Evidence-Based Guidelines s2

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ECC Evidence-Based Guidelines

WORKSHEET for PROPOSED GUIDELINE RECOMMENDATIONS

Home Subcommittee:
PEDS/NRP / Worksheet Author:
Michael E. Speer, M.D.
Date Submitted to Subcommittee: 10/6/03; revised 10/5/04; 11/3/04
Date Worksheet ready to discuss: ______ / Collaborators:
Jeffrey Perlman MB

Proposal. State clearly and explicitly the proposal to add a new guideline; to revise an existing guideline; or to delete an existing guideline:

Hypothermia should be provided to newly born infants with severe perinatal asphyxia.

Relevant Existing Guideline, Practice or Training activity: State AHA published statements of the existing guidelines or practice to be revised, or added to.

(NRP Text 2-9, 1995) Even healthy term infants have a limited ability to produce heat when exposed to a cold environment, particularly during the first 12 hours of life. This ability is diminished even further in infants who are hypoxemic. Infants who suffer heat loss have an increased metabolic rate and require more oxygen – conditions that can cause serious problems for infants who already are asphyxiated.

Step 1A: Refine the hypothesis/recommendation. State proposed guideline recommendation as specifically as possible in a single sentence.

Term infants who have exhibited clinical signs of moderate encephalopathy without early electrographic seizures may benefit from moderate selective cerebral hypothermia, if implemented within the first six hours following birth.

Step 1B: Gather the Evidence. Fill in your search for evidence, and best sources.

• Electronic Databases searched (include both online such as Medline through eMail or PubMed through www.PubMed.gov ; Cochrane Database of Systematic Reviews

• Search terms used in database searches. Underline the most successful in terms of yield.

Cerebral hypothermia; mild cerebral hypothermia; moderate cerebral hypothermia; moderate cerebral hypothermia newborn; hypothermia birth asphyxia; immature animal cerebral hypothermia; hypothermia birth asphyxia; fetal cerebral hypothermia

Standard search terminology for PubMed was used and terms were separated by ‘AND’

• Did you try posting to on-line newsgroups? No Was it helpful?

• Other helpful sources identified & reviewed (abstracts? book chapters? prepublication materials?)

References cited in articles were particularly helpful

• Were article bibliographies hand-searched for relevant references?

Yes (Did these searches get “hits” not identified in other databases noted above?) Sometimes What were major journals yielding hits not found in electronic databases? Pediatrics & Arch Dis Child

• State major ways in which you limited or expanded your search? Criteria for inclusion; criteria for exclusion: (human? animal? minimal study N? type of methodology? peer-reviewed manuscripts only? scientific abstracts = OK? other?)

Search limited to animal and human peer reviewed manuscripts; also trimmed search to include only fetal/neonatal manuscripts

• Number found specifically matching question: 76

Step 2a: Determine the Level of Evidence for each source. Of the articles/sources in Step 1 to be considered further, assign each article a level of evidence—based on study design and methodology (see Summary table below).

1998 AHA-ECC Levels of Evidence Summary

Level of Evidence

/ Definition
Level 1 / Larger randomized clinical trials or meta-analyses of multiple randomized clinical trials
Level 2 / Smaller randomized clinical trials
Level 3 / Prospective, controlled, non-randomized, cohort studies
Level 4 / Historic, non-randomized, cohort or case-control studies
Level 5 / Case series: patients compiled in serial fashion, lacking a control group
Level 6 / Animal, or adult studies or mechanical model studies
Level 7 / Extrapolations from existing data collected for other purposes, theoretical analyses
Level 8 / Rational conjecture (common sense); common practices accepted before evidence-based guidelines

Step 2a WORKSHEET: List the articles you considered best met your original selection criteria for review, now sorted by the Level of Evidence. Use short citations or citation numbers so that articles can be referred to specifically.

