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Blood biomarkers for the prediction of poor neurological outcome after return of circulation following pediatric cardiac arrest: PLS 4220.01 TF SR

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This CoSTR is a draft version prepared by ILCOR, with the purpose to allow the public to comment and is labeled “Draft for Public Comment". The comments will be considered by ILCOR. The next version will be labelled “draft" to comply with copyright rules of journals. The final COSTR will be published on this website once a summary article has been published in a scientific Journal and labeled as “final”.

Conflict of Interest Declaration

The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. The following Task Force members and other authors declared an intellectual conflict of interest, and this was acknowledged and managed by the Task Force Chairs/vice chair and Conflict of Interest committees: Scholefield, B, Topjian A were authors and investigator in pediatric post-cardiac arrest neuro-prognostication studies. Data extraction and risk of bias were conducted by other members of the writing group.

CoSTR Citation

Scholefield BR, Tijssen J, Ganesan S, Topjian A, Bittencourt Couto T, Atkins D, Acworth J, Guerguerian AM on behalf of the International Liaison Committee on Resuscitation Pediatric Life Support Task Force. Biomarkers for the prediction of survival with poor neurological outcome after return of circulation following pediatric cardiac arrest Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Pediatric Life Support Task Force, 2025 XXXX. Available from: http://ilcor.org

Methodological Preamble and Link to Published Systematic Review

The continuous evidence evaluation process for the production of Consensus on Science with Treatment Recommendations (CoSTR) started with a systematic review of tests for predicting good neurological outcome after pediatric cardiac arrest (Scholefield, 2021, PROSPERO CRD42021279221) conducted by the members of the PLS TF with involvement of clinical content experts. This review has been updated and reevaluated for the current systematic review on poor neurological outcome. Evidence for pediatric literature was sought and considered by the Pediatric Life Support Task Force.

Systematic Review

Scholefield B et al. Biomarker tests for the prediction of survival with poor neurological outcome after return of circulation following pediatric cardiac arrest (in preparation)

PICOST

The PICOST

Population: This review is studying children (<18 years) who achieve a return of spontaneous or mechanical circulation (ROC) after resuscitation from in-hospital cardiac arrest (IHCA) and out-of-hospital (OHCA), from any cause.

Intervention: Biomarkers: Blood biomarkers included serum biomarkers either specific to neuronal damage (e.g., neuro-specific enolase (NSE), S100b, GFAP, neurofilament light chain (NfL)) or blood markers of inflammation or systemic ischemic reperfusion (e.g., blood pH or lactate).

Index prognostic tests, recorded less than 12 hours, 12 to <24 hours, 24 to <48 hours, 48 to <72 hours, 72 hours to <7 days, and/or 7 to 10 days after cardiac arrest.

Comparators: There was no control group for intervention/exposure. The accuracy of the prognostic index test was assessed by comparing the predicted outcome with the final outcome, which represents the comparator.

Outcomes: Primary outcome of interest is survival with poor neurological outcome is defined as a Pediatric Cerebral Performance Category (PCPC) score of >3, or Vineland Adaptive Behavioural scale-II <70. PCPC score ranges 1 (normal), 2 (mild disability), 3 (moderate disability), 4 (severe disability), 5 (coma), and 6 (brain death). We also report studies defining poor neurological outcomes with other assessment tools, or as a PCPC score >2, or change in PCPC score from baseline >2.

Study Designs: RCTs and nonrandomized studies (nonrandomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies) were eligible for inclusion. Case series were considered if greater than 5 cases were reported. Unpublished studies (eg, conference abstracts, trial protocols) and animal studies were excluded. We selected studies where the sensitivity and FPR of the prognostic (index) test were reported.

Timeframe: All years and all languages were included as long as there was an English abstract. Literature search updated to Aug 24th 2024.

PROSPERO Registration CRD42021279221

Consensus on Science

Introduction

There is no universal consensus on what the acceptable limits for imprecision should be in prediction for infants and children after cardiac arrest. We defined poor neurological outcome prediction as imprecise when the false positive rate (FPR) was >1%. We defined the reliability of the evidence as reliable if the FPR was <1% and the upper 95% confidence intervals <10% and moderately reliable if FPR was <1% with without a restriction on width of 95% confidence interval.

A low false positive rate means that a low proportion of patients, predicted to have a poor outcome will have a falsely pessimistic prediction (test predicted a poor outcome, but patient went on to have a good outcome). The pediatric task force considered that when focused on accuracy of predicting a poor outcome - a low false positive rate (e.g. <1%) is more desirable to avoid falsely pessimistic prediction than a high sensitivity. The cut-off of <1% FPR (equivalent to 99% specificity) was chosen as the consequences of false pessimism is substantial andmay result in advising discontinuation of life sustaining therapy in a patient who will eventually have a good outcome.

