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 were recused from the discussion as they declared a conflict of interest: (none applicable)
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 and Conflict of Interest committees:
Dr Topjian was an author and investigator in pediatric post-cardiac arrest neuro-prognostication studies.
Dr Scholefield was an author and investigator in pediatric post-cardiac arrest neuro-prognostication studies and received UK NIHR funding for research into post-cardiac arrest neuro-prognostication research.
Dr Rodriguez-Nunez was an author and investigator in pediatric post-cardiac arrest neuro-prognostication studies.
Barnaby R Scholefield, Janice Tijssen, Saptharishi Lalgudi Ganesan, Mirjam Kool, Alexis Topjian, Thomaz Bittencourt Couto, Anne-Marie Guerguerian on behalf of the International Liaison Committee on Resuscitation Pediatric Life Support Task Force. Biomarkers for the prediction of survival with good 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, 2022 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 (Scholefield, 2021, PROSPERO CRD42021279221) conducted by the members of the PLS TF with involvement of clinical content experts. Evidence for pediatric literature was sought and considered by the Pediatric Life Support Task Force. Additional scientific literature was published after the completion of the systematic review and identified by the Pediatric Task Force, and is described before the justifications and evidence to decision highlights section of this CoSTR. These data were taken into account when formulating the Treatment Recommendations.
Webmaster to insert the Systematic Review citation and link to Pubmed using this format when it is available if published
Scholefield B et al. Biomarker tests for the prediction of survival with good neurological outcome after return of circulation following pediatric cardiac arrest (in preparation)
The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)
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.
Studies which include newly born infants or patients in hypoxic coma from causes other than cardiac arrest (e.g., respiratory arrest, toxidromes, drowning, hanging) will be excluded, except when a subpopulation of cardiac arrest patients can be evaluated separately.
Intervention: Index prognostic tests, recorded less than 12 hours, 12 to <24 hours, 24 to <48 hours, 48 to <72 hours, 72hrs to <7 days, and/or 7 to10 days after cardiac arrest and will include:
Biomarkers: Blood biomarkers included serum biomarkers either specific to neuronal damage (e.g., neuro-specific enolase, S100b, GFAP, neurofilament light chain) or blood markers of inflammation or systemic ischemic reperfusion (e.g., procalcitonin, blood pH or lactate).
Comparators: There is no control group for intervention/exposure. However, the accuracy of the prognostic (index) test will be assessed by comparing the predicted outcome with the final outcome, which represents the comparator.
Outcomes: Primary outcome of interest is survival with good neurological outcome*.
*Good neurological outcome is defined as a Pediatric Cerebral Performance Category (PCPC) score of 1, 2 or 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 will also separately report studies defining good neurological outcomes with other assessment tools, or as a PCPC score 1 or 2, or change in PCPC score from baseline ≤2.
Outcome time point(s) will include hospital discharge, 30 days, 60 days, 180 days and/or 1 year.
Study Designs: Randomized controlled trials (RCTs) and non-randomized studies (non-randomized 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 reported. Unpublished studies (e.g., conference abstracts, trial protocols*) and animal studies were excluded. We selected studies where the sensitivity and false-positive rate (FPR) of the prognostic (index) test are reported.
*please note that the search for unpublished trials was limited to a comprehensive search of three clinical trial registries for unpublished completed trials.
1. International Clinical Trials Registry Platform (www.who.int/ictrp/en/)
2. US clinical trials registry (www.ClinicalTrials.gov)
3. Cochrane CENTRAL (http://www.cochranelibrary.com/about/central-landing-page.html)
Timeframe: All years and all languages were included as long as there was an English abstract; unpublished studies (e.g., conference abstracts, trial protocols) were excluded. Literature search updated to Feb 17th 2022.
PROSPERO Registration CRD42021279221
Consensus on Science
We defined good neurological outcome prediction as imprecise when the false positive rate (FPR) was above 30%. However, there is no universal consensus on what the acceptable limits for imprecision should be in prediction for infants and children after cardiac arrest.
A low false positive rate means that a low proportion of patients, predicted to have a good outcome will have a falsely optimistic prediction (test predicted a good outcome, but patient went on to have a bad outcome). The task force felt that when focused on accurate good outcome prediction - a low false positive rate (eg <30%) is more desirable to avoid falsely optimistic prediction than a high sensitivity. The cut off of 30% FPR (equivalent to 70% specificity) was chosen as the consequences of false optimism were felt by the task force to be less critical than false pessimism. False optimism may result in continued life sustaining therapy in a patient who will eventually have a poor outcome. This will involve increased resources and treatment; however, will allow more time for further prognostic evaluation. Also reasons for not achieving a very low false positive rate may be non-neurological causes of poor outcome or death, not attributable to the index test assessment.
