9/28/2017 1 Title of Program: What has Cochrane Neonatal Done For Babies? Speakers/Moderators: Roger F. Soll, MD Planning Committee: Jeffery D. Horbar, MD, Madge E. Buus-Frank, RN, MS, APRN-BC, FAAN, Roger F. Soll, MD Date: September 2017 Learning Objectives: Participants will be presented with evidence from clinical trials and systematic reviews and will be able to evaluate and translate the evidence in the field of neonatology to better serve their practices. Specifically, evidence from a variety of systematic reviews in Neonatal-Perinatal Medicine will be reviewed to evaluate their impact on practice and guidelines. DISCLOSURE : Is there anything to disclose? No financial interests to disclose COMMERCIAL SUPPORT ORGANIZATIONS (if applicable): No Commercial Support This activity has been planned and implemented by The Robert Larner College of Medicine at The University of Vermont and Cochrane Neonatal is accredited by the American Nurses Credentialing Center (ANCC), the Accreditation Council for Pharmacy Education (ACPE), and the Accreditation Council for Continuing Medical Education (ACCME), to provide continuing education for the healthcare team. The University of Vermont designates this web seminar for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Trusted evidence. Informed decisions. Better health. What has Cochrane Done for Babies? Roger F. Soll, MD H. Wallace Professor of Neonatology University of Vermont College of Medicine Coordinating Editor, Cochrane Neonatal President, Vermont Oxford Network Cochrane Neonatal Web Seminar September 29 th 2017 The Basics ∙ Follow slides on the Internet ∙ Listen on your phone or speakerphone ∙ Chat feature - questions anytime ∙ Your phone will be muted during talks ∙ Questioner unmuted during Q&A Use the raised hand icon to queue up for questions Cochrane Preparing, maintaining and promoting the accessibility of systematic reviews of the effects of health care interventions Cochrane Neonatal Prepares and disseminates evidence-based reviews of the effects of therapies in the field of neonatal medicine Editorial Team Jennifer Spano Information Specialist Roger F. Soll Coordinating Editor Colleen Ovelman Managing Editor Michael Bracken Yale University Jeffrey Horbar University of Vermont Bill McGuire Hull York Medical School Gautham Suresh Baylor University Editorial Team
Transcript
9/28/2017
1
Title of Program: What has Cochrane Neonatal Done For Babies?
Speakers/Moderators: Roger F. Soll, MD
Planning Committee: Jeffery D. Horbar, MD, Madge E. Buus-Frank, RN, MS, APRN-BC, FAAN, Roger F. Soll, MD
Date: September 2017
Learning Objectives:
Participants will be presented with evidence from clinical trials and systematic reviews and will be able to evaluate
and translate the evidence in the field of neonatology to better serve their practices. Specifically, evidence from a variety of systematic reviews in Neonatal-Perinatal Medicine will be reviewed to evaluate their impact on practice and guidelines.
DISCLOSURE:
Is there anything to disclose? No financial interests to disclose
COMMERCIAL SUPPORT ORGANIZATIONS (if applicable): No Commercial Support
This activity has been planned and implemented by The Robert Larner College of Medicine at The University of Vermont and Cochrane Neonatal is
accredited by the American Nurses Credentialing Center (ANCC), the Accreditation Council for Pharmacy Education (ACPE), and the Accreditation
Council for Continuing Medical Education (ACCME), to provide continuing education for the healthcare team.
The University of Vermont designates this web seminar for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should claim only the
credit commensurate with the extent of their participation in the activity. Trusted evidence. Informed decisions. Better health.
What has Cochrane Done for Babies?
Roger F. Soll, MD
H. Wallace Professor of NeonatologyUniversity of Vermont College of Medicine
Use the raised hand icon to queue up for questions
Cochrane Preparing, maintaining and promoting
the accessibility of systematic reviews
of the effects of health care interventions
Cochrane Neonatal Prepares and disseminates
evidence-based reviews of the effects
of therapies in the field of neonatal medicine
Editorial Team
Jennifer SpanoInformation Specialist
Roger F. SollCoordinating Editor
Colleen OvelmanManaging Editor
Michael BrackenYale University
Jeffrey HorbarUniversity of Vermont
Bill McGuireHull York Medical School
Gautham SureshBaylor University
Editorial Team
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Editorial Team
Danielle Ehret, MD, MPHUniversity of Vermont
Support
Disclosure
Roger F. Soll is the Coordinating Editor of Cochrane Neonatal previously supported
by a contract from the NICHD andPresident of Vermont Oxford Network
Why These Webinars?