Level of Evidence / List of Articles (use citation number or first author, date)
Level 1
Level 2 / Akisu et al, Prostaglandins Leukot Essent Fatty Acids, 2003. Battin et al, Pediatrics, 2001. Battin et al, Pediatrics, 2003. Shankaran, et al, Pediatrics, 2002.
Level 3
Level 4 / Compagnoni et al, Biol Neonate, 2002. Simbruner et al, Intensive Care Med, 1999.
Level 5 / Azzopardi et al, Pediatrics, 2000. Debillon et al, Dev Med Child Neurol, 2003. Thoresen & Whitelaw, Pediatrics, 2000.
Level 6 / Biswa et al, Crit Care Med, 2002. . Gunn AJ, Pediatr Res, 1999. Oates & Harvey, Arch Dis Child, 1976. Statler, et al, Crit Care Med, 2003. Tooley et al, Pediatrics, 2002. Wagner et al, Pediatr Res, 2002.
Level 7 / Bernard, et al, N Engl J Med, 2002, Clifton et al, Engl J Med, 2001Clifton GL et al, J Neurotrauma, 2002, . Hypothermia after cardiac arrest study group, N Engl J Med, 2002, Jiang J, J Neurosurg, 2000., Shiozaki T, et al, J Neurosurg, 2001
Level 8

Step 2b(1): Critically evaluate the quality of each article/source in terms of research design and methods. Criteria appear in the table below. Combine design and methods scores to obtain an overall quality rating. Quality ratings should be independent of Level, that is a Level 1 study could be excellent or poor as a clinical trial, just as a Level 6 study could be excellent or poor as an animal study.

Component of Study and Rating / Excellent / Good / Fair / Poor / Unsatisfactory

Design

/ Highly appropriate sample or model, randomized, proper controls / More than
adequate design and minimally biased / Adequate, design, but possibly biased / Small or clearly biased population or model, poor or absent controls / Anecdotal, no controls, off target end-points
Methods / Outstanding accuracy, precision, and data collection in its class / More than adequate in its class / Adequate under the circumstances / Weakly defensible in its class, limited data or measures / Totally bogus

Step 2b(2): Also evaluate the direction of the results and the statistics as supportive, neutral, or opposing the guideline proposal.

Component of Study and Rating /

Supportive of Proposal

/ Neutral / Opposing Proposal
Results /

Outcome of proposed modification superior to conventional or current approach

/ Outcome of proposed modification no different from conventional or current approach / Outcome of proposed modification inferior to conventional or current approach
Statistics /

Significant positive effect of proposed treatment

/ No significant difference among treatments / Significant negative effect of proposed treatment

Summarize the evidence in Level-Quality grids. Sort the Excellent, Good, and Fair quality studies only by both Level, quality rating, and direction of support for the guideline proposal in the summary grids below, using short citations or citation numbers, as before. Do not include poor or unsatisfactory quality studies. In the Neutral or Opposing Evidence grid use bold font to distinguish studies clearly opposing the proposal from merely neutral ones.

Supporting Evidence

Quality of Evidence / Excellent / Bernard, 2002; D Hypothermia after Cardiac Arrest Study Group, 2002 D
Good / Jiang, 2002; D Wagner, 2002
Fair / Compagnoni, 2000E / Clifton, 2002 D
1 / 2 / 3 / 4 / 5 / 6 / 7 / 8

Level of Evidence

A= Return of spontaneous circulation C= Survival to Hospital Discharge E = Other end point

B= Survival of event D = Intact neurological survival

Neutral or Opposing Evidence

Quality of Evidence / Excellent / Biswas, 2002; E
Clifton, 2001; D Shiozaki, 2001 D
Good / Battin, 2003; E Battin, 2001; E Shankaran, 2002 E / Simbruner, 1999 E / Azzopardi, 2000; E Debillon, 2003 E
Fair / Akisu, 2003 / Thoresen, 2002 / Gunn, 1999; Oates, 1976; Statler, 2003; Tooley, 2002
1 / 2 / 3 / 4 / 5 / 6 / 7 / 8

Level of Evidence

A= Return of spontaneous circulation C= Survival to Hospital Discharge E = Other end point

