minutes, followed by an infusion
of 0.25 to 1.25 mcg/kg/hr. The duration of infusion
ranged from 12 to 144 hours. The most significant
adverse effect was hypotension. The author found
dexmedetomidine to be an effective sedative and
recommended further research in the pediatric
population.
In 2005, Berkenbosch, Wankum, and Tobias published
a prospective case series of 48 children (mean age
6.9±3.7 years) receiving dexmedetomidine for
procedural sedation.8 Thirty-three patients received
dexmedetomidine as their primary sedative, while
the remaining patients were treated after failing
midazolam and/or chloral hydrate. The majority of
the patients were sedated for a magnetic resonance
imaging (MRI) study, with the remaining patients
having an electroencephalogram, a nuclear medicine
study, or a combination of studies. Of note, more than
20% of the patients had an underlying neurologic
disorder.
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sedation after cardiac surgery, in the management
of iatrogenic opioid and benzodiazepine withdrawal
and cyclic vomiting syndrome.16-18 While the Results
of these preliminary reports are promising, additional
studies are needed to confirm their findings.
Dexmedetomidine was given with a loading dose of
0.92 ± 0.36 mcg/kg (range 0.3-1.92 mcg/kg) given
over 10 minutes, followed by an infusion of 0.69 ±
0.32 mcg/kg/hr (range 0.25-1.14 mcg/kg/hr). The
mean duration of the procedure was 47 ± 16 minutes,
with a mean recovery time of 84 ± 42 minutes. All
studies were performed successfully. There were
significant decreases from baseline in blood pressure
and heart rate (19.0 ± 18.4 mm Hg and 12.9 ± 12.3
beats/min, respectively), but parameters remained
within normal limits for age. There were also minor
decreases in respiratory rate (3 ± 3.5 breaths/min) and
oxygen saturation (2.6 ± 2%). The authors concluded
that dexmedetomidine was a useful alternative to
traditional options for procedural sedation.8
Koroglu and colleagues reported similar success in
their randomized trial comparing dexmedetomidine
and midazolam for the sedation of 80 children
(1-7 years of age) undergoing MRI.9 The patients
received a loading dose (1 mcg/kg dexmedetomidine
or 0.2 mg/kg midazolam) given over 10
minutes, followed by an infusion (0.5 mcg/kg/hr
dexmedetomidine or 6 mcg/kg/min midazolam).
Inadequate sedation was defined as movement
resulting in difficulty completing the study and the
need for rescue sedation. All patients successfully
completed the study. Adequate sedation was obtained
in 80% of the dexmedetomidine group, compared to
only 20% of the midazolam group. The requirement
for rescue sedation was significantly lower in the
dexmedetomidine group. Heart rate and mean blood
pressure declined in both groups, although no child
experienced significant bradycardia or hypotension.
Respiratory depression was not observed in any
of the children receiving dexmedetomidine, but
desaturation was noted in three children given
midazolam followed by rescue propofol.
Similar benefits have been observed when
dexmedetomidine was given as rescue therapy
to five children who failed therapy with chloral
hydrate and midazolam.10 Additional reports have
documented the utility of dexmedetomidine in
children requiring fiberoptic intubation and in
children undergoing awake craniotomy, sevoflurane
anesthesia, stereotactic radiosurgery and radiation
therapy.11-15 Dexmedetomidine has also been used for
Vol. 2; No. 2; April - June 2015
Adverse Reactions
The most significant adverse reactions associated
with dexmedetomidine are hypotension and
bradycardia, resulting from its sympatholytic activity.
In clinical trials of adults, 28% of patients receiving
dexmedetomidine
experienced
hypotension,
compared to 13% of patients given placebo.
Bradycardia was seen in 7% of treated patients versus
3% of controls. While a reduction in the infusion rate
or administration of IV fluids is often adequate to
alleviate these symptoms, administration of atropine
may be necessary in cases of significant bradycardia.
Transient hypertension has been reported with the
administration of the loading dose due to initial
peripheral vasoconstriction. In clinical trials, the
rate of hypertension was similar in treated patients
and controls (16% compared to 18%). Hypertension
rarely requires intervention beyond slowing the
infusion rate.2,3
Other
adverse
reactions
reported
with
dexmedetomidine during clinical trials included
nausea (11%), fever (5%), vomiting (4%), hypoxia
(4%), tachycardia (3%), and anemia (3%). It is
recommended that dexmedetomidine be used with
caution in patients with advanced heart block or severe
ventricular dysfunction, as well as in hypovolemic
patients or those with chronic hypertension.2,3
Dosing Recommendations
Based on the reports available to date, the
recommended adult dosage range of 0.2 to 0.7
mcg/kg/hr may also be used in children. In adults,
dexmedetomidine may be initiated with a loading
dose of 1 mcg/kg given over 10 minutes, but many
pediatric centers are reducing or omitting the loading
dose in an effort to avoid cardiovascular instability.
Dexmedetomidine may be prepared as a 2 mcg/mL
solution with normal saline or further diluted. It is
compatible with a wide range of IV fluids and drugs
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opioids or benzodiazepines. While dexmedetomidine
appears to be well tolerated, it has the potential to
cause significant hypotension and should be used
only in carefully monitored situations. Additional
controlled studies are needed to define the role of
dexmedetomidine in the sedation of infants and
children. It is now available in India.
frequently used in the pediatric intensive care setting,
including:2
Length of Infusion
Although it has not been well studied, it is possible
that abrupt cessation of dexmedetomidine may
produce withdrawal symptoms similar to those seen
with clonidine withdrawal (ie, agitation, irritability,
headache, and rebound hypertension). For that reason,
the manufacturer recommends that dexmedetomidine
not be used for more than 24 hours.2
In 2004, Shehabi and colleagues published the Results
of a prospective, open-label trial of dexmedetomidine
given for periods greater than 24 hours.20 Twenty
adults received dexmedetomidine for a median time
of 71.5 hours (range of 35 to 168 hours). No loading
dose was given, and the infusion was titrated to
maintain a Ramsay sedation score of 2 to 4. After
abrupt discontinuation of dexmedetomidine, the
mean increase in systolic blood pressure was 7%
(occurring 5 hours after stopping the infusion), with a
mean increase in heart rate of 11% (at 14 hours after
cessation).
In clinical practice, treatment for periods longer than
24 hours has been reported to be well tolerated. In an
observational study of 136 patients at 10 institutions,
Dasta and colleagues reported that a third of the
patients received dexmedetomidine for a period
greater than 24 hours.21 In those patients, the average
length of treatment was 54 hours, with a range of 24.5
to 123.5 hours. There were no reports of rebound
symptoms. Limited data are available regarding
prolonged administration to children. As described
earlier, Serlin reported use up to 144 hours.7 In 2005,
Hammer and colleagues reported the successful
use of dexmedetomidine for 4 days in a child after
tracheal reconstruction for subglottic stenosis.22
References
1. Munoz R, Berry D. Dexmedetomidine: promising drug
for pediatric sedation? [editorial] Pediatr Crit Care Med
2005;6:493-4.
2.Precedex® prescribing information. Hospira, Inc., April,
2004.
3. Dexmedetomidine. Drug Facts and Comparisons. Efacts
[online]. 2005. Available from Wolters Kluwer Health, Inc.
Accessed 11/7/05.
4.Tobias JD, Berkenbosch JW. Initial experience with
dexmedetomidine in paediatric-aged patients. Paediatr
Anaesth 2002;12:171-5.
5. Tobias JD, Berkenbosch JW, Russo P. Additional experience
with dexmedetomidine in pediatric patients. South Med J
2003;96:871-5.
6. Tobias JD, Berkenbosch JW. Sedation during mechanical
ventilation in infants and children: dexmedetomidine versus
midazolam. South Med J 2004;97:451-5.
7. Serlin S. Dexmedetomidine in pediatrics: controlled studies
needed. [letter] Anesth Analg 2004;98:1814.
8. Berkenbosch JW, Wankum PC, Tobias JD. Prospective
evaluation of dexmedetomidine for noninvasive procedural
sedation in children. Pediatr Crit Care Med 2005;6:435-9.