To develop an understanding ofthe evidence supplied by systematic reviews in
neonatal perinatal medicine(as well as other large well conducted trials)
and discuss how this evidence might influence your practice.
COCHRANE COLLABORATION
Cochrane Collaborative Groups
• Over 50 Collaborative Review Groups
• Most address specific disease entities/health problems
• The Cochrane Neonatal Review Group; one of the rare groups that address the needs of a population
COCHRANE NEONATAL
What do we do?
- prepare and disseminate evidence-based reviews of theeffects of therapies in the field of neonatal medicine.
- reviews follow a standard method:• a well formulated question• a comprehensive search for eligible trials• critical appraisal of trial quality• quantitative synthesis of the results using meta-analysis
- reviews are regularly updated as new trials are published.
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SYSTEMATIC OVERVIEW
- Applies specific research strategies to identify, appraise, and synthesize data from all relevant clinical studies
Quantitative systematic reviews include meta-analyses:
- statistical methods to combine the results of similar randomized controlled trials to produce a typical estimate of the effect size
META-ANALYSIS
What’s the use of meta-analysis?
• increase statistical power
• increase precision of estimate
• explore differences between study results
• create structure for incorporating new evidence
These Cochrane systematic reviews are published in the Cochrane Database of Systematic Reviews which is contained
in the Cochrane Library.
COCHRANE NEONATAL
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REVIE
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COCHRANE NEONATAL:Published Reviews
What has Cochrane Neonatal done for me lately?
Or more importantly…
What has it done for babies?
COCHRANE NEONATAL
SOMETIMES COCHRANE REVIEWS CHANGE THE WAY WE PRACTICE
AND SAVE BABIES’ LIVES!
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CORTICOSTEROIDS FOR PRETERM BIRTH
Since 1972,- there are multiple randomized controlled trials (N=18)- involving a large number of infants (3735 infants)
but…
Antenatal corticosteroidswere not utilized in the vast majority of patients until…
PROPHYLACTIC CORTICOSTEROIDS PRIOR TO PRETERM BIRTH
EFFECT ON NEONATAL DEATH
Typical relative risk 0.63 (95% CI 0.51 to 0.77)
Typical Relative Risk (95% CI)
Outcome (# of trials)
TypicalRelative Risk
( 95% CI ) 0.5 1.0 2.0 4.00.2
Decreased IncreasedRisk
0.5 1.0 2.0 4.00.2
PROPHYLACTIC CORTICOSTEROIDSPRIOR TO PRETERM BIRTH
RDS (14) 0.64 (0.56, 0.72)
OVERVIEW OF 18 RANDOMIZED CONTROLLED TRIALS
Periventricular hemorrhage (4) 0.57 (0.41, 0.78)
Necrotizing enterocolitis (4) 0.60 (0.33, 1.09)
Bronchopulmonary dysplasia (3) 1.38 (0.90, 2.11)
Neonatal death (13) 0.63 (0.51, 0.77)
Crowley (1992) Typical Relative Risk (95% CI)
Outcome (# of trials)
TypicalRelative Risk
( 95% CI ) 0.5 1.0 2.0 4.00.2
Decreased IncreasedRisk
0.5 1.0 2.0 4.00.2
Stillbirth (12) 0.84 (0.59, 1.21)
OVERVIEW OF 15 RANDOMIZED CONTROLLED TRIALS
Fetal/neonatal infection (15) 0.84 (0.60, 1.17)
Maternal infection (11) 1.26 (0.99, 1.60)
Neurological abnormality (3) 0.65 (0.39, 1.08)
Crowley (1992)
PROPHYLACTIC CORTICOSTEROIDSPRIOR TO PRETERM BIRTH
CORTICOSTEROIDSFOR PRETERM BIRTH
“Antenatal corticosteroid therapy is indicated for women at risk of premature delivery with few exceptions and will result in a substantial decrease in neonatal morbidity and mortality, as well as substantial savings in health care costs”
0%
10%
20%
30%
40%
50%
60%
70%
80%
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
% V
LB
W I
NFA
NT
S
VERMONT OXFORD NETWORK ANNUAL REPORTS 1991-2005
ANTENATAL CORTICOSTEROIDS
NIH Conference
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We’re so proud of this, we
made it part of our logo…
www.cochrane.org
←SOMETIMES COCHRANE REVIEWS TELL US WHAT
WE ALREADY KNOW!
