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.
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 Trusted evidence. Informed decisions. Better health.
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 Roger F. Soll Coordinating Editor Colleen Ovelman Managing Editor Jennifer Spano Information Specialist
Editorial Team Michael Bracken Yale University Jeffrey Horbar University of Vermont Bill McGuire Hull York Medical School Gautham Suresh Baylor University
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
What do we do? COCHRANE NEONATAL - 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
COCHRANE NEONATAL These Cochrane systematic reviews are published in the Cochrane Database of Systematic Reviews which is contained in the Cochrane Library.
COCHRANE NEONATAL: Published Reviews 400 350 300 REVIEWS 250 200 150 100 50 0 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015
COCHRANE NEONATAL What has Cochrane Neonatal done for me lately? Or more importantly What has it done for babies?
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)
PROPHYLACTIC CORTICOSTEROIDS PRIOR TO PRETERM BIRTH OVERVIEW OF 18 RANDOMIZED CONTROLLED TRIALS Outcome (# of trials) Typical Relative Risk Decreased Risk Increased ( 95% CI ) 0.2 0.5 1.0 2.0 4.0 RDS (14) 0.64 (0.56, 0.72) 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) 0.2 0.5 1.0 2.0 4.0 Typical Relative Risk (95% CI)
PROPHYLACTIC CORTICOSTEROIDS PRIOR TO PRETERM BIRTH OVERVIEW OF 15 RANDOMIZED CONTROLLED TRIALS Outcome (# of trials) Typical Relative Risk Decreased Risk Increased ( 95% CI ) 0.2 0.5 1.0 2.0 4.0 Stillbirth (12) 0.84 (0.59, 1.21) 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) 0.2 0.5 1.0 2.0 4.0 Typical Relative Risk (95% CI)
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
ANTENATAL CORTICOSTEROIDS VERMONT OXFORD NETWORK ANNUAL REPORTS 1991-2005 % VLBW INFANTS 80% 70% 60% 50% 40% 30% 20% 10% 0% NIH Conference 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
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SOMETIMES COCHRANE REVIEWS TELL US WHAT WE ALREADY KNOW!
SURFACTANT THERAPY EFFECT ON PNEUMOTHORAX TYPES OF STUDIES (N) Typical Risk Difference Decreased Risk Increased ( 95% CI ) 0.2 0.5 1.0 2.0 4.0 PROPHYLACTIC SURFACTANT 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) NATURAL SURFACTANT (12) -0.17 (-0.21, -0.13) Soll 1997 0.2 0.5 1.0 2.0 4.0 Typical Relative Risk (95% CI)
SURFACTANT THERAPY EFFECT ON NEONATAL MORTALITY TYPES OF STUDIES (N) Typical Risk Difference Decreased Risk Increased ( 95% CI ) 0.2 0.5 1.0 2.0 4.0 PROPHYLACTIC SURFACTANT 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) NATURAL SURFACTANT (12) -0.09 (-0.13, -0.05) Soll 1997 0.2 0.5 1.0 2.0 4.0 Typical Relative Risk (95% CI)
EXOGENOUS SURFACTANT TREATMENT VERMONT OXFORD NETWORK ANNUAL REPORTS 1991-2010 80% 70% FDA APPROVAL % VLBW INFANTS 60% 50% 40% 30% 20% 10% 0% 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009
INTRODUCTION OF ANTENATAL STEROIDS AND POSTNATAL SURFACTANT TREATMENT EFFECT ON MORTALITY IN ELBW INFANTS 90% 80% 70% % ELBW INFANTS 60% 50% 40% 30% 20% 10% 0% 1991 1992 1993 1994 1995 1996 ANTENATAL STEROIDS SURFACTANT THERAPY MORTALTY
SOMETIMES COCHRANE REVIEWS REFINE HOW WE PRACTICE!
