Intra‐arrest blood‐based biomarkers for out‐of‐hospital cardiac arrest: A scoping review

Justin L Benoit; Andrew N Hogan; Katherine M Connelly; Jason T McMullan

doi:10.1002/emp2.13131

. 2024 Mar 18;5(2):e13131. doi: 10.1002/emp2.13131

Intra‐arrest blood‐based biomarkers for out‐of‐hospital cardiac arrest: A scoping review

Justin L Benoit ^1,^✉, Andrew N Hogan ², Katherine M Connelly ³, Jason T McMullan ¹

PMCID: PMC10945310 PMID: 38500598

Abstract

Objective

Blood‐based biomarkers play a central role in the diagnosis and treatment of critically ill patients, yet none are routinely measured during the intra‐arrest phase of out‐of‐hospital cardiac arrest (OHCA). Our objective was to describe methodological aspects, sources of evidence, and gaps in research surrounding intra‐arrest blood‐based biomarkers for OHCA.

Methods

We used scoping review methodology to summarize existing literature. The protocol was designed a priori following the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) Extension for Scoping Reviews. Inclusion criteria were peer‐reviewed scientific studies on OHCA patients with at least one blood draw intra‐arrest. We excluded in‐hospital cardiac arrest and animal studies. There were no language, date, or study design exclusions. We conducted an electronic literature search using PubMed and Embase and hand‐searched secondary literature. Data charting/synthesis were performed in duplicate using standardized data extraction templates.

Results

The search strategy identified 11,834 records, with 118 studies evaluating 105 blood‐based biomarkers included. Only eight studies (7%) had complete reporting. The median number of studies per biomarker was 2 (interquartile range 1–4). Most studies were conducted in Asia (63 studies, 53%). Only 22 studies (19%) had blood samples collected in the prehospital setting, and only six studies (5%) had samples collected by paramedics. Pediatric patients were included in only three studies (3%). Out of eight predefined biomarker categories of use, only two were routinely assessed: prognostic (97/105, 92%) and diagnostic (61/105, 58%).

Conclusions

Despite a large body of literature on intra‐arrest blood‐based biomarkers for OHCA, gaps in methodology and knowledge are widespread.

Keywords: advanced cardiac life support, biomarkers, cardiac arrest, emergency medical services, hematologic tests, out‐of‐hospital, prehospital, pulseless electrical activity, scoping review

1. INTRODUCTION

1.1. Background

Advanced cardiovascular life support for out‐of‐hospital cardiac arrest (OHCA) contains only a single branch point in its algorithm, which is based on the electrical activity of the heart. ¹ , ² , ³ No other physiologic biomarkers are algorithmically defined during the intra‐arrest phase of OHCA resuscitations. Although clinical providers taught the “5 H's and 5 T's,” a differential diagnosis for OHCA, there is no standardization on how to test or when to treat these, and other, potential underlying etiologies. Therefore, intra‐arrest interventions for OHCA are frequently given empirically, without guidance from patient‐specific data. As a result, few efficacious intra‐arrest interventions exist. In the case of pulseless electrical activity (PEA), the treatment algorithm has been reduced to a single medication, epinephrine, and even its utility has been called into question by recent clinical trials. ⁴

1.2. Importance

Blood‐based biomarkers play a central role in the diagnosis and treatment of essentially all critically ill patients. However, for OHCA, this often does not occur until after return of spontaneous circulation (ROSC). The principal reason why intra‐arrest blood‐based biomarkers are not routinely measured is operational: rapid on‐scene treatment is preferred since OHCA is a highly time‐dependent disease process and measuring blood‐based biomarkers outside the hospital setting is challenging. ⁵ Although post‐ROSC blood‐based biomarkers are important for the clinical management of post‐cardiac arrest syndrome, they are unlikely to inform intra‐arrest management, given the dramatic pathophysiologic changes that occur when native heart function is restored. ⁶ Animal models, while critically important for studying the mechanics of cardiopulmonary resuscitation and developing hypotheses, cannot directly inform the pathophysiology of a human patient. For example, animal models of PEA frequently rely on asphyxia or countershocks to induce PEA, but up to 50% of PEA in humans is thought to have a non‐electrical cardiac etiology, with increasing incidence of PEA perhaps driven by the rise in beta‐blocker usage. ⁷

1.3. Goals

The goal of this investigation was to describe the key concepts, methodological aspects, sources of evidence, and gaps in the research surrounding intra‐arrest blood‐based biomarkers for OHCA to guide future research efforts. To achieve this, we used scoping review methodology. ⁸ In North America, intra‐arrest medical care is often provided by paramedics in the prehospital setting, so this was a specific area of interest.