Typical Relative Risk (95% CI)
TYPES OF STUDIES (N)
Typical Risk Difference
( 95% CI ) 0.5 1.0 2.0 4.00.2
Decreased IncreasedRisk
0.5 1.0 2.0 4.00.2
SURFACTANT THERAPY
PROPHYLACTIC SURFACTANT
EFFECT ON PNEUMOTHORAX
SYNTHETIC SURFACTANT (6) -0.05 (-0.09, -0.02)
NATURAL SURFACTANT (8) -0.15 (-0.20, -0.11 )
RESCUE SURFACTANT
SYNTHETIC SURFACTANT (5) -0.09 (-0.12, -0.06)
Soll 1997
NATURAL SURFACTANT (12) -0.17 (-0.21, -0.13)
Typical Relative Risk (95% CI)
TYPES OF STUDIES (N)
Typical Risk Difference
( 95% CI ) 0.5 1.0 2.0 4.00.2
Decreased IncreasedRisk
0.5 1.0 2.0 4.00.2
SURFACTANT THERAPY
PROPHYLACTIC SURFACTANT
EFFECT ON NEONATAL MORTALITY
SYNTHETIC SURFACTANT (7) -0.07 (-0.11,-0.03)
NATURAL SURFACTANT (8) -0.07 (-0.12, -0.03 )
RESCUE SURFACTANT
SYNTHETIC SURFACTANT (5) -0.05 (-0.07, -0.02)
Soll 1997
NATURAL SURFACTANT (12) -0.09 (-0.13, -0.05)
0%
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1993
1995
1997
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2001
2003
2005
2007
2009
% V
LBW
IN
FAN
TS
VERMONT OXFORD NETWORK ANNUAL REPORTS 1991-2010
EXOGENOUS SURFACTANT TREATMENT
FDA APPROVAL
INTRODUCTION OF ANTENATAL STEROIDSAND POSTNATAL SURFACTANT TREATMENT
0%
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20%
30%
40%
50%
60%
70%
80%
90%
1991 1992 1993 1994 1995 1996
% E
LB
W I
NF
AN
TS
ANTENATAL STEROIDS SURFACTANT THERAPY MORTALTY
EFFECT ON MORTALITY IN ELBW INFANTS
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SOMETIMES COCHRANE REVIEWS REFINE HOW WE
PRACTICE!
Relative Risk and 95% CI
STUDY0.5 1.0 2.0 4.00.2
Decreased IncreasedRisk
0.5 1.0 2.0 4.00.2
DELIVERY ROOM vs. TREATMENT SURFACTANT
Dunn 1991
EFFECT ON NEONATAL MORTALITY
Egberts 1993
Kattwinkel 1993
Walti 1995
Bevilacqua 1996
Soll and Morley 2001
TYPICAL ESTIMATE
Kendig 1991
Bevilacqua 1997
PROPHYLACTIC SURFACTANT AND STEROIDS
EFFECT ON MORTALITY DUE TO RDS
0
10
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30
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SURF/STEROID SURF/NO STEROID NO SURF/STEROID NEITHER
MO
RTALIT
Y D
UE T
O R
DS (
%)
PROPHYLACTIC SURFACTANT vs. SELECTIVE TREATMENT OF RDSNEONATAL MORTALITY
PROPHYLACTIC SURFACTANT vs. SELECTIVE TREATMENT OF RDSDEATH OR BPD
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0%
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2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
% C
AS
ES
DR ETT DR SURFACTANT
DR PRACTICES IN VLBW INFANTS
SOMETIMES COCHRANE REVIEWS STOP US FROM
DOING THINGS THAT MIGHT INJURE OUR
BABIES!
