UT Southwestern Medical Center at Dallas C0009 NRP® Current Issues Seminar: Monumental Changes on the Horizon The International Liaison Committee on Resuscitation (ILCOR) Process for Evidence Based Review and the Role of Public Comment Myra H. Wyckoff, MD UT Southwestern Medical Center at Dallas Co-Chair of ILCOR Neonatal Task Force 2016-2020

Faculty Disclosure Information In the past 12 months, I have no relevant financial relationships with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services discussed in this CME activity. I do not intend to discuss an unapproved/investigative use of a commercial product/device in my presentation.

Objectives Understand the purpose of ILCOR Understand how PICO questions are identified and refined for systematic review Identify components of the GRADE process that is used by ILCOR for systematic reviews Understand where to find the systematic reviews on the AHA ILCOR website Understand the role of public comment when the systematic reviews are posted

Achieving Consensus on Resuscitation Science Since 2000, the AAP with the American Heart Association, participates with the International Liaison Committee on Resuscitation (ILCOR) for a complete review of resuscitation science every 5 years. 23 new questions reviewed for 2015 Australian Resuscitation Council

ILCOR 2015 Neonatal Working Group

Guidelines for Neonatal Resuscitation New Consensus on Science and Neonatal Resuscitation Guidelines available online since October 14, 2015 Printed Guidelines supplement published in Circulation, Resuscitation and in Pediatrics Download at: www.heart.org/cpr

NRP Guidelines are set by the AAP NRP Steering Committee NRP 7th Edition will rollout in Spring 2016

Ask An Answerable Question Development of clear, important questions for which to search for evidence is paramount PICO format Patient (the exact population) Intervention (usually experimental group) Comparator (usually the usual practice or a placebo) Outcome (impact on what)

ILCOR Evaluation Process Identify and develop the PICO questions that need scientific review May have to be refined after initial evidence search Rank Outcomes of interest for importance Examples: Time to return of Heart Rate > 100 bpm Survival Neurodevelopmental Outcome at 2-3 years of age Temperature on Admission Need for Intubation

ILCOR Evaluation Process Prioritize the questions and assign reviewers Resources are finite (Particularly TIME!!!) Minimum requirements for every search strategy are specified and done by professional librarians Medline, Embase, and Cochrane Systematic Reviews Hand searches EndNote reference software and access to a resuscitation reference library Every reviewer rates the level and quality of evidence using a standardized evidence evaluation (GRADE system).

Understanding GRADE GRADE: Most widely used method for appraising studies to be included in systematic reviews and guidelines Recommended by Institute of Medicine-to give a common process and language for published guidelines GRADE is a method used by systematic reviewers and guideline developers to assess the quality of evidence Decide whether to recommend an intervention Grade is different from other appraisal tools because it Separates quality of evidence and strength of recommendation The quality of evidence is assessed for each outcome of interest Observational studies can be “up-graded” if they meet certain criteria

Using GRADE Step 1: Assign an a priori ranking of ‘high’ to randomized controlled trials and ‘low’ to observational studies. Randomized trials are initially assigned a higher grade because they are usually less prone to bias than observational studies

Using GRADE Step 2: ‘Downgrade’ or ‘upgrade’ initial ranking. It is common for randomized controlled trials and observational studies to be downgraded because they suffer from identifiable bias. Also, observational studies can be upgraded when multiple high-quality studies show consistent results.

Reasons to Down Grade in Step 2 Risk of Bias Lack of clearly randomized allocation sequence Lack of blinding Lack of allocation concealment Failure to adhere to intention to treat analysis Keeps folks from switching to the treatment they “believe” is best Large losses due to follow-up Exaggerates effect size. There is a positive bias conferred when participants benefitting from the treatment are more likely to stay in the trial

Other Reasons to Down Grade in Step 2 Inconsistency Variability in results from different trials Hard to tell if benefits outweigh the harms Indirectness Population studied is not exactly the population we want to apply the data to Outcome that is available in the literature is not exactly the outcome we care about

Other Reasons to Down Grade in Step 2 Imprecision When wide confidence intervals mar the quality of the data Publication Bias When ‘negative’ findings remain unpublished.

