Biomarkers for prognostication (ALS): Systematic Review

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This Review 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 Review 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 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: Tobias Cronberg is a co-author of some of the included studies in the present review. He was excluded from the bias assessment of these studies.

CoSTR Citation

Sandroni C, Cacciola S, Cronberg T, D’Arrigo S, Hoedemaekers CWE, Kamps M, Nolan JP, Böttiger BW, Andersen LW , Callaway CW, Deakin CD, Donnino MW, Drennan I, Hsu C, Morley PM, Nicholson TC, O’Neil BJ, Neumar RW, Paiva EF, Parr MJ, Reynolds JC, Wang TL, Welsford M, Berg KM, Soar J. Biomarkers for prognostication. Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force, 2020 Jan 1. Available from: http://ilcor.org.

Methodological preamble

The continuous evidence evaluation process for the production of Consensus on Science with Treatment Recommendations (CoSTR) started with a systematic review of prognostication after cardiac arrest (Sandroni C 2020 – PROSPERO: CRD 420 1914 1169) conducted by a systematic review team with involvement of clinical content experts from the ILCOR ALS Task Force.

Systematic review

Sandroni C et al. Biomarkers for prognostication in comatose survivors of cardiac arrest. In preparation.

PICOST

The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)

Population: Adults who are comatose after resuscitation from cardiac arrest (either in-hospital or out-of-hospital), regardless of target temperature.

Intervention: Neuron Specific Enolase (NSE), S-100B, Glial Fibrillary Acidic Protein (GFAP), serum tau protein, and Neurofilament Light Chain (NFL) assessed within one week from cardiac arrest.

Comparator: none.

Outcome: Prediction of poor neurological outcome defined as Cerebral Performance Categories (CPC) 3-5 or modified Rankin Score (mRS) 4-6 at hospital discharge/1 month or later.

Study Design: Prognostic accuracy studies where the 2 x 2 contingency table (i.e., the number of true/false negatives and positives for prediction of poor outcome) was reported, or where those variables could be calculated from reported data, are eligible for inclusion. Unpublished studies, reviews, case reports, case series, studies including less than 10 patients, letters, editorials, conference abstracts, and studies published in abstract form were excluded.

Timeframe: In 2015, an ILCOR evidence review identified four categories of predictors of neurological outcome after cardiac arrest, namely clinical examination, biomarkers, electrophysiology and imaging. In the last four years, several studies have been published and new predictors have been identified, therefore the topic needs an update.

The most recent search of the previous systematic reviews on neuroprognostication was launched on May 31, 2013. We searched studies published from January 1, 2013 onwards.

PROSPERO: CRD 420 1914 1169

Consensus on science

NSE

NSE was investigated in thirteen observational studies [Dhakal 2016 116; Lee 2013 1387; Chung-Esaki 2018 99; Vondrakova 2017 172; Duez 2018 79; Kim 2018 33; Stammet 2015 2104; Zellner 2013 1382; Tsetsou 2018 104; Helwig 2017 68; Moseby-Knappe 2017 89; Zhou 2019 343; Rossetti 2017 e674].

In thirteen studies [Dhakal 2016 116, 78 pts; Lee 2013 1387, 224 pts; Chung-Esaki 2018 99, 72 pts; Vondrakova 2017 172, 153 pts; Duez 2018 79, 115 pts; Kim 2018 33, 125 pts; Stammet 2015 2104, 686 pts; Zellner 2013 1382, 110 pts; Tsetsou 2018 104, 61 pts; Helwig 2017 68, 100 pts; Moseby-Knappe 2017 89, 276 pts; Zhou 2019 343, 34 pts; Rossetti 2017 e674, 329 pts] NSE with a cut-off ranging from 33 to 120 μg/L within 72h predicted poor neurological outcome from hospital discharge to 6 months with specificity ranging from 75% to 100% and sensitivity ranging from 7.8% to 83.6% (certainty of evidence from moderate to very low).

In one study [Vondrakova 2017 172, 153 pts] NSE with a cut-off of 50.2 μg/L at day 4 predicted poor neurological outcome at 1 month with 100% specificity and 42.1% sensitivity (moderate certainty of evidence).

S-100B

S-100B protein was investigated in three observational studies [Jang 2019 e14496; Duez 2018 79; Stammet 2017 153].

In two studies [Jang 2019 e14496, 97 pts; Duez 2018 79, 115 pts] S-100B protein with a cut-off ranging from 3.58 to 16.6 μg/L immediately after ROSC predicted poor neurological outcome from 3 to 6 months with 100% specificity and sensitivity ranging from 2.8% to 26.9% (certainty of evidence from moderate to very low).

In three studies [Jang 2019 e14496, 97 pts; Duez 2018 79, 115 pts; Stammet 2017 153, 687 pts] S-100B protein with a cut-off ranging from 0.193 to 2.59 μg/L at 24h predicted poor neurological outcome from 3 to 6 months with 100% specificity and sensitivity ranging from 10.1% to 77.6% (certainty of evidence from moderate to very low).