Results

The overall quality of evidence for individual tests was rated as very low for all outcomes primarily due to a very serious risk of bias, assessed using the QUIPS tool. The studies were all at a moderate to high risk of bias due to confounding. Because of this and a high degree of heterogeneity, no meta-analyses could be performed.

Lactate

Lactate was evaluated in 6 studies.(De La Llana 2021 202-9, Kramer 2018 113-120, Lopez-Herce 2014 607, Meert 2019 393-402, Moler 2017 318-329, Moler 2015 1898-1908). Only two studies identified a FPR <1% for poor outcome prediction. The first used a lactate threshold >28.8 mmols/L at <1 hour (Kramer 2018 113-120) with a corresponding sensitivity of 11%. The second, used failure of lactate clearance to <2mmol/L by 48 hours with a sensitivity of 23%. (De La Llana 2021 202-9) All other tests with a lactate level >2mmols at 6-12, 24 and 48 hours had a reported FPR of 14-84%. (De La Llana 2021 202-9, Meert 2019 393-402, Moler 2017 318-329, Moler 2015 1898-1908) A lactate >5mmol/L at <1 hour or 24 hours had a FPR of 34% and 11% respectively. (Lopez-Herce 2014 607) Lactate was not a reliable prognostic test.

pH

pH was evaluated in 4 studies. (De La Llana 2021 202-9, Kramer 2018 113-120, Moler 2017 318-329, Moler 2015 1898-1908) pH thresholds were <6.6, <7.0, <7.3, and >7.5 at resuscitation and within 1 hour, 6-12 hours and 24 hours of return of circulation. Extremes of pH <6.6 and >7.5 had a FPR for poor outcome prediction of <5% but very low <14% sensitivity. Blood pH of <7.0 measured 6-12 hours from ROC also had a FPR of 3-4% and a low sensitivity of 3-14% for predicting poor neurological outcome. (Moler 2017 318-329, Moler 2015 1898-1908) pH was not a reliable prognostic test.

Neuronal biomarkers

Three study reported NSE and S100b in 156 children (Bangshoj 2022 1659-1665, Fink 2014 664-674, Kramer 2018 113-120). Cut off values were calculated and reported to classify low FPR for poor neurological outcome. Values were calculated at <1, 6-12, 24, 48 and 72 hours. Wide (10+ fold) variation in cutoff values were reported. At 24 hours s100b levels of 0.128 µg/L (Fink 2014 664-674), 2.0 µg/L (Bangshoj 2022 1659-1665) and 2.24 µg/L (Kramer 2018 113-120) were reported to predict a poor neurological outcome with a FPR of 0% (95% CI 0-20%) and a sensitivity of 29-38%. Similarly, NSE level of both 53.1 µg/L (Fink 2014 664-674), 56 µg/L (Bangshoj 2022 1659-1665) and 132.7 µg/L (Kramer 2018 113-120) predicted a poor neurological outcome with a FPR of 0% (95% CI 0-20%) and a sensitivity of 19-26%. MBP was assessed in one study at 24 and 48 hours with cut off threshold of 5.83 µg/L predicting poor neurological outcome with low FPR 0% (95%CI 0-20%). NSE, S100b and MBP all fulfilled reliable test criteria but with wide range of cutoff thresholds in the individual studies.

Only one study reported UCH-L1, NfL, Tau and GFAP biomarker prediction of poor neurological outcome at 24, 48 and 72 hours.(Fink 2022 E2230518) Cut off threshold values were calculated to produce an optimal FPR of 4-5% (95%CI 1 to 15%) and corresponding sensitivity of 12-61%.

Treatment Recommendations

  • We recommend that no single blood-based biomarker examination test be used in isolation to predict poor neurological outcome in children after cardiac arrest at any time point (strong recommendation, very-low certainty evidence).
  • Clinicians should consider using multiple tests in combination for poor neurological outcome prediction (good practice statement).
  • We suggest against using lactate and pH after return of circulation (ROC), for predicting poor neurological outcome in children after cardiac arrest at any time point (weak recommendation, very-low-certainty evidence).
  • There is insufficient evidence to make a recommendation for or against the use of other blood-based biomarkers (e.g. S100beta, Neuron Specific Enolase, Neurofilament Light Chain (NfL) etc.) after ROC for predicting poor neurological outcome in children after cardiac arrest at any time point.