DELIVERY ROOM vs. TREATMENT SURFACTANT EFFECT ON NEONATAL MORTALITY STUDY Decreased Risk Increased 0.2 0.5 1.0 2.0 4.0 Kendig 1991 Dunn 1991 Egberts 1993 Kattwinkel 1993 Walti 1995 Bevilacqua 1996 Bevilacqua 1997 TYPICAL ESTIMATE Soll and Morley 2001 0.2 0.5 1.0 2.0 4.0 Relative Risk and 95% CI
PROPHYLACTIC SURFACTANT AND STEROIDS EFFECT ON MORTALITY DUE TO RDS 70 MORTALITY DUE TO RDS (%) 60 50 40 30 20 10 0 SURF/STEROID SURF/NO STEROID NO SURF/STEROID NEITHER
PROPHYLACTIC SURFACTANT vs. SELECTIVE TREATMENT OF RDS NEONATAL MORTALITY
PROPHYLACTIC SURFACTANT vs. SELECTIVE TREATMENT OF RDS DEATH OR BPD
DR PRACTICES IN VLBW INFANTS 70% 60% % CASES 50% 40% 30% 20% 10% 0% 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 DR ETT DR SURFACTANT
SOMETIMES COCHRANE REVIEWS STOP US FROM DOING THINGS THAT MIGHT INJURE OUR BABIES!
ROLE OF INFLAMMATION CHORIOAMNIONITIS AND BRONCHOPULMONARY DYSPLASIA % CASES 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% BRONCHOPULMONARY DYSPLASIA ABSENT PRESENT YOON AND COWORKERS. A SYSTEMIC FETAL INFLAMMATORY RESPONSE AND THE DEVELOPMENT OF BRONCHOPULMONARY DYSPLASIA. AM J OBSTET GYNECOL 1999;181:773-9
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
EARLY ( 7 DAYS) POSTNATAL STEROID THERAPY META-ANALYSIS OF 32 RANDOMIZED CONTROLLED TRAILS Outcome (N Studies) Typical Risk Difference ( 95% CI ) Decreased Risk Increased 0.2 0.5 1.0 2.0 4.0 CLD @ 28 DAYS (17) -0.07 (-0.10,-0.03) 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 0.2 0.5 1.0 2.0 4.0 Typical Relative Risk and 95% CI
EARLY ( 7 DAYS) POSTNATAL STEROID THERAPY EFFECT ON COMPLICATIONS OF PREMATURITY OUTCOME (N STUDIES) Decreased 0.2 Risk Increased 0.5 1.0 2.0 4.0 PULMONARY AIR LEAK (16) PATENT DUCTUS ARTERIOSUS (24) INFECTION (25) HYPERTENSION (11) GI HEMORRHAGE (12) SEVERE IVH (26) SEVERE ROP (14) Doyle 2017 0.2 0.5 1.0 2.0 4.0 Relative Risk and 95% CI
LATE (> 7 DAYS) POSTNATAL STEROID THERAPY META-ANALYSIS OF 21 RANDOMIZED CONTROLLED TRAILS Outcome (N Studies) Typical Risk Difference ( 95% CI ) Decreased 0.2 Risk Increased 0.5 1.0 2.0 4.0 CLD @ 28 DAYS (6) -0.11 (-0.17, -0.05) 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) 0.2 0.5 1.0 2.0 4.0 Doyle 2017 Typical Relative Risk and 95% CI
EARLY ( 7 DAYS) POSTNATAL STEROID THERAPY NEURODEVELOPMENTAL OUTCOME IN SURVIVORS OUTCOME (N Studies) Typical Risk Difference Decreased Risk Increased ( 95% CI ) 0.2 0.5 1.0 2.0 4.0 PVL (15) 0.00 (-0.01, 0.02) BAYLEY MDI < 2SD (3) 0.01 (-0.06, 0.06) BAYLEY PDI < 2SD (3) 0.02 (-0.02, 0.07) ABNORMAL NEURO EXAM (5) DEVELOPMENTAL DELAY (1) 0.10 (0.05, 0.15) 0.14 (0.03, 0.24) CEREBRAL PALSY (13) 0.02 (-0.00, 0.05) MOD/SEVERE IMPAIRMENT (7) 0.01 (-0.02, 0.05) Doyle 2017 0.2 0.5 1.0 2.0 4.0 Typical Relative Risk and 95% CI
LATE (> 7 DAYS) POSTNATAL STEROID THERAPY NEURODEVELOPMENTAL OUTCOME IN SURVIVORS Outcome (N) Typical Risk Difference (95%CI) Decreased Risk Increased 0.2 0.5 1.0 2.0 4.0 BAYLEY MDI < 2SD (7) BAYLEY PDI < 2SD (1) ABNORMAL NEURO EXAM (4) CEREBRAL PALSY (15) MOD/SEVERE IMPAIRMENT (9) -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) Doyle 2017 0.2 0.5 1.0 2.0 4.0 Typical Relative Risk and 95% CI
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 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.