0%
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40%
50%
60%
70%
80%
90%
BRONCHOPULMONARY DYSPLASIA
% C
AS
ES
ABSENT PRESENT
YOON AND COWORKERS. A SYSTEMIC FETAL INFLAMMATORY RESPONSE AND THE DEVELOPMENT OF BRONCHOPULMONARY DYSPLASIA.AM J OBSTET GYNECOL 1999;181:773-9
ROLE OF INFLAMMATION
CHORIOAMNIONITIS AND BRONCHOPULMONARY DYSPLASIA
POSTNATAL STEROID THERAPY: MECHANISM OF ACTION
• stabilize cellular or lysosomal membranes• decrease inflammatory response• decrease pulmonary edema
Early Steroid Treatment:• before or at 7 Days• studies 32• enrolled infants 4395
Late Steroid Treatment:• after 7 Days• studies 21• enrolled infants 1424
Doyle L, Cheong JL, Ehrenkranz RA and Halliday HL, Cochrane Library 2017
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Typical Relative Risk and 95% CI
Outcome (N Studies)
TypicalRisk Difference
( 95% CI )0.5 1.0 2.0 4.00.2
Decreased IncreasedRisk
0.5 1.0 2.0 4.00.2
EARLY (≤ 7 DAYS) POSTNATAL STEROID THERAPY
CLD @ 28 DAYS (17) -0.07 (-0.10,-0.03)
META-ANALYSIS OF 32 RANDOMIZED CONTROLLED TRAILS
CLD @ 36 WEEKS (24) -0.07 (-0.09, -0.04)
DEATH/CLD @ 36 WKS (25) -0.06 (-0.09, -0.03)
MORTALITY (30) -0.01 (-0.03, 0.01)
Doyle 2017Relative Risk and 95% CI
OUTCOME (N STUDIES)0.5 1.0 2.0 4.00.2
Decreased IncreasedRisk
0.5 1.0 2.0 4.00.2
PATENT DUCTUS ARTERIOSUS (24)
EFFECT ON COMPLICATIONS OF PREMATURITY
INFECTION (25)
HYPERTENSION (11)
GI HEMORRHAGE (12)
SEVERE IVH (26)
Doyle 2017
SEVERE ROP (14)
PULMONARY AIR LEAK (16)
EARLY (≤ 7 DAYS) POSTNATAL STEROID THERAPY
Typical Relative Risk and 95% CI
Outcome (N Studies)
TypicalRisk Difference
( 95% CI ) 0.5 1.0 2.0 4.00.2
Decreased IncreasedRisk
0.5 1.0 2.0 4.00.2
LATE (> 7 DAYS) POSTNATAL STEROID THERAPY
CLD @ 28 DAYS (6) -0.11 (-0.17, -0.05)
META-ANALYSIS OF 21 RANDOMIZED CONTROLLED TRAILS
CLD @ 36 WEEKS (11) -0.15 (-0.22, -0.07)
DEATH/CLD @ 36 WKS (11) -0.18 (-0.25, -0.11)
MORTALITY (19) -0.03 (-0.07, 0.02)
Doyle 2017Typical Relative Risk and 95% CI
OUTCOME (N Studies)
Typical Risk Difference
( 95% CI ) 0.5 1.0 2.0 4.00.2
Decreased IncreasedRisk
0.5 1.0 2.0 4.00.2
NEURODEVELOPMENTAL OUTCOME IN SURVIVORS
BAYLEY MDI < 2SD (3) 0.01 (-0.06, 0.06)
BAYLEY PDI < 2SD (3) 0.02 (-0.02, 0.07)
DEVELOPMENTAL DELAY (1)
CEREBRAL PALSY (13) 0.02 (-0.00, 0.05)
Doyle 2017
MOD/SEVERE IMPAIRMENT (7) 0.01 (-0.02, 0.05)
PVL (15)
ABNORMAL NEURO EXAM (5)
0.00 (-0.01, 0.02)
0.10 (0.05, 0.15)
0.14 (0.03, 0.24)
EARLY (≤ 7 DAYS) POSTNATAL STEROID THERAPY
Typical Relative Risk and 95% CI
Outcome (N)0.5 1.0 2.0 4.00.2
Decreased IncreasedRisk
0.5 1.0 2.0 4.00.2
BAYLEY MDI < 2SD (7)
NEURODEVELOPMENTAL OUTCOME IN SURVIVORS
BAYLEY PDI < 2SD (1)
ABNORMAL NEURO EXAM (4)
CEREBRAL PALSY (15)
MOD/SEVERE IMPAIRMENT (9)
Doyle 2017
TypicalRisk Difference
(95%CI)
-0.03 (-0.10, 0.05)
-0.04 (-0.17, 0.09)
0.15 (-0.00, 0.30)
-0.02 (-0.08, 0.03)
0.03 (-0.03, 0.08)
LATE (> 7 DAYS) POSTNATAL STEROID THERAPYPOSTNATAL CORTICOSTEROIDS TO TREAT OR PREVENT
CHRONIC LUNG DISEASE IN PRETERM INFANTS