Justification and Evidence to Decision Framework Highlights

  • The Task Force considered the use of single biomarker tests in predicting a poor neurological outcome.
  • The available evidence had a high risk of bias based on high heterogeneity across studies, small number of studies and small number of patients included in addition to lack of blinding, variation in test assessment and performance, and variability in outcome measurement. Therefore, no meta-analysis was performed. Overall assessment of test performance was based on visual assessment of forest plots.
  • Included studies were observational studies and randomized controlled trials, but not primarily designed to test prognosis of blood biomarkers.
  • Lactate and pH were non-specific markers of hypoxic-ischaemia following cardiac arrest. Extreme values (very high lactate, very low pH) have a low FPR in the included studies, but frequent outliers and very low sensitivity were reported.
  • Four studies identified cut-offs across a range of blood-based biomarkers (S100b, NSE, MBP, UCH-L1, NfL, Tau and GFAP) that are known to represent brain injury and are associated with poor neurological outcome with a low FPR. However, sensitivity was low and the wide range of reported cut off thresholds preclude any accurate description of clinical utility. Furthermore, these tests require specialized laboratory equipment and are not widely available for clinical use, even though they only require the patient's blood.
  • No studies reported any assessment of the confounding influence of medication. None of the included studies specifically excluded the presence of residual sedation at the time clinical examination was assessed.
  • Lack of blinding is a major limitation of biomarker tests, even if the withdrawal of life-sustaining therapy based on test results has not been documented in any of the studies included in our review. No studies included blinding of test results from treating clinicians and only one study had blinded outcome assessment.

Knowledge Gaps

  • This is a relatively new field of research and holds considerable promise. There are a range of potential candidate biomarkers more specific for neurological injury (e.g. NSE, s100b, NFL, GFAP, Tau, UCH-L1) that should be explored.
  • Economic cost evaluation and cost-effectiveness studies are required as biomarker testing can be expensive.
  • Further research is required on multi-modal prognostication, timing, definitions of testing, accurate outcome timing and outcome definition.
  • We encourage wider research and consultation with patients, children, parents, guardians and caregivers, health care professionals and members of the wider society on understanding survivorship after pediatric cardiac arrest to inform correct definitions and framework of neurological outcome for prediction research.

ETD summary table: PLS 4220 01 Post ROC Poor Biomarker combined Et D

References

Bangshoj J, Liebetrau B, Wiberg S, Gjedsted J, Kjaergaard J, Hassager C, et al. The Value of the Biomarkers Neuron-Specific Enolase and S100 Calcium-Binding Protein for Prediction of Mortality in Children Resuscitated After Cardiac Arrest. Pediatric Cardiology. 2022;43(7)1659-1665.

De La Llana RA, Le Marsney R, Gibbons K, Anderson B, Haisz E, Johnson K, et al. Merging two hospitals: The effects on pediatric extracorporeal cardiopulmonary resuscitation outcomes. Journal of Pediatric Intensive Care. 2021;10(3)202-9.

Fink EL, Berger RP, Clark RSB, Watson RS, Angus DC, Richichi R, et al. Serum biomarkers of brain injury to classify outcome after pediatric Cardiac Arrest*. Critical Care Medicine. 2014;42(3)664-674.

Fink EL, Kochanek PM, Panigrahy A, Beers SR, Berger RP, Bayir H, et al. Association of Blood-Based Brain Injury Biomarker Concentrations with Outcomes after Pediatric Cardiac Arrest. JAMA Network Open. 2022;5E2230518.

Kramer P, Miera O, Berger F, Schmitt K. Prognostic value of serum biomarkers of cerebral injury in classifying neurological outcome after paediatric resuscitation. Resuscitation. 2018;122113-120.

Lopez-Herce J, del Castillo J, Matamoros M, Canadas S, Rodriguez-Calvo A, Cecchetti C, et al. Post return of spontaneous circulation factors associated with mortality in pediatric in-hospital cardiac arrest: a prospective multicenter multinational observational study. Critical care (London, England). 2014;18(6)607.

Meert KL, Guerguerian AM, Barbaro R, Slomine BS, Christensen JR, Berger J, et al. Extracorporeal Cardiopulmonary Resuscitation: One-Year Survival and Neurobehavioral Outcome among Infants and Children with In-Hospital Cardiac Arrest*. Critical Care Medicine. 2019;47(3)393-402.

Moler FW, Silverstein FS, Holubkov R, Slomine BS, Christensen JR, Nadkarni VM, et al. Therapeutic Hypothermia after In-Hospital Cardiac Arrest in Children. New England Journal of Medicine. 2017;376(4)318-329.

Moler FW, Silverstein FS, Holubkov R, Slomine BS, Christensen JR, Nadkarni VM, et al. Therapeutic hypothermia after out-of-hospital cardiac arrest in children. New England Journal of Medicine. 2015;372(20)1898-1908.


biomarkers, prediction, neurological outcome.4220.01

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