A high sensitivity means the majority of patients who have the good outcome tested positive and therefore a low proportion will have a falsely pessimistic prediction (test predicted a poor outcome, but patient went on to have a good outcome). When considering accurate poor outcome prediction, then a high sensitivity (with a corresponding low rate of falsely pessimistic prediction) is more desirable than a low false positive rate. Our cut off threshold for considering precise sensitivity was higher (>95%), as the consequences of false pessimism may be a decision to limit or withdraw life sustaining therapy in a patient who will have a good neurological outcome and therefore greater precision in prognostic accuracy is required.
The overall quality of evidence was rated as very low for all outcomes primarily due to a very serious risk of bias, assessed using the QUIPS tool. The individual 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 was evaluated in 5 studies [De La Llana 2021 202, Lopez-Herce 2014 607, Meert 2019 1441, Moler 2017 318, Moler 2015 1898]. Three studies documented <7% FPR for lactate <2mmol/L at <1h and 6-12 hours [Lopez-Herce 2014 607, Moler 2017 318, Moler 2015 1898] although sensitivity in these studies was low (16 - 28%). Lactate with cut off value <2mmol/L, at 24 to 48 hours was sensitive (69-86%) for good neurological outcome. However, this cut-off at 24 and 48h also had high FPR of 61 and 68%. FPR ranged 2 to 72%. Lactate <5mmol at <1h had moderate sensitivity (66%) and FPR (62%) and at 24h high sensitivity (89%) and low FPR (17%), making the latter a useful test for prediction. Lactate clearance over 48h to <2mmol had high sensitivity (100%) and high FPR (77%).
pH was evaluated in 4 studies [De La Llana 2021 202, Lopez-Herce 2014 607, Moler 2017 318, Moler 2015 1898]. pH thresholds were >7.0, >7.3, and <7.5, and in intervals of 0.15 [Kane 2010 S241] at resuscitation and within 1 hour, 6-12 hours and 24 hours of return of circulation. The blood pH measured post resuscitation or < 1 hour from ROC had a wide range of sensitivities of 27 to 95% for predicting good neurological outcome. A pH >7.0 was reported in 3 studies and had a sensitivity to predict survival (68-98%) and good neurological outcome (71-97%). FPR was above 80% for all except for pH cut off >7.0 at <1 hour post ROC (45%), and >7.3 at < 1 hour post return of circulation (38%) for good neurological outcome.
Only one study reported NSE, S100b and MBP values among 43 children [Fink 2014 664]. Cut off values were calculated and reported to classify either high sensitivity or low FPR for good neurodevelopmental outcome. At 24 hours s100b level of 0.128 ng/ml predicted a good neurodevelopmental outcome with a sensitivity of 100% although an associated moderately high FPR of 62%. High (100%) sensitivity for predicting good outcome using NSE at 24hrs was identified at a cut off level of 53.1 ng/ml and 76.7 ng/ml at 48 hours (with a corresponding FPR 81 and 77% respectively). MBP level of 5.83 ng/ml at 24 hours and 5.43 ng/ml at 48 hours also had a high predictive sensitivity of 100% but high FPR of 96 and 88% respectively.
Lower cut off values of s100B (0.001 ng/ml at 24 hours), NSE (0.48 ng/ml at 48 hours), or MBP (0.05 ng/ml at 48 hours) reported a predicted sensitivity of 6 to 29% with corresponding very low FPR of <6% for good neurodevelopmental outcome and survival.
- All evaluated tests were used in combination with other tests by clinicians in these studies. Although the predictive accuracy of tests were evaluated individually, we recommend that no single test should be used in isolation for prediction of good neurological outcome (good practice statement).
- We suggest using normal lactate (<2 mmols) up to 12 hours following return of circulation (ROC), for predicting good neurological outcome of children after cardiac arrest (weak recommendation, very-low-certainty evidence).
- We cannot make a recommendation for or against using time to lactate clearance within 48 hours following ROC for predicting good neurological outcome (weak recommendation, very-low-certainty evidence).
- We suggest against using pH following ROC for predicting good neurological outcome after cardiac arrest (weak recommendation, very-low-certainty evidence).
- We cannot make a recommendation for or against the use of blood neuro-biomarkers (e.g. S100beta, Neuron Specific Enolase) after ROC for predicting good neurological outcome in children after cardiac arrest (weak recommendation, very-low-certainty evidence).
Justification and Evidence to Decision Framework Highlights
- The Task Force considered the use of individual biomarker tests to help the clinician in predicting a good neurological outcome. This assessment is different to predicting a poor neurological outcome, which may involve consideration of withdrawal of life sustaining therapies. Recommendations for or against tests to predict good neurological outcomes cannot be transferred to recommendations for poor outcome prediction.
- The available scientific 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.
- If only one study was available (with small patient sample size) then a suggestion or recommendation could not be made.