In three studies [Jang 2019 e14496, 97 pts; Duez 2018 79, 115 pts; Stammet 2017 153, 687 pts] S-100B protein with a cut-off ranging from 0.159 to 3.67 μg/L at 48h predicted poor neurological outcome from 3 to 6 months with 100% specificity and sensitivity ranging from 5% to 77.6% (certainty of evidence from moderate to very low).

In three studies [Jang 2019 e14496, 97 pts; Duez 2018 79, 115 pts; Stammet 2017 153, 687 pts] S-100B protein with a cut-off ranging from 0.202 to 1.83 μg/L at 72h predicted poor neurological outcome from 3 to 6 months with 100% specificity and sensitivity ranging from 5% to 61.2% (certainty of evidence from moderate to very low).

GFAP

In one study [Helwig 2017 68, 100 pts] GFAP with a cut-off of 0.08 μg/L at 48±12h predicted poor neurological outcome at 1 month with 100% specificity and 21.3% sensitivity (low certainty of evidence).

Serum Tau Protein

In one study [Mattsson 2017 665, 667 pts] serum tau protein with a cut-off ranging from 72.7 to 874.5 ng/L at 24-72h predicted poor neurological outcome at 6 months with 100% specificity and a sensitivity ranging from 4% to 42% (very low certainty of evidence).

NFL

In one study [Moseby-Knappe 2019 64, 717 pts] Serum Neurofilament Light Chain with a cut-off ranging from 1539 to 12317 pg/mL at 24-72h predicted poor neurological outcome at 6 months with 100% specificity and sensitivity ranging from 53.1% to 65% (moderate certainty of evidence).

In one study [Rana 2013 1322, 61 pts] Serum Neurofilament Light Chain with a cut-off ranging from 252 to 405 pg/mL from day 1 to day 7 predicted poor neurological outcome (CPC 4-5) at 6 months with 100% specificity and sensitivity ranging from 55.6% to 94.4% (very low certainty of evidence).

Treatment recommendations

  • We suggest using neuron specific enolase within 72h after ROSC, in combination with other tests, for predicting neurological outcome of adults who are comatose after cardiac arrest (weak recommendation, very-low-certainty evidence).
  • We suggest against using S-100B protein for predicting neurological outcome of adults who are comatose after cardiac arrest (weak recommendation, low-certainty evidence).
  • We suggest against using serum levels of GFAP, serum tau protein, or NFL for predicting poor neurological outcome of adults who are comatose after cardiac arrest (weak recommendation, very low-certainty evidence).

Justification and Evidence to Decision Framework Highlights

As for the 2015 CoSTR on this topic, the Task Force opinion is that a multimodal approach should be used in all cases with all supplementary tests considered in the context of prognostication.

Limited evidence suggests that high levels of neuron specific enolase (NSE) predict poor neurological outcome with 100% specificity at 24-72h after cardiac arrest. There is a wide variability of thresholds for 100% specificity across studies. Lack of blinding was a limitation in most of included studies, even if WLST based only on NSE was not documented.

Although the risk of self-fulfilling prophecy for S-100B protein is lower than that observed in other predictors, the evidence is limited by the low number of available studies and the wide variability of thresholds for 100% specificity across studies.

Although GFAP, Serum NFL, appear to be promising for prognostication after cardiac arrest, supporting evidence is limited to very few studies. Consistent thresholds for 100% specificity need to be identified before any of these biomarkers can be recommended for prognostication in the clinical setting.

These biomarker tests are not widely available. The methods used for measuring these biomarkers need to be more widely available, standardised, and studied.

Knowledge Gaps

Large cohort studies are desirable to identify consistent NSE and S-100B thresholds for predicting poor neurological outcome after cardiac arrest. There is very little evidence concerning the predictive value of these biomarkers when measured later than 72h after ROSC.

Further studies on GFAP, serum tau protein, and NFL are needed to confirm their predictive value after cardiac arrest, to assess their reproducibility, and to identify consistent thresholds for 100% specificity.

Attachments

Evidence-to-Decision Table: NSE ETD

Evidence-to-Decision Table: S-100B ETD

Evidence-to-Decision Table: Other biomarkers ETD

References

Chung-Esaki HM, Mui G, Mlynash M, Eyngorn I, Catabay K, Hirsch KG. The neuron specific enolase (nse) ratio offers benefits over absolute value thresholds in post-cardiac arrest coma prognosis. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2018;57:99-104.

Dhakal LP, Sen A, Stanko CM, Rawal B, Heckman MG, Hoyne JB, Dimberg EL, Freeman ML, Ng LK, Rabinstein AA, Freeman WD. Early absent pupillary light reflexes after cardiac arrest in patients treated with therapeutic hypothermia. Therapeutic hypothermia and temperature management. 2016;6:116-121.

Duez CHV, Grejs AM, Jeppesen AN, Schroder AD, Soreide E, Nielsen JF, Kirkegaard H. Neuron-specific enolase and s-100b in prolonged targeted temperature management after cardiac arrest: A randomised study. Resuscitation. 2018;122:79-86.