B= Survival of event D = Intact neurological survival

Step 3. Determine Class of Recommendation: summary definitions

CLASS / DEFINITION / LEVEL OF EVIDENCE
Class I
Definitely recommended. Definitive,
excellent evidence provides support. / • Always acceptable, safe
• Definitely useful
• Proven in both efficacy & effectiveness
• Must be used in the intended manner for proper clinical indications. / • One or more Level 1 studies are present (with rare
exceptions)
• Study results consistently positive and compelling
Class II:
Acceptable and useful / • Safe, acceptable
• Clinically useful
• Not yet confirmed definitively / • Most evidence is positive
• Level 1 studies are absent, or inconsistent, or lack
power
• No evidence of harm
• Class IIa: Acceptable and useful
Very good evidence provides support / • Safe, acceptable
• Clinically useful
• Considered treatments of choice / • Generally higher levels of evidence
• Results are consistently positive
• Class IIb: Acceptable and useful
Fair-to-good evidence provides support / • Safe, acceptable
• Clinically useful
• Considered optional or alternative
treatments / • Generally lower or intermediate levels of evidence
• Generally, but not consistently, positive results
Class III:
Not acceptable, not useful, may be
harmful / • Unacceptable
• Not useful clinically
• May be harmful. / • No positive high level data
• Some studies suggest or confirm harm.
Indeterminate / • Continuing area of research
• No recommendations until
further research / • Evidence not available
• Higher studies in progress
• Results inconsistent, contradictory
• Results not compelling

Step 3: Determine the Class of Recommendation. Propose a Class of Recommendation for the Guideline Proposal:

Indeterminate

COMMENTS: Reviewers final comments. Summarize the major rationale for your final evidence integration and class of recommendation. Describe any mismatches between the evidence and your final Class of Recommendation? (e.g. evidence very strong, but implementation too difficult or expensive; evidence weak but impossible to perform definitive studies). Describe whether your final Class selection was based purely on the selected evidence, or were there other factors playing a role (e.g. clinical experience, what you have seen work?)

While a significant body of work has been done using various animal models, the long term effects of moderate hypothermia remains unclear in instances of severe neurologic insult (Gunn et al.Tooley et al, Wagner et al) While it is apparent that intraischemic moderate hypothermia exerts a beneficial effect regarding acute neuronal injury, only limited data are available regarding long term effects of either intraischemic or post ischemic moderate hypothermia. Moreover, the exact depth and duration of hypothermia to provide optimal neurologic protection is also still unclear. Additionally, most of the level 6 studies are of minimal clinical relevance.

Adult studies demonstrate a significant effect of modest hypothermia on neurologic outcome following out of hospital arrest (Bernard, 2002, The Hypothermia after Cardiac Arrest Study 2002). Published studies in the newborn infant are limited (Azzopardi, 2000, Shankaran, 2002, Shimbruner 1999, Thoresen, 2000) but the intervention appears to be safe. Two multicenter randomized trials have been recently completed (one is in press) and final results from neurologic follow up is pending in the second study. Both human and primate studies have demonstrated poor outcomes with prolonged deep hypothermia.

There is insufficient evidence to support or refute the routine use of modest hypothermia as a neuroprotective strategy in the term infant at highest risk for developing moderate to severe encephalopathy. Studies indicate that both forms of intervention (i.e. selective cooling applied to the head as well as total body cooling) to a modest degree are not associated with significant side effects.