Postnatal Corticosteroid Use in VLBW Infants VERMONT OXFORD NETWORK ANNUAL REPORTS 1991-2014 % VLBW INFANTS 30% 20% 10% Cochrane Review AAP Statement 0% 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013
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 50% 40% 30% 20% 10% 0%
Risk Difference (%) for Death or CP among all participants vs. rate of CLD (%) in the control group Doyle, L. W. et al. Pediatrics 2005;115:655-661
CLD
Cerebral palsy
SOMETIMES COCHRANE REVIEWS PROVIDE RESULTS THAT MAY BE CONFUSING!
Intraventricular Hemorrhage VERMONT OXFORD NETWORK ANNUAL REPORTS 1991-2015 60% 50% % VLBW INFANTS 40% 30% 20% 10% 0% 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 Any Intraventricular Hemorrhage Severe Intraventricular Hemorrhage
Prophylactic Indomethacin Meta-analysis of 19 trials EFFECT ON PATENT DUCTUS ARTERIOSUS (PDA) Outcome Risk Difference Decreased Risk Increased ( 95% CI ) 0.2 0.5 1.0 2.0 4.0 PATENT DUCTUS ARTERIOSUS (7) -0.27 (-0.32, -0.21) SYMPTOMATIC PDA (14) -0.24 (-0.28, -0.21) PDA LIGATION (8) -0.05 (-0.08, -0.03) FOWLIE 2010: THE COCHRANE LIBRARY 0.2 0.5 1.0 2.0 4.0 Relative Risk and 95% CI
Prophylactic Indomethacin Meta-analysis of 19 trials EFFECT ON CENTRAL NERVOUS SYSTEM INJURY Outcome Risk Difference Decreased Risk Increased ( 95% CI ) 0.2 0.5 1.0 2.0 4.0 INTRAVENTRICULAR HEMORRHAGE (14) -0.04 (-0.08, -0.01) 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 0.2 0.5 1.0 2.0 4.0 Relative Risk and 95% CI
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
Long-Term Effects of Indomethacin Prophylaxis in ELBW Infants Schmidt B and colleagues. N Engl J Med 2001; 344:1966-1972 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 Indomethacin Control Adjusted OR (95% CI) Composite Death or impairment 47% 46% 1.1 (0.8 to 1.4) Components Death CP Cognitive delay Hearing loss Blindness 21% 12% 27% 2% 2% 19% 12% 26% 2% 1% 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)
Prophylactic Indomethacin Meta-analysis of 19 trials STATUS AT LATEST FOLLOW UP Outcome Risk Difference Decreased Risk Increased ( 95% CI ) 0.2 0.5 1.0 2.0 4.0 MORTALITY AT FOLLOW UP (18) -0.01 (-0.04, 0.02) CEREBRAL PALSY (4) 0.00 (-0.03, 0.04) SEVERE ND IMPAIRMENT (3) -0.01 (-0.05, 0.04) FOWLIE 2010: THE COCHRANE LIBRARY 0.2 0.5 1.0 2.0 4.0 Relative Risk and 95% CI
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? PREVENTS: SYMPTOMATIC PDA SEVERE IVH DOES NOT ALTER NEURODEVELOPMENTAL OUTCOME
Indomethacin VERMONT OXFORD NETWORK ANNUAL REPORTS 1991-2015 80% 70% % VLBW INFANTS 60% 50% 40% 30% 20% 10% 0% 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015
SOMETIMES WE IGNORE THE FINDINGS FROM RANDOMIZED CONTROLLED TRIALS AND THE REVIEWS OF THESE TRIALS!