9.Koroglu A, Demirbilek S, Teksan H, et al. Sedative,
haemodynamic and respiratory effects of dexmedetomidine
in children undergoing magnetic resonance imaging
examination: preliminary results. Br J Anaesth 2005;94:8214.
10.Nichols DP, Berkenbosch JW, Tobias JD. Rescue sedation
with dexmedetomidine for diagnostic imaging: a preliminary
report. Paediatr Anaesth 2005;15;199-203.
11.Jooste EH, Ohkawa S, Sun LS. Fiberoptic intubation
with dexmedetomidine in two children with spinal cord
impingements. [letter] Anesth Analg 2005;101:1238-48.
12.Ard J, Doyle W, Bekker A. Awake craniotomy with
dexmedetomidine in pediatric patients. J Neurosurg Anesth
2003;15:263-6.
13.Ibacache ME, Munoz HR, Brandes V, et al. Single-dose
dexmedetomidine reduces agitation after sevoflurane
anesthesia in children. Anesth Analg 2004;98:60-3.
14.Fahy CJ, Okumura M. Sedation for paediatric stereotactic
radiosurgery: the dexmedetomidine experience. Anaesth
Intensive Care 2004;32;809-11.
15.Shukry M, Ramadhyani U. Dexmedetomidine as the primary
sedative agent for brain radiation therapy in a 21- month old
child. Paediatr Anaesth 2005;15;241-2.
Summary
Dexmedetomidine offers an additional choice
for the sedation of children receiving mechanical
ventilation or requiring procedural sedation. It may
be particularly useful in children with underlying
neurologic disorders, who often develop agitation or
adverse hemodynamic and respiratory effects with
Vol. 2; No. 2; April - June 2015
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JOURNAL OF PEDIATRIC CRITICAL CARE
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Sedation Drug Review Dexmedetomidine
16.Chryostomou C, Zeballos T. Use of dexmedetomidine in
a pediatric heart transplant patient. Pediatr Cardiol 2005;
published on-line 8/11/05 (accessed 11/7/05).
17.Finkel JC, Elrefai A. The use of dexmedetomidine to
facilitate opioids and benzodiazepine detoxification in an
infant. Anesth Analg 2004;98:1658-9.
18.Khasawinah TA, Ramirex A, Berkenbosch JW, et al.
Preliminary experience with dexmedetomidine in the
treatment of cyclic vomiting syndrome. Am J Therapeut
2003;10:303-7.
19.Berkenbosch JW, Tobias JD. Development of bradycardia
during sedation with dexmedetomidine in an infant
Vol. 2; No. 2; April - June 2015
concurrently receiving digoxin. Pediatr Crit Care Med
2003;4:203-5.
20.Shehabi Y, Ruettimann U, Adamson H, et al. Intensive Care
Med 2004;30:2188-96.
21.
Dasta JF, Kane-Gill SL, Durtschi AJ. Comparing
dexmedetomidine prescribing patterns and safety in the
naturalistic setting versus published data. Ann Pharmacother
2004;38:1130-5.
22.Hammer GB, Philip BM, Schroeder AR, et al. Prolonged
infusion of dexmedetomidine for sedation following tracheal
resection. Paediatr Anaesth 2005;15;616-20.
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Dr Nameet Jerath*, Dr Anubhav Jain**
*Senior Consultant Pediatric Intensive Care
**Senior Resident Pediatric Intensive Care
Indraprastha Apollo Hopsital, New Delhi
1. Use of High-Flow Nasal Cannula Oxygen
Therapy to Prevent Desaturation During
Tracheal Intubation of Intensive Care Patients
With Mild-to-Moderate Hypoxemia;
analysis, preoxygenation with high-flow nasal
cannula oxygen was an independent protective
factor of the occurrence of severe hypoxemia
(p = 0.037).This study concluded that high-flow
nasal cannula oxygen significantly improved
preoxygenation and reduced prevalence of severe
hypoxemia compared with nonrebreathing bag
reservoir facemask and it’s use could improve
patient safety during intubation.
Romain Miguel-Montanes et al
Crit Care Med 2015; 43:574–583
This prospective quasi-experimental beforeafter study, was undertaken to evaluate preand per procedure oxygenation with either a
nonrebreathing bag (NRM) reservoir facemask
or a high-flow nasal cannula (HFNC) oxygen
during tracheal intubation of ICU patients. Study
was conducted on all adult patients requiring
tracheal intubation in the ICU over a period.
Preoxygenation was performed initialy with
a NRM reservoir facemask and later with the
change of practice, with high-flow nasal cannula
oxygen. Primary outcome noted were median
lowest Spo2 during intubation, and secondary
outcomes were Spo2 after preoxygenation and
the number of patients with saturation less than
80%. Patients excluded were age under 18 years,
intubation for cardiac arrest, severe hypoxemia
Spo2 < 95% under a NRM (with an oxygen flow
of 15 L/min), patients already receiving HFNC,
and patients under non invasive ventilation. One
hundred one patients were included, fulfilling the
inclusion criteria. Median lowest Spo2 during
intubation were 94% (83–98.5) with the NRM bag
reservoir facemask versus 100% (95–100) with
HFNC oxygen (p < 0.0001). Spo2 values at the
end of preoxygenation were higher with HFNC
oxygen than with NRM bag reservoir facemask
and were correlated with the lowest Spo2 reached
during the intubation procedure (p < 0.0001).
Patients in the NRM bag reservoir facemask group
experienced more episodes of severe hypoxemia
(2% vs 14%, p = 0.03). In the multivariate
Vol. 2; No. 2; April - June 2015
Comments
Though an adult study excluding patients with
severe hypoxemia to start with, this study throws
out some interesting observations regarding use of
HFNC as a tool to preoxygenate during intubation.
The advantage of continuing oxygen flow during
intubation without interruption probably helps in
apneic oxygenation with delivery of high Fio2,
pharyngeal dead space washout with optimal
conditioning of inspired gases, and to a certain extent
positive pressure, helping in alveolar recruitment.
Patients with severe hypoxemia are the most
challenging and were excluded from this study.
The practice for this group remains initiation of
bag-mask ventilation after muscle relaxation to
aid the procedure of intubation.
It would be interesting to see how this study
extrapolates to children. Children have a lower
FRC as compared to adults and HFNC may offer
an advantage over NRM in children too.
2.Characteristics and Outcomes of Patients
Admitted to ICU Following Activation of
the Medical Emergency Team: Impact of
Introducing a Two-Tier Response System
Anders Aneman, Steven A. Frost et al
Crit Care Med 2015; 43:765–773
This retrospective observational study was
done on 1,564 ICU admissions. To determine
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They did observe early recognition of reversible
cardiorespiratory conditions, resulting in more of
these patients getting admitted to ICUs directly
without the review by MET team. And the
mortality of patients admitted by MET review
decreased presumable because they were picked
up early by the first tier.
This two-tier arrangement may be useful in busy
hospitals with too many MET activations, as in the
study hospital. But the primary team is and should
be expected to review all patients with concerns.
And this study shows us just that, the primary
team when put to good does detect deteriorations
early and improve outcomes.
the impact of introducing a two-tier system for
responding to deteriorating ward patients on
ICU admissions after medical emergency team
review. In this system, the parent clinical team
responds to less serious first tier criteria, and
the RRS is activated when the patient meets
the more serious second-tier criteria. Though
the median number of medical emergency team
activations/1,000 hospitalizations increased from
22 to 31 (p < 0.0001) but with a decreased rate
of medical emergency team activations leading to
ICU admission (p = 0.03). The median proportion
of medical emergency team reviews leading to
ICU admission increased for those triggered by
tachypnoea (from 11% to 15%;p < 0.0001) and by
hypotension (from 27% to 43%;p < 0.0001) and
decreased for those triggered by reduced level
of consciousness (from 20% to 17%;p < 0.0001)
and by clinical concern (from 18% to 9%;p <
0.0001). The proportions of ICU admissions
following medical emergency team review did not
change significantly for tachycardia, seizure, or
cardiorespiratory arrest. The overall ICU mortality
for admissions following medical emergency
team review for tachypnoea, tachycardia, and
clinical concern decreased (from 29% to 9% p <
0.0001) but did not change for the other triggers.