2. METHODS

2.1. Protocol and eligibility criteria

The study protocol was designed a priori following the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) Extension for Scoping Reviews. ⁸ The protocol is described in total in this manuscript as per the International Prospective Register of Systematic Reviews (PROSPERO). ⁹ All data were publicly available, so the study was exempt from Institutional Review Board approval.

The inclusion criteria were: (1) primary peer‐reviewed scientific manuscript/abstract, (2) OHCA, (3) human patients, and (4) at least one blood sample drawn intra‐arrest. The exclusion criteria were: (1) secondary or non‐peer‐reviewed manuscript/abstract, (2) in‐hospital cardiac arrest, (3) animal/laboratory studies, or (4) no blood drawn before ROSC or extracorporeal cardiopulmonary resuscitation (ECPR). In‐hospital cardiac arrests are defined as those initially treated by hospital‐based medical teams, while OHCA are defined as those initially treated by lay bystanders and/or 9‐1‐1 responders. In‐hospital cardiac arrest was excluded since the underlying pathophysiology often differs from OHCA. Blood draws could occur in any setting, including in the hospital, so long as the patient met the definition of OHCA. We required studies to be peer‐reviewed to ensure a minimum level of quality. We applied no language limitations, date restrictions, or exclusions based on study design.

2.2. Information sources, search strategy, and selection process

A research librarian assisted in conducting an electronic literature search by using the databases PubMed (www.pubmed.ncbi.nlm.nih.gov) and Embase (www.embase.com). We also searched the reference sections from multiple versions of the American Heart Association's Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care, textbooks on cardiac arrest, and relevant review articles found by the search strategy. Finally, we asked experts in the field to provide any additional studies.

We used Medical Subject Headings terms for PubMed and Emtree Subject Headings for Embase to ensure that synonyms and associated terms were included in the search. Multiple searches were conducted in both databases, with each individual search using at least one heading for the broad category of cardiac arrest, and a second heading for the broad category of blood‐based biomarker, combined with the Boolean Operator “AND.” The following headings were used for PubMed: “out‐of‐hospital cardiac arrest,” “heart arrest,” “emergency medical services,” “hospital emergency service,” “metabolism,” “electrolytes,” “biomarkers,” “metabolomics,” “transcriptome,” “troponin,” “d‐dimer,” “blood proteins,” “hormones,” “drug overdose,” and “hematologic tests.” The following headings were used for Embase: “out of hospital cardiac arrest,” “heart arrest,” “emergency health service,” “emergency ward,” “metabolic disorder,” “electrolyte,” “medical parameters,” “metabolomics,” “transcriptome,” “troponin,” “d‐dimer test,” “plasma protein,” “hormones and agents acting on the endocrine system,” “drug overdose,” and “blood examination.”

Two authors independently reviewed all titles from this search strategy for relevance based on the inclusion and exclusion criteria. If appropriate, the entire manuscript was then reviewed. A consensus of the authors was used to determine the final list of articles that met all criteria. The literature search was current as of December 15, 2022.

2.3. Data charting and synthesis

Two authors performed data charting and synthesis in duplicate using a standardized data extraction template developed for this scoping review after the initial search, as described below. A consensus of the authors was used to resolve any inconsistencies and disagreements. We charted the following data for each study:

Last name of first author
Year of publication
Geographic region of subject enrollment
Age category of subjects (pediatrics defined as <15 years old)
Subtype(s) of cardiac arrest investigated
Setting(s) where blood draw(s) occurred
Clinician(s) performing the blood draw(s)
Stage(s) of resuscitation when blood draw(s) occurred (defined below)
Whether serial blood samples were obtained
Blood‐based biomarker investigated
Source(s) of blood
Additive(s) in blood collection tube
Whether laboratory methods for biomarker detection were described
Time interval between blood collection and final processing (prehospital studies only)

The stages of resuscitation when blood draws could occur were categorized as follows. Few studies reported a per‐minute accounting of blood draws, so a 5‐min threshold was used only as a theoretical framework to align study investigators.

Intra‐arrest: while patient is pulseless
At ROSC: <5 min after ROSC
Post‐ROSC: >5 min after ROSC
At termination of resuscitation (ToR): <5 min before or after ToR
At ECPR: <5 min after starting ECPR
Post‐ECPR: >5 min after starting ECPR

For each blood‐based biomarker, we synthesized the following elements:

Biomarker name
Biologic function and/or plausibility as biomarker
Number of studies investigating the biomarker
Category of use for the biomarker (defined below)
Qualitative summary of results (defined below)

We used the Biomarkers, Endpoints, and other Tools (BEST) Resource from the US Food and Drug Administration‐National Institutes of Health (FDA‐NIH) Biomarker Working Group to describe biomarker categories of use: ¹⁰