RECOMMENDATIONS FROMTHE COMMITTEE ON THE FETUS AND NEWBORN 2002
On the basis of limited short-term benefits, the absence of long-term benefits, and the number of serious short-term and long-term complications, the routine use of systemic dexamethasone for the prevention or treatment of chronic lung disease in infants with very low birth weight is not recommended.
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POSTNATAL CORTICOSTEROIDS TO TREAT OR PREVENTCHRONIC LUNG DISEASE IN PRETERM INFANTS
RECOMMENDATIONS FROMTHE COMMITTEE ON THE FETUS AND NEWBORN 2002
Outside the context of a randomized controlled trial, the use of corticosteroids should be limited to exceptional clinical circumstances (e.g., an infant on maximal ventilatory and oxygen support). In those circumstances, parents should be fully informed about the known short- and long-term risks and agree to treat.
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VERMONT OXFORD NETWORK ANNUAL REPORTS 1991-2014
Postnatal Corticosteroid Usein VLBW Infants
AAP Statement
Cochrane Review
0%
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19
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19
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Postnatal Steroids
Doyle, L. W. et al.Pediatrics 2005;115:655-661
Risk Difference (%) for Death or CP among all participants vs. rate of CLD (%) in the control group
CLD
Cerebral palsy
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SOMETIMES COCHRANE REVIEWS PROVIDE
RESULTS THAT MAY BE CONFUSING!
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Intraventricular Hemorrhage
Any Intraventricular Hemorrhage Severe Intraventricular Hemorrhage
Relative Risk and 95% CI
OutcomeRisk Difference
( 95% CI ) 0.5 1.0 2.0 4.00.2
Decreased IncreasedRisk
0.5 1.0 2.0 4.00.2
PATENT DUCTUS ARTERIOSUS (7) -0.27 (-0.32, -0.21)
Meta-analysis of 19 trials
EFFECT ON PATENT DUCTUS ARTERIOSUS (PDA)
SYMPTOMATIC PDA (14) -0.24 (-0.28, -0.21)
PDA LIGATION (8) -0.05 (-0.08, -0.03)
FOWLIE 2010: THE COCHRANE LIBRARY
Prophylactic Indomethacin
Relative Risk and 95% CI
OutcomeRisk Difference
( 95% CI ) 0.5 1.0 2.0 4.00.2Decreased IncreasedRisk
Long-Term Effects of Indomethacin Prophylaxis in ELBW InfantsSchmidt B and colleagues. N Engl J Med 2001; 344:1966-1972
Original Article
Long-Term Effects of Indomethacin
Prophylaxis in Extremely-Low-Birth-
Weight Infants
Barbara Schmidt, M.D., Peter Davis, M.D., Diane Moddemann,
M.D., Arne Ohlsson, M.D., Robin S. Roberts, M.Sc., Saroj Saigal,
M.D., Alfonso Solimano, M.D., Michael Vincer, M.D., and Linda L.
Wright, M.D., for the Trial of Indomethacin Prophylaxis in Preterms
Investigators*
N Engl J Med 2001; 344:1966-1972June 28, 2001DOI:
10.1056/NEJM200106283442602
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Schmidt and colleagues randomly assigned 1202 extremely low birth weight infants to receive either indomethacin (0.1 mg/kg) or placebo intravenously once daily for three days.