The introduction of a two-tier response to clinical
deterioration increased ICU admissions triggered
by cardiorespiratory criteria, whereas admissions
triggered by more subjective criteria decreased.
The overall ICU mortality for patients admitted
following medical emergency team review
decreased, suggesting that the two-tier system led
to earlier recognition of reversible pathology or a
decision not to escalate the level of care.
3.Comparison of Video Laryngoscopy Versus
Direct
Laryngoscopy
During
Urgent
Endotracheal Intubation: A Randomized
Controlled Trial
Michael J. Silverberg, Nan Li et al:
Crit Care Med 2015; 43:636–641
This study hypothesized that Glidescope video
laryngoscopy (GVL) would be superior to direct
laryngoscopy (DL) during urgent endotracheal
intubation. The investigators did a prospective
randomized controlled trial on 117 patients,
intubated using GVL or direct laryngoscopy.
Patients excluded were if the intubation was
elective or had a known history of difficult
intubation, presence of limited mouth opening,
oropharyngeal masses, or swollen tongue,
suggesting the inability to use a DL or GVL, or
oxygen saturation less than 92% after bag valve
mask ventilation. Cardiac arrest patients were not
excluded. Patients undergoing urgent endotracheal
intubation were randomized to GVL or DL as the
primary intubation device. Acute Physiology and
Chronic Health Evaluation II scores were similar
between the two groups. First-attempt success was
achieved in 74% of the GVL group compared to
40% in the DL group (p < 0.001). All unsuccessful
DL patients were successfully intubated with
GVL, 82% on the first attempt. There was no
significant difference in rates of complications
between DL and GVL: esophageal intubations
Comments
The utility of a rapid response team is almost
established now. It consists of a team usually drawn
from the ICU and/or Emergency departments to
respond to acute deteriorations in the wards. The
idea is to catch them early and hopefully prevent
further deterioration with optimal treatment.
This study reviewed a two-tier system introduced
in a Sydney hospital where in the first responders
are the primary admitting team. The rapid
response team comes into play as the second tier.
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(7% vs 0%; p = 0.05), aspiration events (7% vs
9%; p = 0.69), desaturation (8% vs 4%; p = 0.27),
and hypotension (13% vs 11%; p = 0.64). They
concluded that Glidescope video laryngoscopy
improves the first-attempt success rate during
urgent endotracheal intubation performed by
pulmonary and critical care medicine fellows
when compared with direct laryngoscopy.
They were then randomly assigned to undergo
suctioning (n=170) and no suctioning (n= 182).
In the study, microbiologically confirmed
ventilator associated pneumonia occurred in 15
patients of group 1 and 32 patients of group 2
(p=0.018). In terms of ventilator days, ventilatorassociated pneumonia rates were 9.6 of 1,000
ventilator days and 19.8 of 1,000 ventilator days,
respectively (p=0.0076). Ventilator-associated
condition prevalence was 21.8% in group 1 and
22.5% in group 2 (p = 0.84). Among the 47 patients
with ventilator-associated pneumonia, 25 (58.2%)
experienced a ventilator-associated condition.
Neither length of ICU stay nor mortality differed
between groups; only ventilator-associated
condition was associated with increased mortality.
The total number of antibiotic days was 1,696 in
group 1, representing 61.6% of the 2,754 ICU
days, and 1,965 in group 2, representing 68.5% of
the 2,868 ICU days (p=< 0.0001).
The group confirmed the efficacy of subglottic
secretion suctioning in significantly reduction
of VAP and that this preventive measure should
be part of the VAP bundle in their conclusions.
Subglottic suctioning did not change the rate of
Ventilator associated conditions.
Comments
Urgent endotracheal intubation is a common
procedure in the emergency room. In the era of
advanced and high quality care, such a common
procedure should have high success rates and
less of comorbidities. Video laryngoscopes have
been recently available as an alternative to aid
intubations with supposedly better success rates
by “not yet trained” staff-read fellows.
In this study, Glidescope video laryngoscopy have
shown better results to DL in first-attempt success
even among nonexpert practitioners though the
comorbidities remained the same. Additionaly the
steeper learning curve observed with GVL makes it
a particularly suitable device for use in the critically
ill given their high complication rates, extensive
comorbidities, and lower cardiopulmonary reserve.
However, there is concern that only learning the
GVL leaves a skill gap that may be important in a
situation where a GVL is not available, not working,
or where a DL may be a more appropriate device.
Comments
VAP bundles have failed to show further reductions
in the incidence of VAP. Morever the definition of
VAP itself has come under scrutiny and ventilator
associated condition (VAC) has been proposed as
a better marker of surveillance.
One of the postulated contributors to VAP is
aspiration of subglottic secretions. This study
assessed the benefits of suctioning the subglottis
(below the cords, above the tracheal tube cuff) in
preventing VAP in a center where VAP bundle is
already enforced. They did notice a reduction in
the incidence of VAP and the associated antibiotic
days. There was no change in the newly proposed
VAC rate.
Whether this should become a part of VAP bundle
in our ICUs is still to be studied and assessed.
Frequent use of smaller tubes, uncuffed tubes and
technical feasibility of a suctioning port may be
some of the hindrances.
4. Prevention of Ventilator-Associated Pneumonia
and Ventilator-Associated Conditions: A
Randomized Controlled Trial With Subglottic
Secretion Suctioning
Pierre Damas, Frédéric Frippiat et al
Crit Care Med 2015; 43:22–30
In this Belgian study a randomized controlled
clinical trial was done on adult patients admitted in
ICU intubated with an endotracheal tube allowing
subglottic secretion suctioning. The study was done
to document the efficacy of subglottic suctioning
in all ICUs of a tertiary hospital in which a VAP
bundle was already in use for 2 years. 352 adult
patients intubated with a tracheal tube allowing
subglottic secretion suctioning were included.
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5.Association of Timing of Tracheostomy on
Clinical Outcomes in PICU Patients
with the increasing complexities of diseases being
managed in the ICUs. Earlier tracheostomy was
considered early if performed prior to 21 days
of mechanical ventilation. More recent studies
describe early tracheostomy between 2 and 10 days,
with late tracheostomy occurring after 14 days.
Current study recommends early tracheostomy
benefits without adversely affecting mortality.
It is important to review this study in the background
of the TracMan trial (JAMA. 2013;309(20):21212129) where early tracheostomy (within 4 days)
was not shown to have any benefits compared to
late tracheostomy (after 10 days).
We probably are not too good at predicting
duration of mechanical ventilation to consider
early tracheostomy in adults at least. We would
need more convincing studies before routine
“early” tracheostomy is recommended in children.
Adrian J. Holloway, Michael C. Spaeder et al:
Pediatric Crit Care Med 2015; 16: e52–e58
Tracheostomy is a common procedure in the
ICU when prolonged mechanical ventilation is
expected. This study, a retrospective cohort study
was done to associate timing of tracheostomy with
clinical outcomes in PICU patients. Patients were
stratified by the number of ICU days elapsed prior
to tracheostomy. Early tracheostomy was defined
as less than 14 days following ICU admission and
late tracheostomy as greater than or equal to 14
days following ICU admission.
88 patients underwent elective tracheostomy.
15 patients met exclusion criteria: five patients
had scheduled elective tracheostomy while at
their baseline state of health, two patients had
emergent tracheostomy placement, and eight
patients had no invasive mechanical ventilation
requirements prior to tracheostomy. 24 patients
had early tracheostomy and 49 underwent
late tracheostomy. Patients undergoing early
tracheostomy had a lower severity of illness at
ICU admission p = 0.03. Post-tracheostomy ICU
length of stay (LOS) was 4 days shorter and posttracheostomy hospital LOS was 5 days shorter in
patients who had underwent early tracheostomy.
Adjusting for Paediatric Index of Mortality 2 risk of
mortality, post-tracheostomy ICU LOS remained
shorter in the early tracheostomy group (p = 0.04).