Diagnostic: presence of disease or subtype
Monitoring: draw repeatedly to assess disease status
Response: demonstrate biologic response to medical intervention
Predictive: predict favorable or unfavorable effect from medical intervention
Prognostic: predict likelihood of clinical outcome
Safety: adverse event after medical intervention
Surrogate endpoint: predicts a specific clinical benefit
Susceptibility: potential for developing a disease not currently present

We counted the number of studies and biomarkers that fit into predefined categories. The overall goal of a scoping review is to identify key concepts and gaps in research, so a quantitative critical appraisal of individual studies and/or statistical combination of multiple studies is out of scope. A qualitative summary of results for each biomarker was undertaken to provide the reader with a general understanding of the available research, but this should not be considered a definitive assessment of biomarker utility. We used the following generalizations in these qualitative summaries:

Associated: available studies have generally demonstrated associations (unadjusted and/or adjusted analyses)
No association: available studies have generally not demonstrated any associations
Uncertain association: available studies have produced conflicting results
Short‐term patient outcomes: ROSC, survival to hospital admission, or similar
Long‐term patient outcome: survival to hospital discharge, cerebral performance category score, or similar

Only published data were reported, and missing data were reported as such. Due to the large volume of missing data and the number of years since publication, contacting individual study investigators for additional data was not feasible. Studies that had incomplete reporting to fully assess all inclusion and exclusion criteria were reported as such.

3. RESULTS

The search strategy identified a total of 11,834 records, of which 6914 were non‐duplicates. After applying all inclusion and exclusion criteria, 118 studies were included in the scoping review, as shown in Figure 1. ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ , ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ , ⁴⁶ , ⁴⁷ , ⁴⁸ , ⁴⁹ , ⁵⁰ , ⁵¹ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ , ⁵⁶ , ⁵⁷ , ⁵⁸ , ⁵⁹ , ⁶⁰ , ⁶¹ , ⁶² , ⁶³ , ⁶⁴ , ⁶⁵ , ⁶⁶ , ⁶⁷ , ⁶⁸ , ⁶⁹ , ⁷⁰ , ⁷¹ , ⁷² , ⁷³ , ⁷⁴ , ⁷⁵ , ⁷⁶ , ⁷⁷ , ⁷⁸ , ⁷⁹ , ⁸⁰ , ⁸¹ , ⁸² , ⁸³ , ⁸⁴ , ⁸⁵ , ⁸⁶ , ⁸⁷ , ⁸⁸ , ⁸⁹ , ⁹⁰ , ⁹¹ , ⁹² , ⁹³ , ⁹⁴ , ⁹⁵ , ⁹⁶ , ⁹⁷ , ⁹⁸ , ⁹⁹ , ¹⁰⁰ , ¹⁰¹ , ¹⁰² , ¹⁰³ , ¹⁰⁴ , ¹⁰⁵ , ¹⁰⁶ , ¹⁰⁷ , ¹⁰⁸ , ¹⁰⁹ , ¹¹⁰ , ¹¹¹ , ¹¹² , ¹¹³ , ¹¹⁴ , ¹¹⁵ , ¹¹⁶ , ¹¹⁷ , ¹¹⁸ , ¹¹⁹ , ¹²⁰ , ¹²¹ , ¹²² , ¹²³ , ¹²⁴ , ¹²⁵ , ¹²⁶ , ¹²⁷ , ¹²⁸

These studies are described in detail in Tables 1, 2, 3, 4, 5, 6. Incomplete reporting was common, especially for the stage of resuscitation when the blood draw occurred (eg, intra‐arrest, post‐ROSC). Due to these missing data, we could not fully assess the inclusion and exclusion criteria for 31 studies, but they were included in the scoping review to provide a broader overview of the state of the science. Only eight studies (7%) had complete reporting with no missing data.

TABLE 1.

Blood gas and energy studies.