ELECTIVE HIGH FREQUENCY OSCILLATORY VENTILATION META-ANALYSIS OF 19 RANDOMIZED CONTROLLED TRIALS OUTCOME (STUDIES) Risk Difference Decreased Risk Increased ( 95% CI ) 0.2 0.5 1.0 2.0 4.0 PULMONARY AIRLEAK (13) 0.04 (0.01, 0.07) IVH (12) 0.02 (-0.01, 0.05) 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) CLD/DEATH @ 36 WKS PMA (17) -0.05 (-0.08, -0.01) COOLS 2015 0.2 0.5 1.0 2.0 4.0 Relative Risk and 95% CI
High Frequency Ventilation VERMONT OXFORD NETWORK ANNUAL REPORTS 1991-2014 30% % VLBW INFANTS 20% 10% 0% 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013
CHRONIC LUNG DISEASE IN VLBW INFANTS VERMONT OXFORD NETWORK ANNUAL REPORTS 1994-2010 % VLBW INFANTS 40% 30% 20% 10% 0% 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
MORTALITY IN VLBW INFANTS VERMONT OXFORD NETWORK ANNUAL REPORTS 1991-2010 20% % VLBW INFANTS 15% 10% 5% 0% 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009
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 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.
Inhaled Nitric Oxide in VLBW Infants Vermont Oxford Network Annual Reports 2000-2012 Range 3 rd quartile 1 st quartile 20% % VLBW INFANTS 15% 10% 5% 0% 2008 2009 2010 2011 2012 2013
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 HYPOXIC ISCHEMIC ENCEPHALOPATHY WHOLE BODY COOLING AND SELECTIVE HEAD COOLING STUDY Typical Risk Difference Decreased Risk Increased (95%CI) 0.2 0.5 1.0 2.0 4.0 SELECTIVE HEAD COOLING DEATH -0.05 (-0.14, 0.04) MAJOR DISABILITY -0.09 (-0.24, 0.05) DEATH OR MAJOR DISABILITY -0.09 (-0.21, 0.03) WHOLE BODY COOLING DEATH -0.10 (-0.16, -0.04) MAJOR DISABILITY -0.18 (-0.29, -0.09) DEATH OR MAJOR DISABILITY -0.16 (-0.23, -0.09) Updated by Berg 2012 0.2 0.5 1.0 2.0 4.0 Typical Relative Risk and 95% CI
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 of 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 Whole Body 74% Selective Head 17% Both 9% Pfister. PAS. 2013
PROBLEMS WITH META-ANALYSIS Only fair agreement between large clinical trials and meta-analyses LeLorier 1997
META-ANALYSIS OF MULTIPLE SMALL STUDIES COMPARED TO SINGLE LARGE STUDY ASPIRIN FOR PREVENTION OF PRE-ECLAMPSIA CHARACTERISTIC Odds Ratio Decreased Risk Increased (95% CI) 0.2 0.5 1.0 2.0 4.0 META-ANALYSIS 0.30 (0.20, 0.42) SINGLE LARGE RCT 0.82 (0.72, 1.05) 0.2 0.5 1.0 2.0 4.0 Odds Ratio and 95% CI
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.
RCTs Cochrane Reviews You cannot make a silk purse from a sow s ear
TRIALS BASED (at least in part) on 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?
So what is the fate of Cochrane Neonatal? Bridging funds: University of Vermont Cochrane Central Possible future sponsorship: Vermont Oxford Network
Questions
For CME Credits use the following link: https://www.surveymonkey.com/r/vs9ck2z For Nursing Contact Hours use the following link: https://www.surveymonkey.com/r/fjpdjrz Future webinars! Prevention and Treatment of Retinopathy of Prematurity