Participants will be presented with evidence from clinical trials - - PowerPoint PPT Presentation

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 29th 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

• f the effects of health care interventions

Cochrane Neonatal

Prepares and disseminates evidence-based reviews of the effects

• f 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

Editorial Team

Danielle Ehret, MD, MPH University of Vermont

Support

Disclosure

Roger F. Soll is the Coordinating Editor of Cochrane Neonatal previously supported by a contract from the NICHD and President of Vermont Oxford Network

Why These Webinars?

To develop an understanding of the 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 the

effects 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.

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

50 100 150 200 250 300 350 400

1997 1999 2001 2003 2005 2007 2009 2011 2013 2015

REVIEWS

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!

CORTICOSTEROIDS FOR PRETERM BIRTH

Since 1972,

• there are multiple randomized controlled trials (N=18)
• involving a large number of infants (3735 infants)

but… Antenatal corticosteroids were 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) Typical Relative Risk ( 95% CI ) 0.5 1.0 2.0 4.0 0.2 Decreased Increased Risk 0.5 1.0 2.0 4.0 0.2

PROPHYLACTIC CORTICOSTEROIDS PRIOR 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) Typical Relative Risk ( 95% CI ) 0.5 1.0 2.0 4.0 0.2 Decreased Increased Risk 0.5 1.0 2.0 4.0 0.2 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 CORTICOSTEROIDS PRIOR TO PRETERM BIRTH

CORTICOSTEROIDS FOR 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 % VLBW INFANTS

VERMONT OXFORD NETWORK ANNUAL REPORTS 1991-2005

ANTENATAL CORTICOSTEROIDS

NIH Conference

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 4.0 0.2 Decreased Increased Risk 0.5 1.0 2.0 4.0 0.2

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 4.0 0.2 Decreased Increased Risk 0.5 1.0 2.0 4.0 0.2

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% 10% 20% 30% 40% 50% 60% 70% 80% 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 % VLBW INFANTS

VERMONT OXFORD NETWORK ANNUAL REPORTS 1991-2010

EXOGENOUS SURFACTANT TREATMENT

FDA APPROVAL

INTRODUCTION OF ANTENATAL STEROIDS AND POSTNATAL SURFACTANT TREATMENT

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 1991 1992 1993 1994 1995 1996

% ELBW INFANTS ANTENATAL STEROIDS SURFACTANT THERAPY MORTALTY

EFFECT ON MORTALITY IN ELBW INFANTS

SOMETIMES COCHRANE REVIEWS REFINE HOW WE PRACTICE!

Relative Risk and 95% CI STUDY 0.5 1.0 2.0 4.0 0.2 Decreased Increased Risk 0.5 1.0 2.0 4.0 0.2

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

10 20 30 40 50 60 70

SURF/STEROID SURF/NO STEROID NO SURF/STEROID NEITHER

MORTALITY DUE TO RDS (%)

PROPHYLACTIC SURFACTANT vs. SELECTIVE TREATMENT OF RDS NEONATAL MORTALITY

PROPHYLACTIC SURFACTANT vs. SELECTIVE TREATMENT OF RDS DEATH OR BPD

0% 10% 20% 30% 40% 50% 60% 70% 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

% CASES DR ETT DR SURFACTANT

DR PRACTICES IN VLBW INFANTS

SOMETIMES COCHRANE REVIEWS STOP US FROM DOING THINGS THAT MIGHT INJURE OUR BABIES!

0% 10% 20% 30% 40% 50% 60% 70% 80% 90%

BRONCHOPULMONARY DYSPLASIA % CASES 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

POSTNATAL STEROID THERAPY: POTENTIAL RISKS

• hypertension
• hyperglycemia
• infection
• cardiomyopathy
• gi bleeding/perforation
• decreased somatic growth
• decreased brain growth
• neurodevelopmental problems

POSTNATAL STEROID THERAPY: SYSTEMATIC OVERVIEW

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

Typical Relative Risk and 95% CI

Outcome (N Studies) Typical Risk Difference

( 95% CI ) 0.5 1.0 2.0 4.0 0.2

Decreased Increased Risk

0.5 1.0 2.0 4.0 0.2

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 2017

Relative Risk and 95% CI OUTCOME (N STUDIES) 0.5 1.0 2.0 4.0 0.2

Decreased Increased Risk

0.5 1.0 2.0 4.0 0.2 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)