The primary outcome was a composite of death, cerebral palsy, cognitive delay, deafness, and blindness at a corrected age of 18 months.
Secondary short-term outcomes were patent ductus arteriosus, pulmonary hemorrhage, chronic lung disease, ultrasonographicevidence of intracranial abnormalities, necrotizing enterocolitis, and retinopathy.
Secondary long-term outcomes were hydrocephalus necessitating the placement of a shunt, seizure disorder, and microcephaly within the same time frame.
Long-Term Effects of Indomethacin Prophylaxis in ELBW InfantsSchmidt B and colleagues. N Engl J Med 2001; 344:1966-1972
Outcome
CompositeDeath or impairment
Components
DeathCPCognitive delayHearing lossBlindness
Indomethacin
47%
21%12%27%2%2%
Control
46%
19%12%26%2%1%
Adjusted OR (95% CI)
1.1 (0.8 to 1.4)
1.2 (0.9 to 1.6)1.1 (0.7 to 1.6)1.0 (0.8 to 1.4)1.0 (0.4 to 2.5)1.3 (0.5 to 3.6)
Long-Term Effects of Indomethacin Prophylaxis in ELBW InfantsSchmidt B and colleagues. N Engl J Med 2001; 344:1966-1972
Relative Risk and 95% CI
OutcomeRisk Difference
( 95% CI ) 0.5 1.0 2.0 4.00.2Decreased IncreasedRisk
0.5 1.0 2.0 4.00.2
Prophylactic Indomethacin
MORTALITY AT FOLLOW UP (18) -0.01 (-0.04, 0.02)
Meta-analysis of 19 trials
STATUS AT LATEST FOLLOW UP
CEREBRAL PALSY (4) 0.00 (-0.03, 0.04)
SEVERE ND IMPAIRMENT (3) -0.01 (-0.05, 0.04)
FOWLIE 2010: THE COCHRANE LIBRARY
Hierarchy of outcomes according to importance to patientsto assess effect of prophylactic indomethacin
Mortality
Neurodevelopmental outcome
Severe IVH
PDA ligation
PDA murmur
Prophylactic Indomethacin:Glass half full or half empty?
DOES NOT ALTERNEURODEVELOPMENTALOUTCOME
PREVENTS:SYMPTOMATIC PDASEVERE IVH
Indomethacin
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VERMONT OXFORD NETWORK ANNUAL REPORTS 1991-2015
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SOMETIMES WE IGNORE THE FINDINGS FROM
RANDOMIZED CONTROLLED TRIALS AND THE REVIEWS OF THESE
TRIALS!
Relative Risk and 95% CI
OUTCOME (STUDIES)Risk Difference
( 95% CI ) 0.5 1.0 2.0 4.00.2
Decreased IncreasedRisk
0.5 1.0 2.0 4.00.2
ELECTIVE HIGH FREQUENCY OSCILLATORY VENTILATION
IVH (12) 0.02 (-0.01, 0.05)
META-ANALYSIS OF 19 RANDOMIZED CONTROLLED TRIALS
SEVERE IVH (18) 0.01 (-0.01, 0.04)
PVL (17) 0.00 (-0.01, 0.02)
SEVERE RETINOPATHY (12) -0.04 (-0.07, -0.01)
CHRONIC LUNG DISEASE (17) -0.05 (-0.08, -0.02)
DEATH (17) -0.01 (-0.03, 0.02)
COOLS 2015
CLD/DEATH @ 36 WKS PMA (17) -0.05 (-0.08, -0.01)
PULMONARY AIRLEAK (13) 0.04 (0.01, 0.07)
0%
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VERMONT OXFORD NETWORK ANNUAL REPORTS 1991-2014
High Frequency Ventilation
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S
VERMONT OXFORD NETWORK ANNUAL REPORTS 1994-2010
CHRONIC LUNG DISEASEIN VLBW INFANTS
0%
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1993
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VERMONT OXFORD NETWORK ANNUAL REPORTS 1991-2010
MORTALITY IN VLBW INFANTS
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NITRIC OXIDE FOR RESPIRATORY FAILURE IN PRETERM INFANTS
EFFECT ON DEATH OR BPD AT 36 WEEKS PMANIH Consensus Development Conference Statement: Inhaled Nitric-
Oxide Therapy for Premature Infants
Taken as a whole, the available evidence does not support use of iNO in early-routine, early-rescue, or later-rescue regimens in the care of premature infants of <34 weeks' gestation who require respiratory support.