Reasons to Up Grade in Step 2 Large Effect When the effect is so large that bias common to observational studies cannot possibly account for the result Dose-response relationship When the response is proportional to the degree of exposure

GRADE Step 3 Step 3: Assign final grade for the quality of evidence as… ‘high’: We are very confident that the effect in the studies reflects the actual effect ‘moderate’: We are quite confident that the effect in the studies is close to the true effect, but it is also possible it is substantially different ‘low’: The true effect may differ significantly from the estimate ‘very low’: The true effect is likely to be substantially different from the estimated effect

GRADE Step 4 Step 4: Consider other factors that impact on the strength of the recommendation for a course of action Balance between desirable and undesirable effects In cases where the benefit to harm ratio are less clear, then patient values and preferences, as well as costs need to be carefully considered

GRADE Step 5 Step 5: Make a strong or weak recommendation For or against

GRADE Unless the recommendation is based on moderate or strong evidence…. We need to be advocating for more research The recommendations should not “squelch” research

An Example ILCOR Evidence Review Using the GRADE System

Umbilical Cord Milking (NRP #849) EVREV 1: Marya Strand, MD, MS; COI#222 EVREV 1: Takahiro Sugiura, MD; COI#224 Taskforce: Neonatal

COI Disclosure Marya Strand, MD, MS COI#222 Commercial/industry None Potential intellectual conflicts Takahiro Sugiura, MD COI#224

2010 Treatment Recommendation Evidence from a single, small, randomized controlled trial (Hosono 2008) suggest that among premature newborns (24-28 weeks gestation), milking the umbilical cord immediately after birth may decrease the need for packed red blood cells transfusions during the initial hospital stay. This single study was not adequately powered to fully assess the safety or efficacy of this intervention. Secondary analysis of data from this small randomized trial (Hosono 2009) suggests that among premature newborns (24-28 weeks gestation), milking the umbilical cord immediately after birth may increase hemoglobin at birth, improve hemodynamic stability during the first 5 days of life, and decrease the incidence of chronic lung disease at 36 weeks postmenstrual age.

2015 PICO Population: Very preterm infants (≤28 wks EGA) Outcomes: 9—Infant death 8—Neurodevelopmental outcome at 2-3 years 8—Severe Intracranial Hemorrhage 7—All grade Intracranial Hemorrhage 7—Cardiovascular stability (initial MBP) 7—Temperature on admission 6—Hematologic indices Initial hemoglobin, PRBC transfusion 6—Hyperbilirubinemia Phototherapy, Exchange transfusion Population: Very preterm infants (≤28 wks EGA) Intervention: Umbilical cord milking Comparison: Immediate umbilical cord clamping

Inclusion/Exclusion & Articles Found Inclusions/Exclusions Randomized or observational studies Infants born at ≤28 weeks’ gestation Search terms initially identified 690 potential articles Number Included in Evidence Profile tables RCTs: 4 non-RCTs: 1

Draft Treatment Recommendations There is insufficient published human evidence to suggest the routine use of cord milking for infants born at less than 29 weeks of gestation but cord milking may be considered a reasonable alternative to immediate cord clamping to improve initial mean blood pressure, hematological indices and ICH. However, there is no evidence for improvement or safety in long term outcomes. (Weak recommendation, low level of evidence) All studies included in this evidence review milked 20 cm of umbilical cord toward the umbilicus 3 times while the infant was held at the level of the introitus or below the level of the placenta prior to cord clamping.

Risk of Bias in Studies RCTs Non-RCTs

Outcome- Infant Death RCTs Non-RCTs

Evidence Profile Table-Infant Death RCTs Non-RCT

Outcome-Intracranial Hemorrhage (ICH) <Severe ICH-RCT> Any ICH-RCT Any ICH non-RCT

Evidence Profile Table-ICH RCT Non-RCT High quality evidence of a reduction of any IVH (OR 0.37, 95% CI 0.18-0.77) but no difference in severe IVH (OR 0.44, 95% CI 0.07-2.76).

Outcome - Hematologic Indices Initial hemoglobin: RCT Initial hemoglobin: non-RCT Received transfusion: RCT

Evidence profile table -hematologic indices RCT Non-RCT Moderate quality evidence that cord milking increased the initial hemoglobin measurement (2.56 g/dl, 95% CI 1.91-3.2 g/dl) and high quality evidence that cord milking decreased the need for transfusion (OR 0.2, 95% CI 0.09-0.44).