Typical Risk Difference ( 95% CI )

0.5 1.0 2.0 4.0 0.2

Decreased Increased Risk

0.5 1.0 2.0 4.0 0.2

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 2017

Typical Relative Risk and 95% CI OUTCOME (N Studies) Typical Risk Difference ( 95% CI )

0.5 1.0 2.0 4.0 0.2

Decreased Increased Risk 0.5 1.0 2.0 4.0 0.2

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 4.0 0.2 Decreased Increased Risk 0.5 1.0 2.0 4.0 0.2 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

Typical Risk 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 THERAPY

POSTNATAL CORTICOSTEROIDS TO TREAT OR PREVENT CHRONIC LUNG DISEASE IN PRETERM INFANTS RECOMMENDATIONS FROM THE 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.

POSTNATAL CORTICOSTEROIDS TO TREAT OR PREVENT CHRONIC LUNG DISEASE IN PRETERM INFANTS RECOMMENDATIONS FROM THE COMMITTEE ON THE FETUS AND NEWBORN 2002 Outside the context of a randomized controlled trial, the use

• f corticosteroids should be limited to exceptional clinical

circumstances (e.g., an infant on maximal ventilatory and

• xygen support). In those circumstances, parents should be

fully informed about the known short- and long-term risks and agree to treat.

0% 10% 20% 30% 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 % VLBW INFANTS

VERMONT OXFORD NETWORK ANNUAL REPORTS 1991-2014

Postnatal Corticosteroid Use in VLBW Infants

AAP Statement Cochrane Review

0% 10% 20% 30% 40% 50%

1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

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

SOMETIMES COCHRANE REVIEWS PROVIDE RESULTS THAT MAY BE CONFUSING!

0% 10% 20% 30% 40% 50% 60% 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 % VLBW INFANTS

VERMONT OXFORD NETWORK ANNUAL REPORTS 1991-2015

Intraventricular Hemorrhage

Any Intraventricular Hemorrhage Severe Intraventricular Hemorrhage

Relative Risk and 95% CI Outcome Risk Difference ( 95% CI ) 0.5 1.0 2.0 4.0 0.2 Decreased Increased Risk 0.5 1.0 2.0 4.0 0.2 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 Outcome Risk Difference

( 95% CI ) 0.5

1.0 2.0 4.0 0.2

Decreased Increased Risk

0.5 1.0 2.0 4.0 0.2

INTRAVENTRICULAR HEMORRHAGE (14)

• 0.04 (-0.08, -0.01)

Meta-analysis of 19 trials EFFECT ON CENTRAL NERVOUS SYSTEM INJURY

SEVERE IVH (14)

• 0.05 (-0.07, -0.02)

PROGRESSIVE IVH (2)

• 0.08 (-0.29, 0.13)

PERIVENTRICULAR LEUKOMALACIA (5)

• 0.05 (-0.08, -0.01)

WHITE MATTER INJURY (1)

• 0.04 (-0.07, 0.00)

FOWLIE 2010: THE COCHRANE LIBRARY

Prophylactic Indomethacin

Long-Term Effects of Indomethacin Prophylaxis in ELBW Infants Schmidt 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

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, ultrasonographic evidence 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 Infants Schmidt B and colleagues. N Engl J Med 2001; 344:1966-1972

Outcome Composite Death or impairment Components Death CP Cognitive delay Hearing loss Blindness 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 Infants Schmidt B and colleagues. N Engl J Med 2001; 344:1966-1972

Relative Risk and 95% CI Outcome Risk Difference

( 95% CI )

0.5 1.0 2.0 4.0 0.2

Decreased Increased Risk

0.5 1.0 2.0 4.0 0.2

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 patients to assess effect of prophylactic indomethacin

Mortality Neurodevelopmental outcome Severe IVH PDA ligation PDA murmur

Prophylactic Indomethacin: Glass half full or half empty?