Total hospital LOS was over 4 weeks shorter in
patients who underwent early tracheostomy
(p < 0.001). There was no difference in mortality
in relation to timing of tracheostomy.
Study concluded that a longer duration of
ventilation prior to tracheostomy is associated
with increased ICU morbidities and length of stay.
Early tracheostomy may have significant benefits
without adversely affecting mortality.
6. Pediatric Critical Care Physician-Administered
Procedural Sedation Using Propofol: A
Report From the Pediatric Sedation Research
Consortium Database
Pradip P. Kamat, Courtney E. McCracken et al:
Pediatric Crit Care Med 2015; 16:11–20
This study is an observational cohort review
of a prospectively collected research database
from Pediatric Sedation Research Consortium
[PSRC] of patients who were given propofol
for procedural sedation by pediatric critical care
physicians outside of the operating rooms. A total
of 91,189 sedations using propofol were analysed
from the database over a five-year period. Most
sedations were performed in dedicated sedation or
radiology units. A propofol bolus alone was used in
52.8%, and 41.7% received bolus plus continuous
infusion. Commonly used adjunctive medications
were lidocaine (35.3%), opioids (23.3%), and
benzodiazepines(16.4%). Successful completion
of a procedure was documented as an outcome
measure. Study assessed the incidence of adverse
events (AE) and serious AEs (SAE) as outcome
measures.
Of 91,189 recorded sedations, 4,596 sedations had
one or more SAE. Procedures were successfully
Comments
Tracheostomy is a common procedure in
patients expected for prolong ventilation. Rate of
tracheostomies have increased during recent times
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completed in 99.9% of patients . Overall
adverse event incidence was 5.0% (95%CI,
4.9–5.2%), which included airway obstruction
(1.6%), desaturation (1.5%), coughing (1.0%),
and emergent airway intervention (0.7%). AE
and SAE rates varied significantly by location
(p < 0.001 for both rates). Risk factors associated
with adverse event included: location of sedation,
number of adjunctive medications, upper
and lower respiratory diagnosis, prematurity
diagnosis.
The study concluded that Pediatric procedural
sedation performed using propofol can be
performed by pediatric subspecialists such as
pediatric critical care physicians with a very high
rate of successful completion and with a low
incidence of AE. AE rates are impacted by location
of sedation and the use of multiple medications.
database which is the largest prospectively collected
database in severe sepsis and septic shock patients
that also records clinical practice patterns over
time and has been used to improve outcomes. They
evaluated lactate elevation (with special attention
to values > 4 mmol/L) and presence or absence
of hypotension as a marker of clinical outcome.
SSC database consisted of 28,150 patients at 218
hospitals which were analysed while 4,419 subjects
were missing serum lactate measurements and were
excluded. The in-hospital mortality odds ratios
were 1.17 (p = 0.153), 0.97 (p = 0.721), and 1.64
(p < 0.001) for lactate greater than 4 mmol/L and
not hypotensive, lactate less than or equal to 4
mmol/L and hypotensive, and lactate greater than
4 mmol/L and hypotensive, respectively. Patients
who presented with lactate greater than 4 mmol/L
with hypotension showed a significantly higher
mortality of 44.5% compared with the other three
groups, who had a mortality of approximately 29%.
In patients with high lactate levels (> 4 mmol/L)
who were not hypotensive, i.e., patients with the socalled cryptic septic shock, the adjusted odds ratios
were not statistically significant.
All lactate values greater than or equal to 2
mmol/L have a clinical value because their
association with increased mortality is shown to
increase linearly.
This supports the use of the cutoff of greater
than 4 mmol/L as a qualifier for future clinical
trials in severe sepsis or septic shock in patient
populations who use quantitative resuscitation
and the Surviving Sepsis Campaign bundles as
standard of care.
Comments
Propofol is considered as the sedative-hypnotic
agent of choice for pediatric procedural sedation,
where it has been sanctioned by hospital policy.
Rapid onset, reliable onset of deep sedation/
anesthesia, and short duration of action, which
results in rapid recovery, and minimal adverse
events are among the benefits of propofol.
There have been some concerns of use of propofol
by non-anesthesiologists outside of the operating
rooms. This study is another approval of sorts for
the safe use of propofol for procedural sedation
in children by trained pediatric critical care
physicians.
There is a word of caution though. The incidence
of adverse effects was about 5%. The place
of sedation and presence of upper or lower
respiratory infection increased the risk of adverse
events. The drug is safe only in safe hands.
Comments
Lactate is a useful predictor of outcome in severe
sepsis and septic shock and it is commonly used
in ICU. However the true role of lactate in severe
sepsis is still controversial.
This review of surviving sepsis campaign database
shows a linear relationship between rising lactate
levels and in hospital mortality. Especially lactate
levels more than 4mmol/L and hypotension
are associated with significant mortality. The
surviving sepsis bundle now does emphasize on
lactate clearance as a resuscitation target.
7.
Lactate Measurements in Sepsis-Induced
Tissue Hypoperfusion: Results From the
Surviving Sepsis Campaign Database
Brian Casserly, Gary S. Phillips et al
Crit Care Med 2015; 43:567–573
This article analysed the Surviving Sepsis Campaign
Vol. 2; No. 2; April - June 2015
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JOURNAL OF PEDIATRIC CRITICAL CARE
Case Report
Dengue Encephalitis Presenting as Febrile Status Epilepticus: A Case
Report
V S V Prasad
Pediatric Intensive Care Unit, Lotus Childrens Hospital, Hyderabad
ABSTRACT
Dengue fever is the most important Arboviral infection in the world, with an estimated 100 million cases of
dengue infection worldwide every year with a large proportion of patients being children (1). Encephalitis is
a rare complication of dengue virus infection and may occur as a consequence of intracranial hemorrhage,
cerebral edema, hyponatremia, cerebral anoxia, release of toxic products or direct viral invasion.
Key words- Dengue fever, Encephalitis, Cerebral Edema, ICH.
Dengue fever is the most important Mosquitotransmitted disease in terms of morbidity and
mortality. It is caused by one of the four related but
distinct, Flavivirus serotypes (DEN 1-4).
Clinical symptoms range from mild fever to a severe
and potentially life threatening hemorrhagic disease.
Early recognition, careful monitoring and appropriate
fluid therapy has resulted in a decline in mortality rate
to 1-5%. Various atypical manifestations of dengue
virus infection including CNS involvement have
been reported1-4. The prognosis is poor in patiens with
CNS involvement. Encephalopathy/Encephalitis is
a rare complication of dengue virus infection and
may occur due to intracranial hemorrhage, cerebral
edema, hyponatremia, cerebral anoxia, or toxic
encephalopathy.
We present a case of Dengue Encephalitis in a three
year old girl, presenting as febrile status epilepticus.
and resuscitated appropriately. Seizure control was
achieved with a stat dose of intravenous Lorazepam
and followed up with the standard loading dose of
intravenous phenytoin A provisional diagnosis of
febrile status epilepticus was considered at this point
in time.
Her initial laboratory investigations (hematological,
liver function tests and coagulation profile) were
within norma limitsl. Blood culture drawn at
admission was sterile. Rapid diagnostic test for
malaria was negative. Dengue NS1 Antigen test was
positive. A neuroimaging study (CT Plain) and CSF
analysis were reported normal.
She improved subsequently and was clinically
and hemodynamically stable and was successfully
extubated 12 hours later. The immediate post
extubation period was uneventful. Her sensorium
remained normal and she was seizure free for
more than 24 hours on a maintainance dose of
phenytoin. However, she continued to remain febrile.
Her repeat blood counts 24 hours later revealed
thrombocytopenia. Her neurological condition
worsened with progressive irritability followed by
recurrence of seizures with poor respiratory efforts
and signs of intravascular hypovolemia despite
subcutaneous edema. She had to be emergently
intubated and mechanically ventilated. Neurological
examination revealed anisocoria with poor muscle tone
and power with areflexia. Her repeat neuroimaging
study (CT- Brain) revealed effacement of sulcal and
cisternal space with obliteration of the third and
fourth ventricles suggestive of cerebral edema. Her
Case Report
A previously healthy 3 year old girl was admitted
with a history of high grade fever and vomiting
for one day, and was brought to ER in continuous
status epilepticus. On arrival, she was febrile with
altered sensorium and a Glagow Coma Scale of 7/15,
with signs of shock. She was electively intubated
Correspondence:
Dr. V.S.V PRASAD
Deparment of Pediatric Intensive Care
Lotus Childrens’ Hospital, Hyderabad.