Study ^a	Region	Design	Population ^b	Setting and clinician drawing blood	Sample timing ^c	Blood biomarker(s)	Sample collection	Laboratory methods ^d
Abramson et al. 2022 ¹⁴	Americas	Retrospective cohort	Age: adult Subtype: none	Setting: prehospital Clinician: paramedic	Stage: intra‐arrest Serial: no	Glucose	Source: Ø Tube: Ø	Ø Time: 1 min
Ahn et al. 2018 ¹⁶	Asia	Interventional	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: yes	Bicarb	Source: arterial Tube: Ø	Described
Bartos et al. 2020 ¹⁹	Americas	Retrospective cohort	Age: adult Subtype: VF	Setting: hospital Clinician: Ø	Stage: intra‐arrest Serial: no	pH, pO₂, pCO₂, lactate	Source: arterial Tube: Ø	Ø
Bender et al. 2007 ²⁰	Europe	Interventional	Age: adult Subtype: none	Setting: prehospital Clinician: physician, paramedic	Stage: intra‐arrest, post‐ROSC Serial: yes	pH, pO₂, Bicarb, BE, Na, K, Hg	Source: venous, arterial Tube: Ø	Ø Time: Ø
Bishop and Weisfeldt 1976 ²¹	Americas	Prospective cohort	Age: Ø Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: yes	pH, pO₂, Na, K, osmolality	Source: arterial Tube: Ø	Ø
Brugger et al. 2019 ²⁴	Europe	Retrospective cohort	Age: adult, peds Subtype: cold	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pH, K	Source: Ø Tube: Ø	Ø
Calbay et al. 2019 ²⁶	Asia	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest, at ROSC Serial: yes	pH, pO₂, pCO₂, BE, lactate	Source: arterial Tube: heparin	Described
Cannon et al. 1987 ²⁷	Americas	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pH, pO₂, pCO₂, Na, K, Cl, CO₂, glucose, Mag	Source: arterial, venous Tube: Ø	Described
Chen et al. 2011 ²⁸	Asia	Retrospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pH, pCO₂, Bicarb, glucose, WBC, Hct, Cr, Na, K, AST, CK‐MB, troponin‐I	Source: Ø Tube: Ø	Ø
Chien et al. 2010 ²⁹	Asia	Retrospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pH, pCO₂, pO₂, Bicarb	Source: Ø Tube: Ø	Described
Corral Torres et al. 2020 ³¹	Europe	Prospective cohort	Age: adult Subtype: none	Setting: prehospital Clinician: physician, nurse	Stage: intra‐arrest Serial: no	pH, pCO₂, Bicarb, BE, Na, K, Ca, lactate	Source: venous Tube: Ø	Described Time: 1 min
Dadeh and Nuanjaroan 2018 ³²	Asia	Retrospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	Lactate	Source: Ø Tube: Ø	Ø
Daou et al. 2020 ³³ ^a	Australia	Retrospective cohort	Age: adult Subtype: ECPR	Setting: hospital Clinician: Ø	Stage: intra‐arrest, at ECPR Serial: no	pH, AST, Cr, lactate	Source: Ø Tube: Ø	Ø
Dorph et al. 2004 ³⁴	Europe	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pCO₂	Source: arterial Tube: Ø	Described
Gando et al. 1997 ³⁸	Asia	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest, at ToR, post‐ROSC Serial: yes	pH, Bicarb, lactate, pyruvate, ionized Ca, total Ca	Source: arterial Tube: heparin, perchloric acid	Described
Gennis et al. 1985 ⁴⁴	Americas	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pH, pCO₂, bicarb	Source: arterial, venous Tube: heparin	Described
Gruebl et al. 2021 ⁴⁵	Europe	Retrospective cohort	Age: adult Subtype: none	Setting: prehospital Clinician: Ø	Stage: intra‐arrest Serial: no	pH, K, lactate	Source: arterial, venous Tube: Ø	Described Time: 1 min
Hong et al. 2021 ⁴⁸	Asia	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: physician	Stage: intra‐arrest Serial: yes	pH, pO₂, pCO₂, Bicarb, lactate	Source: arterial Tube: heparin	Described
Janata et al. 2003 ⁵² ^a	Europe	Retrospective cohort	Age: adult Subtype: PE	Setting: ED Clinician: Ø	Stage: Ø Serial: no	pH, lactate	Source: Ø Tube: Ø	Ø
Jouffroy et al. 2014 ⁵⁴	Europe	Retrospective cohort	Age: adult Subtype: ECPR	Setting: hospital Clinician: Ø	Stage: at ECPR, post‐ECPR Serial: yes	Lactate, BE	Source: arterial Tube: Ø	Described
Kim et al. 2016 ⁵⁶	Asia	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pH, pO₂, pCO₂, Bicarb, BE, lactate, Na, K, glucose	Source: arterial Tube: heparin	Described
Kurkciyan et al. 2000 ⁶² ^a	Europe	Retrospective cohort	Age: Ø Subtype: PE	Setting: ED Clinician: Ø	Stage: Ø Serial: no	pH, lactate	Source: Ø Tube: Ø	Ø
Langhelle et al. 2000 ⁶⁴	Europe	Interventional	Age: adult Subtype: none	Setting: prehospital Clinician: physician	Stage: intra‐arrest Serial: yes	pH, pCO₂, pO₂, BE	Source: arterial Tube: plain	Described Time: 1 min
Lin et al. 2013 ⁶⁵	Asia	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pH, pO₂, pCO₂, Bicarb, BE, Na, K, glucose, Cr, AST, ALT, Hg, WBC, ammonia	Source: Ø Tube: heparin	Described
Lin et al. 2018 ⁶⁷	Asia	Retrospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pH, K	Source: Ø Tube: Ø	Ø
Lin et al. 2021 ⁶⁸	Asia	Retrospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pH	Source: Ø Tube: Ø	Ø
Linde et al. 2022 ⁶⁹	Europe	Retrospective cohort	Age: adult Subtype: ECPR	Setting: Ø Clinician: Ø	Stage: intra‐arrest Serial: no	pH, pO₂, pCO₂, BE, lactate, K	Source: Ø Tube: Ø	Ø
Longstreth et al. 1986 ⁷²	Americas	Prospective cohort	Age: Ø Subtype: cardiac	Setting: prehospital Clinician: Ø	Stage: intra‐arrest, post‐ROSC Serial: yes	Glucose	Source: Ø Tube: Ø	Ø Time: Ø
