1. 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

2. 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.

3. 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

4. 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

5. ILCOR 2015 Neonatal Working Group

6. 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:

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

8. 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)

9. 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

10. 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).

11. 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

12. 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

13. 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.

14. 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

15. 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

16. 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.

17. 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

18. 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

19. 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

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

21. 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

22. An Example ILCOR Evidence Review Using the GRADE System

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

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

25. 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.

26. 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

27. 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

28. 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.

29. Risk of Bias in Studies
RCTs
Non-RCTs

30. Outcome- Infant Death
RCTs
Non-RCTs

31. Evidence Profile Table-Infant Death
RCTs
Non-RCT

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

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

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

35. 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 g/dl) and high quality evidence that cord milking decreased the need for transfusion (OR 0.2, 95% CI ).

36. 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 ).
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 ( mm Hg) in the intervention group.

37. 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 ) but no difference (from 1 study [Hosono 2008]) in severe IVH (OR 0.44, 95% CI ).
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 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 ).

38. 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.

39. 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.

40. 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.

41. 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

42. 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 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.

43. 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

44. 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

45. 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.

46. 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