Email: [email protected]
Tel: +9140404444 / 40404400.
Vol. 2; No. 2; April - June 2015
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JOURNAL OF PEDIATRIC CRITICAL CARE
Case Report
Dengue Encephalitis Presenting as Febrile Status Epilepticus: A Case Report
condition deteriorated rapidly despite institution of
all neuroprotective measures and supportive care.
Her pupils remained, mid dilated, fixed and nonreactive with no spontaneous respiratory efforts.
She had signs of severe brain stem dysfunction
and a repeat EEG showed iso-electric tracing. She
succumbed thereafter over the next 24 hours.
Normal EEG
Normal CT Scan
Abnormal EEG
Figure 2 EEG Patient
Discussion
The relationship between severe dengue fever
and neurological disturbance was first described
in 1976 and since then several publications have
added to the information available on the disease(1-9).
Encephalopathy/Encephalitis in severe dengue
Abnormal CT Scan
Figure 1
Lab Data↓ Day 1 of Illness
23/08
Hb – (gm/dl)
10
Ht (Hematolint)– (%) 33
TLC 12.700
AST / ALT (U/L)
N
Platelets
BUN – (mg/dl)
Creatinine (mg/dl)
APTT/PT/INR
Na+ (meq/L)
K+ (meq/L)
CSF
NS1 Angtigen
24/08
25/08
10.1
29
5500
26/08
9.2
28.4/9.2
2900
4,40,000
66,000
75,000
N
48.1/17.5/ 1.33
N
>100/18.1/1.3
146
178, 179
3.3
2.7, 3.2
SGOT=211
SGPT=94.6
136
4
(CSF=Cells-4 (L) Sugar-76.5, Protein-88.7 HSV PCR –Ve,
+Ve
Vol. 2; No. 2; April - June 2015
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JOURNAL OF PEDIATRIC CRITICAL CARE
Case Report
Dengue Encephalitis Presenting as Febrile Status Epilepticus: A Case Report
absence of other features of systemic disease can
present early during viremia and carries grave
prognosis. A high index of suspicion and aggressive
management may decrease the high risk of mortality
associated with this disease.
is an atypical manifestation and may appear in
various forms including altered sensorium, seizures,
meningeal involvement, behavioural disorder and
focal signs.
Pathophysiology of neurological involvement
may include the following factors: direct tissue
lesions caused by virus, capillary hemorrhage,
Disseminated intravascular coagulation (DIC),
metabolic disorder (hyponatremia and metabolic
acidosis) and cerebral edema caused by increased
vascular permeability2-4. In this particular patient
transient improvement in neutrological status
followed by progressive deterioration was deceptive.
One explanation could be a continued Capillary
leakage in the CNS even without any evidence of
excessive fluid therapy leading to cerebral edema
in addition to an inflammatory process triggered by
Dengue virus leading to progression of encephalitis.
In a series of six cases of encephalopathy, Lum et
al (1996) identified the dengue virus in cases with
clinical picture of encephalitis, confirmed by CSF
microscopy and EEG3, 4.
In dengue endemic areas Pancharoen et al identified
patients with Encephalitis/Encephalopathy without
other features of disease, and on investigation found
to be Dengue positive. Dengue virus antigen was
detected in the cortical gray matter by IHC 5-9.
Referreces
1. Solomon T. Dung N.M. et al. Neurological manifestations of
dengue infection. The Lancet Mar 2000; 355 : 1053-9
2. Kho L.K. Sumarmo H; wulur E.C. et al. Dengue Hemorrhagic
Fever accompanied by Encephalopathy in Jakarta Southeast
Asian J Trop Med Public Health 1981; 23 : 83-6.
3. Lum L.C., Lam S.K., Choy Y.S., et al. Dengue Encephalitis:
A True Entity ?. Am J Trop Med Hyg 1996; 54: 256-59
4. Angikand G. Luaute J. Laille M. et al. Brain involvement in
Dengue Fever. Journal of Clinical Neuroscience 2001; 8 : 63 – 5.
5. Kuuo G., Gomez I., Gubler D.J. Detecting anti dengue IgM
immune complexes using an enzyme linked immunosorbent
assay. An J Trop Med Hyg 1987: 36 : 153-9
6.Thakare J. Walhecar B. Banerjee K. Hemorrhagic
Manifestations and Encephalopathy in cases of Dengue in
India. Southeast Asian J Trop Med Public Health 1996; 27 ;
471-75
7. Pancharoen C., Thisyakoran U. Neurological Manifestations
in Dengue patients. Southeast Asian J Trop Med Public
Health 2001; 32 : 341 – 45
8. Migostoric M.P. Ramor R.G., Nicol A.F. et al. Retrospective
study on dengue fatal cases. Clinical Neuropath 1997 ; 16 :
204-8
9. Nogueira R.M.R., Filippis A.M.B. Coelho J.M.O. et al.
Dengue virus infection of the cetnral nervous systems (CNS):
A case report from Brazil, South Asian J. Trop Med public
Health 2002: 33: 68-71.
Conclusion
Encephalitis is a rare manifestation of severe dengue
fever. Neurological manifestations of Dengue in
Vol. 2; No. 2; April - June 2015
74
JOURNAL OF PEDIATRIC CRITICAL CARE
Case Report
Catastrophic Neurologic Manifestations of a Common
Immunodeficiency Syndrome
Nitika Agrawal*, Gnanam Ram*, Shiv Kumar*, Bidisha Banarjee**
*Deptt. of Pediatric Intensive Care Unit, **Deptt. of Pediatric Neurology, Manipal Hospital, Bangalore, India
ABSTRACT
A high index of suspicion is needed in pediatric patients with neurological symptoms being the sole
presenting manifestation, to diagnose infection with the Human Immunodeficiency Virus (HIV). This is
a write up of two such cases who were admitted to the pediatric intensive care unit with neurological
manifestations.
A 6 year old previously healthy child, who initially presented with intermittent drowsiness and fluctuation
in blood pressure, later during hospital stay, developed progressive motor, cognitive, visual and language
difficulties. Investigations revealed the child to be HIV positive and magnetic resonance imaging (MRI)
findings were consistent with progressive multifocal leucoencephalopathy.
A 12 yr old child had stroke initially (for which extensive work up had been done) and later, after 8 months
presented with the same complaints along with severe pneumonia .He succumbed to severe opportunistic
infections. That he was HIV positive, had not been detected during the first admission as left sided weakness
was the only presenting manifestation.
Key words- HIV, Children, Leukoencephalopathy, neurological manifestations, progressive
anion gap metabolic acidosis. As he continued to
have intermittent drowsiness and hypertension, a
magnetic resonance imaging (MRI) was done which
revealed symmetrical foci of restricted diffusion and
subtle flair hyperintensity in bilateral globi pallidi.
Considering the metabolic abnormalities and the
MRI findings, organic academia (methylmelonic
academia) was suspected but work up for organic
academia (tandem mass spectrometry and urine for
organic acids) was negative. During further hospital
stay child had weight loss, rigidity, choreoathetoid
movements, worsening cognition and aphasia.