Makino et al. 2005 ⁷⁴ ^a	Asia	Prospective cohort	Age: Ø Subtype: none	Setting: ED Clinician: Ø	Stage: Ø Serial: no	pH, pCO₂, bicarb, BE, Na, K, Cl, ionized Ca, Mag, Phos, lactate, albumin	Source: arterial Tube: heparin	Described
Masuda et al. 2003 ⁷⁵	Asia	Prospective cohort	Age: adult Subtype: witness	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pH, pCO₂, BE	Source: arterial, venous Tube: heparin	Described
Matsuyama et al. 2020 ⁷⁷	Asia	Retrospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pCO₂	Source: Ø Tube: Ø	Ø
Meislin 1980 ⁷⁸	Americas	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: yes	pH, pO₂, pCO₂	Source: arterial Tube: Ø	Described
Morimura 2009 ⁷⁹	Asia	Prospective cohort	Age: adult Subtype: VF/pVT	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pH, pCO₂, pO₂, Bicarb	Source: arterial Tube: Ø	Ø
Nehme et al. 2016 ⁸³	Australia	Retrospective cohort	Age: adult Subtype: cardiac	Setting: prehospital Clinician: paramedic	Stage: intra‐arrest Serial: no	Glucose	Source: capillary Tube: Ø	Described Time: 1 min
Nelskyla et al. 2022 ⁸⁴	Europe	Prospective cohort	Age: adult Subtype: cardiac	Setting: prehospital Clinician: physician	Stage: intra‐arrest, at ROSC Serial: yes	pO₂, pCO₂	Source: arterial Tube: heparin	Described Time: 1 min
Nishioka et al. 2021 ⁸⁵	Asia	Retrospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	Lactate	Source: Ø Tube: Ø	Ø
Nowak et al. 1987 ⁸⁷	Americas	Prospective cohort	Age: Ø Subtype: cardiac	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pH, pCO₂	Source: arterial, venous Tube: Ø	Ø
Okada et al. 2020 ⁸⁸	Asia	Retrospective cohort	Age: adult Subtype: ECPR	Setting: hospital Clinician: Ø	Stage: intra‐arrest Serial: no	pH	Source: Ø Tube: Ø	Ø
Okada et al. 2020 ⁸⁹ ^a	Asia	Retrospective cohort	Age: adult Subtype: cold	Setting: ED Clinician: Ø	Stage: Ø Serial: no	pH, K, lactate	Source: Ø Tube: Ø	Ø
Okada et al. 2021 ⁹⁰ ^a	Asia	Retrospective cohort	Age: peds Subtype: none	Setting: ED Clinician: Ø	Stage: Ø Serial: no	pH	Source: Ø Tube: Ø	Ø
Ornato et al. 1985 ⁹¹ ^a	Americas	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: physician	Stage: Ø Serial: no	pH, pO₂, pCO₂	Source: arterial Tube: heparin	Ø
Prause et al. 2001 ⁹⁵	Europe	Prospective cohort	Age: adult Subtype: none	Setting: prehospital Clinician: physician	Stage: intra‐arrest Serial: no	pH, pCO₂, pO₂, lactate, BE	Source: arterial Tube: Ø	Described Time: 2 min
Pytte et al. 2008 ⁹⁶	Europe	Prospective cohort	Age: adult Subtype: none	Setting: prehospital Clinician: physician	Stage: at ToR Serial: yes	pH, pCO₂, pO₂, BE	Source: arterial Tube: Ø	Described Time: 1 min
Rivers et al. 1992 ⁹⁷	Americas	Prospective cohort	Age: Ø Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest, at ROSC Serial: yes	pH, pO₂, pCO₂, Bicarb, Hg	Source: arterial, venous Tube: Ø	Described
Sariaydin et al. 2017 ⁹⁸	Asia	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pH, pCO₂, Bicarb, lactate, glucose, Hg, Cr, WBC, Na, K	Source: venous Tube: heparin	Described
Shih et al. 2019 ¹⁰³	Asia	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pH	Source: Ø Tube: Ø	Ø
Shin et al. 2017 ¹⁰⁴	Asia	Retrospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pH, pCO₂, pO₂, Bicarb, Na, K, Cl, glucose, lactate	Source: Ø Tube: Ø	Described
Shin et al. 2020 ¹⁰⁵ ^a	Asia	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: physician, nurse, paramedic	Stage: Ø Serial: no	pH, pCO₂, pO₂, Bicarb, Na, K, Cl, Cr, glucose, ionized Ca, lactate, Hg, Hct	Source: arterial, venous, capillary Tube: heparin	Described
SOS‐KANTO 2017 ¹⁰⁷ ^a	Asia	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: Ø Serial: no	Lactate, ammonia	Source: Ø Tube: Ø	Ø
Spindelboeck et al. 2013 ¹⁰⁸	Europe	Retrospective cohort	Age: adult Subtype: none	Setting: prehospital Clinician: physician	Stage: intra‐arrest Serial: no	pO₂	Source: arterial Tube: Ø	Described Time: 1 min
Spindelboeck et al. 2016 ¹⁰⁹	Europe	Prospective cohort	Age: Ø Subtype: none	Setting: prehospital Clinician: physician	Stage: intra‐arrest, post‐ROSC Serial: no	pH, pO₂, pCO₂, BE	Source: arterial Tube: Ø	Described Time: 1 min
Su et al. 2008 ¹¹¹	Asia	Retrospective cohort	Age: adult Subtype: elderly	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pH, pCO₂, Hg, glucose, K troponin‐I	Source: Ø Tube: Ø	Ø
Su et al. 2009 ¹¹²	Asia	Retrospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pH, pCO₂, glucose, Cr, Hg, K	Source: Ø Tube: Ø	Ø
Tallman et al. 2017 ¹¹⁴ ^a	Americas	Prospective cohort	Age: adult, peds Subtype: none	Setting: ED Clinician: Ø	Stage: Ø Serial: no	pH, pCO₂, pO₂, Bicarb, BE, Na, K, glucose, lactate	Source: venous, osseous Tube: Ø	Described
Weil et al. 1985 ¹²³ ^a	Americas	Prospective cohort	Age: adult Subtype: none	Setting: ED, hospital Clinician: Ø	Stage: intra‐arrest, post‐ROSC Serial: yes	pH, pCO₂, Bicarb, lactate, Na, K, Hg, osmolality	Source: arterial Tube: heparin	Ø
Williams et al. 2016 ¹²⁴ ^a	Australia	Retrospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: Ø Serial: yes	Lactate	Source: arterial, venous Tube: Ø	Ø