Proposed Consensus on Science Statements For the critical outcome of death we found low quality evidence (downgraded for imprecision) from 3 RCTs [Hosono 2008; Katheria 2014, 1045; March 2013, 1] that there is no difference in death (OR 0.76, 95% CI 0.25-2.29). We did not identify any evidence to address the critical outcome of “neurologic outcome at 2-3 years”. For the critical outcome of cardiovascular stability we found low quality evidence (downgraded for imprecision) from 2 studies [Hosono 2008; Katheria 2014] that the initial mean blood pressure was 5.43 mm Hg higher (1.98-8.87 mm Hg) in the intervention group.

Proposed Consensus on Science Statements For the important outcome of IVH, we found low quality evidence (downgraded for imprecision) from 2 RCT studies [Hosono 2008; March 2013] of a reduction of any IVH (OR 0.37, 95% CI 0.18-0.77) but no difference (from 1 study [Hosono 2008]) in severe IVH (OR 0.44, 95% CI 0.07-2.76). For the important outcome of hematologic indices, we found low quality evidence (downgraded for imprecision) from 2 studies [Hosono 2008; Katheria 2014] that cord milking increased the initial hemoglobin measurement (2.27 g/dl, 95% CI 1.57-2.98 g/dl) and low quality evidence (downgraded for imprecision) from 3 studies [Hosono 2008; Katheria 2014; March 2013] that cord milking decreased need for transfusion (OR 0.2, 95% CI 0.09-0.44).

Draft Treatment Recommendations We suggest against the routine use of cord milking for infants born at less than 29 weeks of gestation but cord milking may considered a reasonable alternative to immediate cord clamping to improve initial mean blood pressure, hematological indices and ICH. However, there is no evidence for improvement or safety in long term outcomes. (Weak recommendation, low level of evidence) All studies included in this evidence review milked 20 cm of umbilical cord toward the umbilicus 3 times while the infant was held at the level of the introitus or below the level of the placenta prior to cord clamping.

Values and Preferences Statement: In making this recommendation we place a high value on the simplicity/economy of this intervention with no demonstrated negative outcome, acknowledging the lack of evidence regarding critical long-term outcomes.

Knowledge Gaps Specific research required There are insufficient subjects in the reviewed studies to make strong recommendations for or against this intervention. We need the results of several on-going international trials that are not yet completed. We need information on important long-term neuro-developmental outcomes Cord milking vs Delayed cord clamping One RCT [Rabe　2011] demonstrated similar hematologic indices between cord milking and delayed cord clamping.

How many of you heard about the opportunity for the public to review the ILCOR Preliminary Reviews and offer comment? 1-Yes, I heard about it! 2-No, I heard nothing

The Role of Public Comment All reviews posted to the AHA SEERS website 2 weeks prior to the Consensus Conference  The public, especially those who teach and use resuscitation skills but were not part of the ILCOR process were encouraged to visit the SEERS home page at http://www.ilcor.org/seers to view these recommendations (and to provide feedback).  Comments submitted by the time of the CoSTR meeting were discussed in the CoSTR debates. Public commenting was open until February 28, 2015 and was reviewed prior to finalizing wording of ILCOR CoSTR document.

How many of you went to the AHA website and posted a public comment regarding a Neonatal ILCOR Review? 1-Yes, I did it! 2-No, did not happen

ILCOR CoSTR Meeting The in-depth review for each of 23 PICO questions was completed and presented in Dallas in Feb. 2015 Neonatal Task Force debated the evidence reviewers findings until consensus reached on wording for… the consensus on what the available science meant treatment recommendation values and preferences that went into making that treatment recommendation and knowledge gaps This wording used to build the ILCOR CoSTR Document

Conclusions The ILCOR evidence review process is long but results in comprehensive, meaningful review of the best science to apply to our resuscitation algorithms. The work is never done. The ILCOR Neonatal Task Force meets this December to begin debate on the most pressing PICO questions to review for 2020.

Potential Change in Your Practice YOU can play an important part in the process by offering public comment both regarding the PICO questions selected as well as the preliminary evidence reviews and treatment recommendations. Public Invitation will be sent through AAP list serves including the NRP Instructor Database