- Lactate and pH are potential markers of ischemia, poor perfusion and anaerobic metabolism and are known to be associated with poor outcomes after cardiac arrest. Lactate metabolism is complex and consideration of confounders and other predictors is critical.
- Included studies were observational studies and randomized controlled trials, but not primarily designed to test prognosis of blood biomarkers.
- Lactate is measured on blood gas analyzers and is easily accessible. Considering the low but (not negligible) cost of testing lactate and pH, a problem of inequity is low but possible. Lactate and blood pH is widely available in settings with intensive care units, but many settings do not have intensive care units.
- Only one study [Fink, 2014 664] has identified cut-offs for 2 blood neuronal biomarkers (S100b and NSE) that are associated with good neurological outcome with a high sensitivity. However, FPR is high for these cut-offs. Furthermore, these tests require specialized laboratory equipment and are not widely available, 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.
- No studies included blinding of test results from treating clinicians and only one study had blinded outcome assessment.
- 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.
- This is a relatively new field of research and holds considerable promise. There are other potential candidate biomarkers (e.g. NFL, GFAP, Tau, UCH-L1) that should be explored and subgroups may exist where FPR is much lower. Higher number of participants need to be included in future studies.
- 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 good neurological outcome for prediction research.
De La Llana RA, Le Marsney R, Gibbons K, Anderson B, Haisz E, Johnson K, Black A, Venugopal P and Mattke AC. Merging two hospitals: The effects on pediatric extracorporeal cardiopulmonary resuscitation outcomes. Journal of pediatric intensive care. 2021 202-209.
Fink EL, Berger RP, Clark RSB, Watson RS, Angus DC, Richichi R, Panigrahy A, Callaway CW, Bell MJ and Kochanek PM. Serum biomarkers of brain injury to classify outcome after pediatric Cardiac Arrest*. Critical care medicine. 2014;42:664-674.
Kane DA, Thiagarajan RR, Wypij D, Scheurer MA, Fynn-Thompson F, Emani S, Del Nido PJ, Betit P and Laussen PC. Rapid-response extracorporeal membrane oxygenation to support cardiopulmonary resuscitation in children with cardiac disease. Circulation. 2010;122:S241-S248.
Lopez-Herce J, del Castillo J, Matamoros M, Canadas S, Rodriguez-Calvo A, Cecchetti C, Rodriguez-Nunez A, Carrillo A and Iberoamerican Pediatric Cardiac Arrest Study Network R. Post return of spontaneous circulation factors associated with mortality in pediatric in-hospital cardiac arrest: a prospective multicenter multinational observational study. Crit Care. 2014;18:607.
Meert KL, Delius R, Slomine BS, Christensen JR, Page K, Holubkov R, Dean JM and Moler FW. One-Year Survival and Neurologic Outcomes After Pediatric Open-Chest Cardiopulmonary Resuscitation. Annals of Thoracic Surgery. 2019;107:1441-1446.
Moler FW, Silverstein FS, Holubkov R, Slomine BS, Christensen JR, Nadkarni VM, Meert KL, Browning B, Pemberton VL, Page K, Gildea MR, Scholefield BR, Shankaran S, Hutchison JS, Berger JT, Ofori-Amanfo G, Newth CJL, Topjian A, Bennett KS, Koch JD, Pham N, Chanani NK, Pineda JA, Harrison R, Dalton HJ, Alten J, Schleien CL, Goodman DM, Zimmerman JJ, Bhalala US, Schwarz AJ, Porter MB, Shah S, Fink EL, McQuillen P, Wu T, Skellett S, Thomas NJ, Nowak JE, Baines PB, Pappachan J, Mathur M, Lloyd E, Van Der Jagt EW, Dobyns EL, Meyer MT, ers RC, Clark AE and Dean JM. Therapeutic Hypothermia after In-Hospital Cardiac Arrest in Children. New England Journal of Medicine. 2017;376:318-329.
Moler FW, Silverstein FS, Holubkov R, Slomine BS, Christensen JR, Nadkarni VM, Meert KL, Clark AE, Browning B, Pemberton VL, Page K, Shankaran S, Hutchison JS, Newth CJL, Bennett KS, Berger JT, Topjian A, Pineda JA, Koch JD, Schleien CL, Dalton HJ, Ofori-Amanfo G, Goodman DM, Fink EL, McQuillen P, Zimmerman JJ, Thomas NJ, Van Der Jagt EW, Porter MB, Meyer MT, Harrison R, Pham N, Schwarz AJ, Nowak JE, Alten J, Wheeler DS, Bhalala US, Lidsky K, Lloyd E, Mathur M, Shah S, Wu T, Theodorou AA, ers RC and Dean JM. Therapeutic hypothermia after out-of-hospital cardiac arrest in children. New England Journal of Medicine. 2015;372:1898-1908.