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Note: Symbol “Ø” denotes incomplete reporting of methods.

Abbreviations: ALT, aminotransferase; AST, aminotransferase; BE, base excess; Bicarb, bicarbonate; Ca, calcium; CK‐MB, creatine kinase‐myocardial band; Cl, chloride; Cr, creatinine; ED, emergency department; Hct, hematocrit; Hg, hemoglobin; K, potassium; Mag, magnesium; Na, sodium; pCO₂, partial pressure of carbon dioxide (arterial or venous); Plt, platelet; pO₂, partial pressure of oxygen (arterial or venous); WBC, white blood cell count.

^{^a}

Incomplete reporting to assess all inclusion and exclusion criteria.

^{^b}

Population subtype—VF/pVT: ventricular fibrillation or pulseless ventricular tachycardia; cardiac: suspected cardiac etiology of arrest; ECPR: extracorporeal cardiopulmonary resuscitation; refractory: cardiac arrest not responding to standard advanced life support; PE: suspected pulmonary embolism; witness: cardiac arrest witnessed by layperson or emergency medical services; CKD: chronic kidney disease; cold: accidental hypothermia; TTM: targeted temperature management; elderly: geriatric patients.

^{^c}

Timing of blood sample collection—intra‐arrest: while patient is pulseless; at ROSC: <5 min after return of spontaneous circulation; post‐ROSC: >5 min after return of spontaneous circulation; at ToR: <5 min before or after termination of resuscitation; at ECPR: <5 min after starting ECPR; post‐ECPR: >5 min after starting ECPR.

^{^d}

For prehospital studies, time interval between blood collection and final processing.

TABLE 2.

Cardiac studies.