Further work up done for wilson disease (24 hr urine
copper) was negative. HIV ELISA was done due to
weight loss (in the 10 days of hospital stay) and new
onset loose stools. It was positive and confirmation
was done by Western blot analysis. Both parents
were also found to be HIV positive. Repeat MRI
revealed mutifocal bilateral fairly symmetrical
white matter hyper intensities in frontal, parietal,
occipital lobes and cerebellar hemispheres along
with lesions in bilateral globi pallidi. Diagnosis of
Case Report
Case -1
A 6 Yr old previously healthy boy, born of second
degree consanguinous marriage had been admitted
with complaints of headache, non bilious vomiting
and lethargy for 6 days. There had been no history of
fever, weight loss, cough or loose stools. Child had
a past history of urinary tract infection (klebseilla)
20 days ago. On examination he was drowsy
(responding to verbal commands) with neck stiffness
and intermittent hypertension. He had been started on
antibiotics and acyclovir, pending cerebro-spinal fluid
(CSF) reports. Initial computerized tomography (CT)
brain was normal. CSF, blood and urine screening
for infection were negative. Blood investigations
revealed hyponatremia, hypokalemia and a high
Correspondence:
Dr Nitika Aggarwal DNB FNB
Deptt. Of pediatric intensive care unit, Manipal Hospital,
Bangalore, India
E-mail: [email protected]
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JOURNAL OF PEDIATRIC CRITICAL CARE
Case Report
Catastrophic Neurologic Manifestations of a Common Immunodeficiency Syndrome
possible progressive multifocal leucoencephalopathy
(PML) was made based on clinical and neuroimaging
evidence. He was shifted to another hospital with a
dedicated anti retroviral therapy (ART) center for
further treatment, as per parents request. He expired
after a month’s time.
of affected children are not on proper anti retroviral
therapy, progressive HIV-1 encephalopathy is the
main CNS manifestation.3 A presentation with stroke
or progressive multifocal leukoencephalopathy in
otherwise undiagnosed HIV children is limited to
case reports.
Progressive multifocal leukoencephalopathy (PML)
is a demyelinating disease of the CNS cause by
ubiquitous John Cunningham (JC) virus. PML is
an AIDS defining illness and HIV associated cases
account for up to 85% of all cases of PML.4 It has
been documented in persons having CD4 count
>200 as well, suggesting the diagnosis as a immune
reconstitution inflammatory syndrome.5
The gold standard for diagnosis of PML requires
typical histopathologic triad (demyelination, bizarre
astrocytes, and enlarged oligodendroglial nuclei)
coupled with demonstration of presence of JC virus.6
However with facility constraints, a clinical finding
with brain imaging can be diagnostic for possible
PML. MRI brain is notably superior to other imaging
modalities. Similar MRI findings may be seen in
multiple sclerosis and AIDS associated dementia.
However, dementia or multiple sclerosis is rare in
children.
The area showing involvements are frontal and
parieto-occipital lobe in majority although other
brain areas have been described as well.6,7 On MRI,
the affected regions are hypointense on T1- weighted
images and hyperintense on T2-weighted and fluidattenuated inversion recovery (FLAIR).
There is no definitive treatment for PML. Various
trials of cytotoxic, immunomodulatory and antiviral
agents have not shown promising benefits.8 An initial
benefit of mefloquine has been noted, but later on
refuted by larger trial9,10 During pre-highly active
antiretroviral therapy (HAART) era, survival was
extremely poor in adults and children with PML.
Survival among adults has improved during HAART
era from 10% to 50% and mean time of survival from
time of diagnosis of PML has increased from 0.4 %
to 1.8 yrs.11,12 No comparable data exists for children.
Stroke is most common cause of focal neurological
deficit in children with HIV-1. The prevalence varies
from 1-5%.13,14 HIV infection is believed to cause
stroke by predisposing to opportunistic infections,
Case -2
A 12 yr boy weighing 28 kg was referred for
complaints of fever, cough, worsening tachypnea with
left hemiparesis for the last two weeks. There was a
past history of left upper limb monoparesis 8 months
ago. MRI done for the same then, had revealed an
ischemic infarct involving the right parieto-occipital,
semiovale and frontal regions. Extensive work up
had been done during that episode and he had been
discharged home on physiotherapy.
This time he had to be intubated and ventilated for
respiratory failure (pneumonia with acute respiratory
distress syndrome). Investigations revealed child to
be HIV positive with total leucocyte count 6520/mm3
CD4 count 0.52% with CD4/CD8 ratio 0.01, viral
load of HIV-1 ribonucleic acid (RNA) polymerase
chain reaction (PCR) 2,14,895 copies/milliliter.
Chest skiagram and computerized tomography (CT)
thorax were suggestive of Pneumocystis carini/
cytomegalovirus (CMV) infection. A bronchoalveolar
lavage was done which was positive for CMV PCR.
Child also had evidence of CMV retinitis. Child was
treated with antibiotics for opportunistic bacterial
infections, gancyclovir along with anti retroviral
therapy. He succumbed to sepsis and multiorgan
failure after a month of pediatric intensive care unit
stay. As parents denied consent for their HIV test it
was not done.
Discussion
The neurological manifestations of Acquired
Immunodeficiency Syndrome (AIDS) may result from
direct neuronal infection, cytokine mediated effects
of virus and/or immune dysregulation.1 Incidence
of central nervous system (CNS) involvement is 3
times more in children than in adults. Neurological
involvement has been reported in 50-60% of children
with HIV and is the initial manifestation in up to 18 %
of children.2 In developing countries where majority
Vol. 2; No. 2; April - June 2015
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JOURNAL OF PEDIATRIC CRITICAL CARE
Case Report
Catastrophic Neurologic Manifestations of a Common Immunodeficiency Syndrome
by increasing cardio embolic stroke due to direct
cardiac involvement, by interfering with blood
coagulation through antiphospholipid antibodies
or reduced protein S or by causing arteriopathy.13
Pre ART era had an equal proportion of ischemic
and hemorrhagic stroke, however post ART era has
witnessed increased ischemic infarcts. Index case
number 2 presented with cerebral ischemic infarct as
a presenting manifestation. The treatment for stroke
is symptomatic with secondary preventive strategies
should be started after initial management.15 The
role of thrombolysis is uncertain with absence of
randomized trial.
A high index of suspicion is needed to diagnose
Acquired Immunodeficiency Syndrome in children
presenting only with neurologic manifestations.
pediatric HIV infection. J. Nutr. 1996; 126 (10) 2663-73.
3. Van Rie A, Harrington PR, Dow A, Robertson K. Neurologic
and neurodevelopmental manifestations of pediatric
HIV/AIDS: a global perspective. Eur J Paediatr Neurol.
2007;11(1):1-9
4. Mamidi A, DeSimone JA, Pomerantz RJ. Central nervous
system infections in individuals with HIV-1 infection.
J Neurovirol 2002; 8:158-167.
5. Berenguer JP, Miralles P, Arrizabalaga J, Ribera E, Dronda
F, Baraia-Etxaburu J et al. Clinical course and prognostic
factors of progressive multifocal leukoencephalopathy in
patients treated with highly active antiretroviral therapy. Clin
Infect Dis 2003;36:1047—52.
6. Berger JR, Aksamit AJ, Clifford DB, Davis L, Koralnik IJ,
Sejvar JJ et al. PML diagnostic criteria: consensus statement
from the AAN Neuroinfectious Disease Section. Neurology.
2013;9;80(15):1430-8.
7. Cinque P, Koralnik IJ, Clifford DB. The evolving face
of human immunodeficiency virus-related progressive
multifocal leukoencephalopathy: defining a consensus
terminology. J Neurovirol. 2003;9(1):88–92.
8. Kaplan JE, Benson C, Holmes KH, Brooks JT, Pau A, Masur
H. Guidelines for prevention and treatment of opportunistic
infections in HIV-infected adults and adolescents:
recommendations from CDC, the National Institutes of Health,
and the HIV Medicine Association of the Infectious Diseases
Society of America. MMWR Recomm Rep 2009; 58:1-207.
9. Beppu M, Kawamoto M, Nukuzuma S, Kohara N. Mefloquine
improved progressive multifocal leukoencephalopathy in
a patient with systemic lupus erythematosus. Intern Med.
2012;51(10):1245-7.
10.J Clifford DB, Nath A, Cinque P, Brew BJ, Zivadinov R,
Gorelik L, Zhao Z, Duda P.A study of mefloquine treatment
for progressive multifocal leukoencephalopathy: results and
exploration of predictors of PML outcomes. Neurovirol.
2013; 19(4):351-8.