DOES NOT ALTER NEURODEVELOPMENTAL OUTCOME PREVENTS: SYMPTOMATIC PDA SEVERE IVH

Indomethacin

0% 10% 20% 30% 40% 50% 60% 70% 80% 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 % VLBW INFANTS

VERMONT OXFORD NETWORK ANNUAL REPORTS 1991-2015

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 4.0 0.2 Decreased Increased Risk 0.5 1.0 2.0 4.0 0.2

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% 10% 20% 30% 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 % VLBW INFANTS

VERMONT OXFORD NETWORK ANNUAL REPORTS 1991-2014

High Frequency Ventilation

0% 10% 20% 30% 40% 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 % VLBW INFANTS

VERMONT OXFORD NETWORK ANNUAL REPORTS 1994-2010

CHRONIC LUNG DISEASE IN VLBW INFANTS

0% 5% 10% 15% 20% 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 % VLBW INFANTS

VERMONT OXFORD NETWORK ANNUAL REPORTS 1991-2010

MORTALITY IN VLBW INFANTS

NITRIC OXIDE FOR RESPIRATORY FAILURE IN PRETERM INFANTS EFFECT ON DEATH OR BPD AT 36 WEEKS PMA

NIH 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

• f <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% 5% 10% 15% 20%

2008 2009 2010 2011 2012 2013

% VLBW INFANTS

Vermont Oxford Network Annual Reports 2000-2012

Inhaled Nitric Oxide in VLBW Infants

3rd quartile Range 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

DEATH OR MAJOR DISABILITY

• 0.16 (-0.23, -0.09)

MAJOR DISABILITY

• 0.18 (-0.29, -0.09)

DEATH

• 0.10 (-0.16, -0.04)

WHOLE BODY COOLING DEATH OR MAJOR DISABILITY

• 0.09 (-0.21, 0.03)

MAJOR DISABILITY

• 0.09 (-0.24, 0.05)

DEATH

• 0.05 (-0.14, 0.04)

Typical Relative Risk and 95% CI 0.5 1.0 2.0 4.0 0.2

HYPOTHERMIA FOR HYPOXIC ISCHEMIC ENCEPHALOPATHY

WHOLE BODY COOLING AND SELECTIVE HEAD COOLING

Updated by Berg 2012

SELECTIVE HEAD COOLING STUDY Typical Risk Difference (95%CI) 0.5 1.0 2.0 4.0 0.2 Decreased Increased Risk

HYPOTHERMIA FOR THE TREATMENT OF HYPOXIC 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 TRANSLATING EVIDENCE 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

• f age

DIFFICULTY OF TRANSLATING EVIDENCE 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

Odds Ratio and 95% CI CHARACTERISTIC Odds Ratio

(95% CI)

0.5 1.0 2.0 4.0 0.2 Decreased Increased Risk 0.5 1.0 2.0 4.0 0.2

META-ANALYSIS OF MULTIPLE SMALL STUDIES COMPARED 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 bias

The tendency for investigators to preferentially submit studies with positive results, and the tendency for editors to choose positive studies for publication

• Heterogeneity

Concerning variation in the direction or the degrees of results between individual studies

PROBLEMS WITH COCHRANE REVIEWS AND META-ANALYSIS

Too many reviews that end with the conclusion that “more trials are needed.”

“You cannot make a silk purse from a sow’s ear”

RCTs Cochrane Reviews

TRIALS BASED (at least in part)

• n RESULTS OF META-ANALYSIS
• Prophylactic Indomethacin
• Vitamin A
• Emollient Ointments
• DART Trial
• Inositol
• Caffeine

Search: “Neonate” Limit: all infants; randomized controlled trial 7059 RCT identified Cochrane Neonatal 1355 RCTs included

COCHRANE NEONATAL SYSTEMATIC REVIEWS ARE USEFUL

• In guiding evidence-based practice
• To formulate research questions
• To create a context in which to view new

evidence

So what is the fate of Cochrane Neonatal?

Bridging funds: University of Vermont Cochrane Central Possible future sponsorship: Vermont Oxford Network So what is the fate of Cochrane Neonatal?

Questions

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For Nursing Contact Hours use the following link:

https://www.surveymonkey.com/r/FJPDJRZ

Future webinars! Prevention and Treatment of Retinopathy of Prematurity