Citation Marker / Full Citation (abstracts appear below)
{Akisu, 2003 #1} / Akisu, M., A. Huseyinov, et al. (2003). "Selective head cooling with hypothermia suppresses the generation of platelet-activating factor in cerebrospinal fluid of newborn infants with perinatal asphyxia." Prostaglandins Leukot Essent Fatty Acids 69(1): 45-50.
{Azzopardi, 2000 #2} / Azzopardi, D., N. J. Robertson, et al. (2000). "Pilot study of treatment with whole body hypothermia for neonatal encephalopathy." Pediatrics 106(4): 684-94.
{Battin, 2001 #3} / Battin, M. R., J. A. Dezoete, et al. (2001). "Neurodevelopmental outcome of infants treated with head cooling and mild hypothermia after perinatal asphyxia." Pediatrics 107(3): 480-4.
{Battin, 2003 #4} / Battin, M. R., J. Penrice, et al. (2003). "Treatment of term infants with head cooling and mild systemic hypothermia (35.0 degrees C and 34.5 degrees C) after perinatal asphyxia." Pediatrics 111(2): 244-51.
{Bernard, 2002 #5} / Bernard, S. A., T. W. Gray, et al. (2002). "Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia." N Engl J Med 346(8): 557-63.
{Biswas, 2002 #6} / Biswas, A. K., D. A. Bruce, et al. (2002). "Treatment of acute traumatic brain injury in children with moderate hypothermia improves intracranial hypertension." Crit Care Med 30(12): 2742-51.
{Clifton, 2002 #7} / Clifton, G. L., E. R. Miller, et al. (2002). "Hypothermia on admission in patients with severe brain injury." J Neurotrauma 19(3): 293-301.
{Clifton, 2001 #8} / Clifton, G. L., E. R. Miller, et al. (2001). "Lack of effect of induction of hypothermia after acute brain injury." N Engl J Med 344(8): 556-63.
{Compagnoni, 2002 #9} / Compagnoni, G., L. Pogliani, et al. (2002). "Hypothermia reduces neurological damage in asphyxiated newborn infants." Biol Neonate 82(4): 222-7.
{Debillon, 2003 #10} / Debillon, T., P. Daoud, et al. (2003). "Whole-body cooling after perinatal asphyxia: a pilot study in term neonates." Dev Med Child Neurol 45(1): 17-23.
{Gunn, 1999 #11} / Gunn, A. J., L. Bennet, et al. (1999). "Cerebral hypothermia is not neuroprotective when started after postischemic seizures in fetal sheep." Pediatr Res 46(3): 274-80.
{, 2002 #12} / (2002). "Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest." N Engl J Med 346(8): 549-56.
{Jiang, 2000 #13} / Jiang, J., M. Yu, et al. (2000). "Effect of long-term mild hypothermia therapy in patients with severe traumatic brain injury: 1-year follow-up review of 87 cases." J Neurosurg 93(4): 546-9.
{Oates, 1976 #14} / Oates, R. K. and D. Harvey (1976). "Failure of hypothermia as treatment for asphyxiated newborn rabbits." Arch Dis Child 51(7): 512-6.
{Shankaran, 2002 #15} / Shankaran, S., A. Laptook, et al. (2002). "Whole-body hypothermia for neonatal encephalopathy: animal observations as a basis for a randomized, controlled pilot study in term infants." Pediatrics 110(2 Pt 1): 377-85.
{Shiozaki, 2001 #16} / Shiozaki, T., T. Hayakata, et al. (2001). "A multicenter prospective randomized controlled trial of the efficacy of mild hypothermia for severely head injured patients with low intracranial pressure. Mild Hypothermia Study Group in Japan." J Neurosurg 94(1): 50-4.
{Simbruner, 1999 #17} / Simbruner, G., C. Haberl, et al. (1999). "Induced brain hypothermia in asphyxiated human newborn infants: a retrospective chart analysis of physiological and adverse effects." Intensive Care Med 25(10): 1111-7.
{Statler, 2003 #18} / Statler, K. D., H. L. Alexander, et al. (2003). "Moderate hypothermia may be detrimental after traumatic brain injury in fentanyl-anesthetized rats." Crit Care Med 31(4): 1134-9.
{Thoresen, 2000 #19} / Thoresen, M. and A. Whitelaw (2000). "Cardiovascular changes during mild therapeutic hypothermia and rewarming in infants with hypoxic-ischemic encephalopathy." Pediatrics 106(1 Pt 1): 92-9.
{Tooley, 2002 #20} / Tooley, J., S. Satas, et al. (2002). "Significant selective head cooling can be maintained long-term after global hypoxia ischemia in newborn piglets." Pediatrics 109(4): 643-9.
{Wagner, 2002 #21} / Wagner, B. P., J. Nedelcu, et al. (2002). "Delayed postischemic hypothermia improves long-term behavioral outcome after cerebral hypoxia-ischemia in neonatal rats." Pediatr Res 51(3): 354-60.

Annotated Bibliography