Study ^a	Region	Design	Population ^b	Setting and clinician drawing blood	Sample timing ^c	Blood biomarker(s)	Sample collection	Laboratory methods ^d
Aarsetoy et al. 2018 ¹¹ ^a	Europe	Prospective cohort	Age: adult Subtype: cardiac	Setting: prehospital, ED Clinician: paramedic	Stage: Ø Serial: no	hs‐cTnT, NT‐proBNP, copeptin	Source: venous Tube: EDTA	Described Time: 24–48 h
Aarsetoy et al. 2020 ¹²	Europe	Prospective cohort	Age: adult Subtype: cardiac	Setting: prehospital, ED Clinician: paramedic	Stage: intra‐arrest, at ToR, post‐ROSC Serial: no	hs‐cTnT, NT‐proBNP, copeptin	Source: venous Tube: EDTA	Ø Time: 24–48 h
Cakmak et al. 2020 ²⁵	Europe	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	Copeptin, hs‐cTnT, CK‐MB	Source: venous Tube: heparin	Described
Lai et al. 2004 ⁶³ ^a	Americas	Prospective cohort	Age: adult Subtype: none	Setting: Ø Clinician: Ø	Stage: Ø Serial: no	Troponin‐T	Source: venous Tube: citrate	Described
Nagao et al. 2004 ⁸¹ ^a	Asia	Prospective cohort	Age: adult Subtype: cardiac	Setting: ED Clinician: Ø	Stage: Ø Serial: no	BNP	Source: venous Tube: EDTA + aprotinin	Described
Paradis et al. 1994 ⁹⁴ ^a	Americas	Interventional	Age: adult Subtype: refractory	Setting: ED Clinician: physician	Stage: intra‐arrest Serial: yes	Atrial natriuretic peptide	Source: arterial, venous Tube: Ø	Described
Timilsina et al. 2022 ¹¹⁶	Asia	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pH, BE, lactate, NT‐proBNP, troponin	Source: Ø Tube: Ø	Ø

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Note: Symbol “Ø” denotes incomplete reporting of methods.

Abbreviations: BE, base excess; BNP, brain natriuretic peptide; CK‐MB, creatine kinase‐myocardial band; ED, emergency department; EDTA, ethylenediaminetetraacetic acid; hs‐cTnT, high sensitivity cardiac troponin T; NT‐proBNP, N‐terminal prohormone of brain natriuretic peptide.

^{^a}

Incomplete reporting to assess all inclusion and exclusion criteria.

^{^b}

^{^c}

^{^d}

For prehospital studies, time interval between blood collection and final processing.

TABLE 3.

Cell counts, electrolytes, hepatic, and renal studies.

Study ^a	Region	Design	Population ^b	Setting and clinician drawing blood	Sample timing ^c	Blood biomarker(s)	Sample collection	Laboratory methods ^d
Ahn et al. 2011 ¹⁵	Asia	Prospective cohort	Age: Ø Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	K	Source: arterial Tube: Ø	Ø
Asano et al. 2021 ¹⁷ ^a	Asia	Retrospective cohort	Age: adult Subtype: witness	Setting: ED Clinician: Ø	Stage: Ø Serial: no	WBC, Hg, Plt count, D‐dimer, Cr, Na, K, troponin‐I, CK	Source: Ø Tube: Ø	Described
Balci et al. 2017 ¹⁸	Asia	Retrospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	Na, K, Cr, glucose, Hg, troponin	Source: Ø Tube: Ø	Ø
Choi et al. 2020 ³⁰	Asia	Retrospective cohort	Age: adult Subtype: cardiac	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	K	Source: Ø Tube: Ø	Ø
Gando et al. 1988 ³⁶	Asia	Prospective cohort	Age: Ø Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: yes	pH, total Ca, ionized Ca, total protein	Source: arterial Tube: plain	Described
Gando et al. 1990 ³⁷	Asia	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: yes	pH, total protein, total Ca, ionized Ca	Source: arterial, venous Tube: plain	Described
Han et al. 2021 ⁴⁶	Asia	Retrospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	CRP, delta neutrophil index, neutrophil–lymphocyte ratio, platelet–lymphocyte ratio	Source: Ø Tube: Ø	Described
Johnston and Murphy 2005 ⁵³	Europe	Retrospective cohort	Age: Ø Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	K	Source: arterial, venous Tube: heparin	Described
Kasai et al. 2012 ⁵⁵ ^a	Asia	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: Ø Serial: no	Ammonia	Source: venous Tube: heparin	Described
Kim et al. 2020 ⁵⁹	Asia	Retrospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	K, total Ca, ionized Ca, Mag, albumin, Phos, BUN, Cr	Source: Ø Tube: Ø	Ø
Lin et al. 2013 ⁶⁶ ^a	Asia	Prospective cohort	Age: adult Subtype: CKD	Setting: ED Clinician: Ø	Stage: Ø Serial: no	pH, Bicarb, Na, K, Cl, Cr, glucose, Ca, Mag, lactate, CRP, ammonia, troponin‐T, CK‐MB, CK, AST, ALT, WBC, Hg, Plt count	Source: Ø Tube: heparin, potassium ethylenediaminetetraacetic acid	Described
Matsuyama et al. 2018 ⁷⁶ ^a	Asia	Retrospective cohort	Age: adult Subtype: TTM	Setting: ED Clinician: Ø	Stage: Ø Serial: no	Albumin	Source: Ø Tube: Ø	Ø
Nojima et al. 2022 ⁸⁶	Asia	Retrospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	Ammonia	Source: Ø Tube: Ø	Ø
Shida et al. 2020 ¹⁰¹ ^a	Asia	Retrospective cohort	Age: adult Subtype: cardiac	Setting: ED Clinician: Ø	Stage: Ø Serial: no	K	Source: Ø Tube: Ø	Ø
Shida et al. 2022 ¹⁰² ^a	Asia	Retrospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: Ø Serial: no	Na	Source: Ø Tube: Ø	Ø
Tamura et al. 2019 ¹¹⁵ ^a	Asia	Retrospective cohort	Age: adult Subtype: cardiac	Setting: ED Clinician: Ø	Stage: Ø Serial: no	Cr	Source: Ø Tube: Ø	Ø
Tsai et al. 2018 ¹¹⁷	Asia	Retrospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pH, pCO₂, Cr, AST, Na, K, troponin‐I, Bicarb, Hg, WBC	Source: Ø Tube: Ø	Described
Urban et al. 1988 ¹²⁰	Europe	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pH, ionized Ca, total Ca	Source: arterial Tube: heparin	Described
Yanagawa et al. 2009 ¹²⁶ ^a	Asia	Retrospective cohort	Age: Ø Subtype: none	Setting: ED Clinician: Ø	Stage: Ø Serial: no	pH, pCO₂, pO₂, Bicarb, BE, Na, K, Cl, Cr, BUN, glucose, total Ca, Phos, total protein, albumin, total bilirubin, AST, ALT, GGT, Alk Phos, amylase, cholinesterase, CK, WBC, Hg, ammonia, Plt count	Source: Ø Tube: Ø	Ø
Yune et al. 2015 ¹²⁸ ^a	Asia	Retrospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: Ø Serial: yes	Delta neutrophil index, BUN, Cr, WBC, Plt count, Hct	Source: Ø Tube: Ø	Described