11.Casado JL, Corral I, García J, Martinez-San Millán J,
Navas E, Moreno A, Moreno S. Continued declining
incidence and improved survival of progressive multifocal
leukoencephalopathy in HIV/AIDS patients in the current
era. Eur J Clin Microbiol Infect Dis. 2014; 33(2):179-87.
12.Engsig FN, Hansen AB, Omland LH, Kronborg G, Gerstoft
J, Laursen AL, Pedersen C, Mogensen CB, Nielsen L,
Obel N.Incidence, clinical presentation, and outcome of
progressive multifocal leukoencephalopathy in HIV-infected
patients during the highly active antiretroviral therapy era: a
nationwide cohort study. J Infect Dis. 2009;199 (1):77-83.
13.Dobbs MR, Berger JR. Stroke in HIV infection and AIDS.
Expert Rev Cardiovasc Ther. 2009;7:1263-71.
14.Benjamin LA, Bryer A, Emsley HC, Khoo S, Solomon T,
Connor MD.HIV infection and stroke: current perspectives
and future directions. Lancet Neurol. 2012 ;11(10):878-90.
15.Heikinheimo T, Chimbayo D, Kumwenda JJ, Kampondeni S,
Allain TJ. Stroke outcomes in Malawi, a country with high
prevalence of HIV: a prospective follow-up study. PLoS One.
2012 ;7 :e33765.
Legend
Image 1: Axial
FLAIR MRI
Brain showing
hyperintensities
bilateral globus
pallidi and parietooccipital subcortical
white matter.
Image 2: Axial
T2 WI showing
hyperintensities
bilateral globus
pallidi
and parieto-occipital
subcortical white
matter.
References
1. González-Scarano F, Martín-García J. The neuropathogenesis
of AIDS. Nat Rev Immunol. 2005; 5 (1): 69-81
2. Mintz M. Neurological and developmental problems in
Vol. 2; No. 2; April - June 2015
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JOURNAL OF PEDIATRIC CRITICAL CARE
Critical Thinking
PICU Quiz
Dr Nameet Jerath
Senior Consultant Pediatric Intensivist and Pulmonologist, IP Apollo Hospital, New Delhi
Question 1:
A 10-day-old child presents with respiratory distress
and cyanosis. The CXR shows extensive bilateral
infiltrates and the SpO2 with O2 through nonrebreather mask is around 80%. You decide to do a
hyperoxia test, where you measure the SpO2(PaO2)
before and after breathing 100% O2. What is NOT
true of hyperoxia test:
a. Rules out significant intra-cardiac and extra
cardiac (pulmonary) shunts
b.V/Q abnormalities may not show improvement
until 100% O2 is provided for the test
c.Failed test (no improvement in SpO2) in a
newborn confirms a congenital heart disease.
d. Intra-pulmonary shunts of > 50% are remarkably
resistant to 100% O2
d.LMW Heparin is preferred immediately after
surgery
e. LMW Heparin can be easily titrated by a PTTk
levels
Question 4:
Part of the rationale for intubation and mechanical
ventilation in a child with cardiogenic shock is to
decrease cardiac demand. The presence of respiratory
distress and increased work of breathing can result
in what percentage of cardiac output being required
simply to supply the respiratory apparatus?
a.0%
b.5%
c.10%
d.40%
e.90%
Question 2:
Which of the following is NOT TRUE regarding
oxygen delivery devices?
a. O2 masks should never have flows less than 3-4
L/min
b. Partial rebreathing masks allow rebreathing of
exhaled air but donot increase CO2
c. Non-rebreathing masks allow very high FiO2 even
at low flow rates
d. Venturi mask allows a set FiO2 inspite of changing
breathing pattern
e. Nasal cannula O2 in newborns may provide
positive airway pressure
Question 5:
A 6-year old child with meningococcemia is on
ventilator for 5 days and improving gradually. He is
on Dopamine @ 10 mcg/kg/min, Adrenaline @ 0.09
mcg/kg/min and Noradrenaline @ 0.2 mcg/kg/min.
His peripheries are cold and the vitals show: HR 178,
BP 110/70, SpO2 97%. The CVP is 11 and SCVO2 is
75%. What is the best option at this stage?
a. Increase Dopamine to 20 mcg/kg/min
b. Wean off Noradrenaline
c. Increase Adrenaline to 0.2 mcg/kg/min
d. Give a fluid bolus of 20 cc/kg
e. Add Milrinone @ 1.25 mcg/kg/min
Question 3:
Which of the following is an advantage of LMW
Heparin over unfractionated (UF) Heparin?
a.LMW Heparin has predictable effects as an
infusion
b. LMW Heparin does not need very strict monitoring
c.
UF Heparin effect can be reversed
pharmacologically
Vol. 2; No. 2; April - June 2015
Question 6:
A 10 year old child, road traffic accident victim
presents to the hospital unresponsive. CPR is started.
Monitor when attached shows normal QRS complex
but no associated pulse except palpable pulse with
each cardiac compression. This child should be
given-
78
JOURNAL OF PEDIATRIC CRITICAL CARE
Critical Thinking
PICU Quiz
a. Synchronized cardioversion
b. Defibrillation
c.Adrenaline
d.Atropine
e. Calcium gluconate
cycle.
Question 10:
A 5-year-old known asthmatic presents to the
emergency department with an acute exacerbation.
He has a RR of 50, HR 180, SpO2 of 90% in room
air. He is started on back-to-back nebulizations with
levosalbutamol. On review after about 10 minutes
you find him clinically improved with less respiratory
distress and less wheezing but the SpO2 is now 87%
in room air. What is the best explanation for the drop
in SpO2?
a. Nebulizations were not driven by O2
b. The child has actually worsened
c. Worsening of V/Q mismatch
d. Known with levosalbutamol, salbutamol is safer
e. The child has an added pneumonia
Question 7:
A 18-month-old girl is post op day 5 following a
liver transplantation. She is on immunosuppresantsmycophenolate and tacrolimus. You are informed
of a potassium report of 7.2 mEq/L and find tall T
waves on the ECG monitor with occasional PVCs.
She is hemodynamically stable otherwise. Which of
the following is the quickest to reduce extracellular
potassium levels?
a. Sodabicarb infusion
b. Calcium gluconate infusion
c. Calcium chloride infusion
d. Insulin/Dextrose infusion
e.Dialysis
QUIZ Answers and explanantions
Answer 1: c. Failed test (no improvement in SpO2)
in a newborn confirms a CHD.
Hyperoxia should improve oxygenation (SpO2 or
PaO2) in the absence of any significant shunt. Since
most “significant” shunts are cardiac and fixed, in an
appropriate clinical scenario failure of oxygenation to
improve with hyperoxia test suggests cardiac shunt. A
significant pulmonary shunt (more than 30%) in a bad
pulmonary disease too will show no improvement
with hyperoxia and is therefore not confirmatory of
cardiac disease. These patients may however respond
wonderfully to positive pressure ventilation which
the cardiac patients obviously will not.
Question 8:
A 10-year-old boy is transferred to the pediatric ICU
with blurred vision, dizziness, and slurred speech.
Temperature is 36.7°C (98°F), HR is 110/min, BP is
102/65 mm Hg, and RR is 22/min. His SpO2 is 93%
on room air. Laboratory values are: WBCs, 214,000/
µL; hemoglobin, 7 g/dL; plateletes, 50,000/µL;
sodium, 145 mEq/L; potassium, 3.5 mEq/L; blood
urea nitrogen, 18 mg/dL; creatinine, 0.45 mg/dL.
Smear shows a predominance of blasts. Which of the
following is the most appropriate plan of action to
relieve his symptoms?
a. Immediate neurology consultation
b.Plasmapheresis
c.Leukopheresis
d. Blood transfusion
e.Corticosteroids
Answer 2: c. Non-rebreathing masks allow very
high FiO2 even at low flow rates
Non-rebreathing masks are high flow masks and
need a significant flow rate to flush-out and replenish
the “mask-gas”. Simple masks do need this basic
flow to replenish the gas and should be used with
oxygen flows of 3-4L/min at least to prevent CO2
rebreathing. Venturi masks though far from being
accurate do allow FiO2s irrespective of the breathing
pattern.