There are rare clinical situations, including pulmonary hypertension or hypoplasia, that have been inadequately studied in which iNO may have benefit in infants of <34 weeks' gestation.
In such situations, clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties.
0%
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2008 2009 2010 2011 2012 2013
% V
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Vermont Oxford Network Annual Reports 2000-2012
Inhaled Nitric Oxide in VLBW Infants
3rd quartileRange
1st quartile SOMETIMES THE COCHRANE REVIEW TELLS US THAT WE SHOULD BE
READY TO CONSIDER CHANGE
(AND NEW PRACTICES)
COOLING FOR INFANTS WITH HYPOXIC ISCHEMIC ENCEPHALOPATHY
HYPOTHERMIA FOR THE TREATMENT OFHYPOXIC ISCHEMIC ENCEPHALOPATHY
ILCOR recommendations
“Intensive care nurseries should now consider adopting one of the validated protocols for the selection of term infants with HIE, be appropriately equipped and train staff to offer hypothermia according to the protocol of the currently published large hypothermia trials”
“Because HIE is a relatively uncommon condition, it would be highly desirable where possible to centralize this treatment to larger intensive care units.”
“With the data presently available, there is no longer any reasonable justification to deny this apparently efficacious treatment for those who most urgently need it.”
Hoehn and coworkers. Resuscitation 2008
COOLING IN HYPOXIC ISCHEMIC ENCEPHALOPATHY
What are we supposed to do?
DIFFICULTY OF TRANSLATINGEVIDENCE TO PRACTICE
Efficacy:
Mild hypothermia is a promising therapy in a highly selected population of infants with
moderate to severe hypoxic ischemic encephalopathy when treated before 6 hours of age
DIFFICULTY OF TRANSLATINGEVIDENCE TO PRACTICE
Effectiveness and Efficiency:
• Does it work in the most affected infants? Does it provide a benefit to less severely affected infants?
• Does it work outside the restricted time window predicted by animal models and tested in clinical trials?
• Does selective or whole body hypothermia work better?
• What is the relationship of hypothermia to other therapeutic interventions?
ENCEPHALOPATHY REGISTRY:Hypothermic Therapy 2006 to 2011
• 99 participating centers
• 2457 infants treated with hypothermia
• 726 (30%) did not meet criteria from RCTs
– 40% with mild encephalopathy
– 60% treated after 6 hours
– 17% of all infants < 36 weeks gestation
Pfister. PAS. 2013
Whole Body 74%Selective Head 17%Both 9%
Only fair agreement between large clinical trials and meta-analyses
LeLorier 1997
PROBLEMS WITH META-ANALYSIS
9/28/2017
15
Odds Ratio and 95% CI
CHARACTERISTICOdds Ratio
(95% CI) 0.5 1.0 2.0 4.00.2
Decreased IncreasedRisk
0.5 1.0 2.0 4.00.2
META-ANALYSIS OF MULTIPLE SMALL STUDIESCOMPARED TO SINGLE LARGE STUDY
ASPIRIN FOR PREVENTION OF PRE-ECLAMPSIA
META-ANALYSIS 0.30 (0.20, 0.42)
SINGLE LARGE RCT 0.82 (0.72, 1.05)
META-ANALYSIS
Methodological flaws in meta-analyses
• Publication biasThe tendency for investigators to preferentially
submit studies with positive results, and the tendency for editors to choose positive studies for publication
• HeterogeneityConcerning variation in the direction or the degrees of results between individual studies
PROBLEMS WITH COCHRANE REVIEWSAND META-ANALYSIS
Too many reviews that end with the conclusion that “more trials are needed.”
“You cannot makea silk purse
from a sow’s ear”
RCTs
Cochrane Reviews
TRIALS BASED (at least in part)on RESULTS OF META-ANALYSIS