Helwig K, Seeger F, Holschermann H, Lischke V, Gerriets T, Niessner M, Foerch C. Elevated serum glial fibrillary acidic protein (gfap) is associated with poor functional outcome after cardiopulmonary resuscitation. Neurocritical care. 2017;27:68-74.

Jang JH, Park WB, Lim YS, Choi JY, Cho JS, Woo JH, Choi WS, Yang HJ, Hyun SY. Combination of s100b and procalcitonin improves prognostic performance compared to either alone in patients with cardiac arrest: A prospective observational study. Medicine. 2019;98:e14496.

Kim JH, Kim MJ, You JS, Lee HS, Park YS, Park I, Chung SP. Multimodal approach for neurologic prognostication of out-of-hospital cardiac arrest patients undergoing targeted temperature management. Resuscitation. 2018;134:33-40.

Lee BK, Jeung KW, Lee HY, Jung YH, Lee DH. Combining brain computed tomography and serum neuron specific enolase improves the prognostic performance compared to either alone in comatose cardiac arrest survivors treated with therapeutic hypothermia. Resuscitation. 2013;84:1387-1392.

Mattsson N, Zetterberg H, Nielsen N, Blennow K, Dankiewicz J, Friberg H, Lilja G, Insel PS, Rylander C, Stammet P, Aneman A, Hassager C, Kjaergaard J, Kuiper M, Pellis T, Wetterslev J, Wise M, Cronberg T. Serum tau and neurological outcome in cardiac arrest. Annals of neurology. 2017;82:665-675.

Moseby-Knappe M, Pellis T, Dragancea I, Friberg H, Nielsen N, Horn J, Kuiper M, Roncarati A, Siemund R, Unden J, Cronberg T. Head computed tomography for prognostication of poor outcome in comatose patients after cardiac arrest and targeted temperature management. Resuscitation. 2017;119:89-94.

Moseby-Knappe M, Mattsson N, Nielsen N, Zetterberg H, Blennow K, Dankiewicz J, Dragancea I, Friberg H, Lilja G, Insel PS, Rylander C, Westhall E, Kjaergaard J, Wise MP, Hassager C, Kuiper MA, Stammet P, Wanscher MCJ, Wetterslev J, Erlinge D, Horn J, Pellis T, Cronberg T. Serum neurofilament light chain for prognosis of outcome after cardiac arrest. JAMA Neurol. 2019;76:64-71.

Rana OR, Schroder JW, Baukloh JK, Saygili E, Mischke K, Schiefer J, Weis J, Marx N, Rassaf T, Kelm M, Shin DI, Meyer C, Saygili E. Neurofilament light chain as an early and sensitive predictor of long-term neurological outcome in patients after cardiac arrest. International journal of cardiology. 2013;168:1322-1327.

Rossetti AO, Tovar Quiroga DF, Juan E, Novy J, White RD, Ben-Hamouda N, Britton JW, Oddo M, Rabinstein AA. Electroencephalography predicts poor and good outcomes after cardiac arrest: A two-center study. Critical care medicine. 2017;45:e674-e682.

Stammet P, Collignon O, Hassager C, Wise MP, Hovdenes J, Aneman A, Horn J, Devaux Y, Erlinge D, Kjaergaard J, Gasche Y, Wanscher M, Cronberg T, Friberg H, Wetterslev J, Pellis T, Kuiper M, Gilson G, Nielsen N. Neuron-specific enolase as a predictor of death or poor neurological outcome after out-of-hospital cardiac arrest and targeted temperature management at 33 degrees c and 36 degrees c. Journal of the American College of Cardiology. 2015;65:2104-2114.

Stammet P, Dankiewicz J, Nielsen N, Fays F, Collignon O, Hassager C, Wanscher M, Unden J, Wetterslev J, Pellis T, Aneman A, Hovdenes J, Wise MP, Gilson G, Erlinge D, Horn J, Cronberg T, Kuiper M, Kjaergaard J, Gasche Y, Devaux Y, Friberg H. Protein s100 as outcome predictor after out-of-hospital cardiac arrest and targeted temperature management at 33 degrees c and 36 degrees c. Critical care (London, England). 2017;21:153.

Tsetsou S, Novy J, Pfeiffer C, Oddo M, Rossetti AO. Multimodal outcome prognostication after cardiac arrest and targeted temperature management: Analysis at 36 degrees c. Neurocritical care. 2018;28:104-109.

Vondrakova D, Kruger A, Janotka M, Malek F, Dudkova V, Neuzil P, Ostadal P. Association of neuron-specific enolase values with outcomes in cardiac arrest survivors is dependent on the time of sample collection. Critical care (London, England). 2017;21:172.

Zellner T, Gartner R, Schopohl J, Angstwurm M. Nse and s-100b are not sufficiently predictive of neurologic outcome after therapeutic hypothermia for cardiac arrest. Resuscitation. 2013;84:1382-1386.

Zhou SE, Maciel CB, Ormseth CH, Beekman R, Gilmore EJ, Greer DM. Distinct predictive values of current neuroprognostic guidelines in post-cardiac a


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