Question 9:
Most of gas exchange during mechanical ventilation
with a normal inspiration: exhalation ratio occurs
during:
a.Inspiration.
b. The inspiratory plateau.
c.Exhalation.
d. Gas exchange is uniform throughout the respiratory
Vol. 2; No. 2; April - June 2015
Answer 3: LMW Heparin does not need very
strict monitoring.
79
JOURNAL OF PEDIATRIC CRITICAL CARE
Critical Thinking
PICU Quiz
UFH has the advantage of having a pharmacological
antidote. The absence of such an antidote for LMWH
is a disadvantage with this form of heparin and is
therefore not a drug of choice in the immediate postoperative period. The biggest advantage with LMWH
is that very little monitoring is required, if at all.
starts its effect in 15-30 minutes. Insulin/Dextrose
also causes a larger reduction in K levels compared
to Sodabicarb, 1meq/l vs 0.5mEq/L.
Answer 8: c. Leukopheresis
Hyperleukocytosis and its associated effects due to
sluggish circulation is an emergency. Leukopheresis
is needed urgently. Steroids before leukoreduction
has the potential of triggering a massive tumor lysis.
Answer 4: d. 40%
Normally about 10% of the resting body energy
and cardiac output requirements are taken up by
the respiratory mechanics. In distress, especially in
children with compliant chest walls this can go upto
50% of the cardiac output.
Answer 9: d. Gas exchange is uniform throughout
the respiratory cycle.
The Tidal Volume is a small fraction of the Total
Lung Capacity. This together with the massive
surface area of the lungs and almost no resistance
makes gas exchange almost continuous throughout
the respiratory cycle in spontaneously as well as
mechanically ventilated lungs. (Though very strictly
there is a minor difference in alveolar PO2, varying
by about 3mmHg with each breath, which can be
disregarded).
Answer 5: b. Wean off Noradrenaline
This child is improving. Now the peripheries are
cold with maintained blood pressures. Reducing
noradrenaline will reduce peripheral vasoconstriction
and improve peripheral circulation.
Answer 6: c. Adrenaline
The situation is of PEA or pulseless electrical
activity. Any such pulseless patient with normal QRS
complexes has to be treated as asystole. Adrenaline
and continued CPR is the treatment here.
Answer 10: c. Worsening of V/Q mismatch
Hypoxemia is a potent vasoconstrictor and protective
by minimizing V/Q mismatch. Some of the nebulized
bronchodilator diffuses across the ventilated
alveoli and causes the dilatation of vasoconstricted
alveolar vessels. This now causes increased flow to
nonventilated segments, worsening mismatch and
the SpO2. Usually not clinically significant and can
be avoided by driving nebulization with oxygen.
Answer 7: d. Insulin/Dextrose infusion
Hyperkalemia is an emergency. Calcium has
membrane stabilizing effects and is needed in the
emergent treatment of hyperkalemia but it doesnot
effect the K levels. Sodabicarb has the onset of effect
in 30-60 minutes while Insulin/Dextrose infusion
Vol. 2; No. 2; April - June 2015
80
JOURNAL OF PEDIATRIC CRITICAL CARE
College of Pediatric Critical Care and IAP Intensive Care Chapter
Advanced Pediatric Intensive Care Course(APICC)
PROGRAM TEMPLATE
Introduction by Course Director
Day 1
Day 2
Session 1- LECTURES (20 min each lecture and
10 min discussion)
LECTURES (20 min lecture and 10 min discussion)
1. Refractory Hypoxemia-
1. HFOV-when and how do I do it.
2. Critical USG- what an Intensivist should know
2. Advanced Neurocritical care- current concepts
in monitoring and management
3. Pediatric ECMO- when and how
4. Research in PICU-How to conduct a clinical
trial-
3. Refractory shock-management principle
4. SLED, CRRT, IHD: Who wins the race?
WORKSTATION with Case scenario- 2nd round (45
min each will rotate)
Tea Break
1 . Critical USG ( Demonstrate chest USG and use
of USG for procedure)-
Workstation with Case scenario- 1st round (45 min
each will rotate)
2. ECMO (Connections and how to start)-
1. HFOV (Demonstrate-Setting up the oscillator &
Nitric oxide) with case scenario of ARDS
Lunch break
2. Neuromonitoring: (demonstrate-ICP monitoring,
EEG monitoring) with Case scenario Head Injury
and raised ICP- Dr
3. Prone position4. Bronchoscopy and difficult airway-
Lunch Break
Workstation 3rd round (30 min each)
3.Hemodynamic Monitoring: (CVP, IBP, ECHO
monitoring) with case scenario of Shock-
1. Difficult ventilation scenario (asthma and ARDS)2.Infection Control Practices (show all products,
demonstrate video and educational material and
protocol-
4.
Dialysis (Demonstrate HD machine and
connection and PD) WITH Case scenario-ARF-
3. Refractory seizures case scenario-
Case Discussion (30 min each)
4.
Pediatric Emergency Transport
ventilator and protocols)-
1. TPN & Nutrition bundle2. Fulminant Liver failure: cases-
(Transport
3. Cardiac arrhythmia: cases-
Panel (30 minutes)
4.Burns & Poisoning- practical tips for good
outcome –
End of life decisions- understand Indian legal system
---
PANEL (1hour)
Antibiotic stewardship:
antifungal use-
Rational
antibiotic
and
For suggestions regarding content, please contact:
Dinesh Chirla: [email protected]; 09849790003
Anil Sachdev: [email protected]; 09810098360
Praveen Khilnani: [email protected]; 09810159466
Vol. 2; No. 2; April - June 2015
81
JOURNAL OF PEDIATRIC CRITICAL CARE
17th National Conference of Pediatric Critical Care
&
st
1 International Conference on Rare Diseases
Workshops : 26 November, 2015  CME : 27 November, 2015
Main Conference : 28 – 29 November, 2015
Venue : B.M. Birla Science & Technology Centre, Jaipur
Organized by:
IAP – Intensive Care Chapter
IAP – Rajasthan Chapter & Jaipur Branch
Department of Pediatrics, SMS Medical College, Jaipur
Pre-Conference Workshops
Basic Pediatric Intensive Care Course
(BPICC)
th
Date : 26 Nov., 2015
(Fees : INR 2500 each)







Date : 26th & 27th Nov., 2015
Limited Seats
Mechanical Ventilation
on
Hemodynamic Monitoring
first come first
Pediatric Gastro, Neuro-Renal
serve basis
Simulation Workshop
Bronchoscopy Workshop
Cardiac Critical Care
Nursing Critical Care (Fees : INR 1500)
(Fees : INR 3500)
*
CME
Date : 27th Nov., 2015
(Fees : INR 2500)
REGISTRATION FEE DETAILS
From 1st March to
31st July, 2015
From 1st Aug. to
31st Oct., 2015
From 1st Nov. to
on-spot
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Non-Member
PG Students*
INR 6500
INR 7500
INR 4000
INR 7500
INR 8000
INR 4500
INR 8000
INR 9000
INR 6000
Acc. Person
INR 4500
INR 5500
INR 7000
SAARC Delegate
Foreign Delegate
USD 150
USD 250
USD 150
USD 250
USD 200
USD 350
Category
* A bonafide letter attested by HOD of the respective institution is mandatory.
 Payment to be drawn in favour of “NCPCC 2015" payable at Jaipur.
 In order to attend workshop, conference registration is mandatory. A delegate can attend only one workshop.
Dr. Manish Sharma
Dr. Ashok Gupta
Org. Secretary, NCPCC 2015
Org. Secretary, Rare Diseases Conference
Conference Secretariat :
26, Mohan Nagar, Gopalpura By Pass, Tonk Road, Jaipur–302018 (Rajasthan)
Mobile : +91-9829300541
Email : [email protected]; [email protected]
Vol. 2; No. 2; April - June 2015
82
JOURNAL OF PEDIATRIC CRITICAL CARE
Website: www.ncpcc2015.com