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Note: Symbol “Ø” denotes incomplete reporting of methods.

Abbreviations: Alk Phos, alkaline phosphatase; ALT, aminotransferase; AST, aminotransferase; Bicarb, bicarbonate; BUN, blood urea nitrogen; Ca, calcium; CK, creatine kinase; CK‐MB, creatine kinase‐myocardial band; Cl, chloride; Cr, creatinine; CRP, C‐reactive protein; ED, emergency department; GGT, gamma‐glutamyl transferase; Hct, hematocrit; Hg, hemoglobin; K, potassium; Mag, magnesium; Na, sodium; pCO₂, partial pressure of carbon dioxide (arterial or venous); Phos, phosphate; Plt, platelet; WBC, white blood cell count.

^{^a}

Incomplete reporting to assess all inclusion and exclusion criteria.

^{^b}

^{^c}

^{^d}

For prehospital studies, time interval between blood collection and final processing.

TABLE 4.

Coagulation, complement, and endothelium studies.

Study ^a	Region	Design	Population ^b	Setting and clinician drawing blood	Sample timing ^c	Blood biomarker(s)	Sample collection	Laboratory methods ^d
Aarsetoy et al. 2021 ¹³	Europe	Prospective cohort	Age: adult Subtype: cardiac	Setting: prehospital, ED, hospital Clinician: paramedic	Stage: intra‐arrest, at ToR, post‐ROSC Serial: yes	TAT, FXIa‐AT, FIXa‐AT	Source: venous Tube: EDTA	Described Time: 24–48 h
Bottiger et al. 1995 ²²	Europe	Prospective cohort	Age: adult Subtype: none	Setting: prehospital ED, hospital Clinician: physician	Stage: intra‐arrest, at ROSC, post‐ROSC Serial: yes	TAT, fibrin monomers, D‐dimer, PAI‐1	Source: venous Tube: citric acid + theophylline + adenosine + dipyridamole	Described Time: 1 h
Bottiger et al. 2002 ²³	Europe	Prospective cohort	Age: adult Subtype: none	Setting: prehospital ED, hospital Clinician: physician	Stage: intra‐arrest, at ROSC, post‐ROSC Serial: yes	C3a, SC5b‐9, neutrophil elastase, sP‐selectin, sICAM‐1	Source: venous Tube: EDTA	Described Time: 1 h
Duvekot et al. 2015 ³⁵	Europe	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	TAT, tPA, PAI‐1, TAFI, protein C, TEM, aPTT, PT‐INR, fibrinogen, plasminogen, D‐dimer, Hg, Plt function	Source: Ø Tube: Ø	Described
Gando et al. 1997 ³⁹	Asia	Prospective cohort	Age: adult Subtype: none	Setting: ED, hospital Clinician: Ø	Stage: intra‐arrest, post‐ROSC, at ToR Serial: yes	Plt count, Plt function, 6‐keto‐PGF1α, TXB2, 11‐dehydro‐TXB2	Source: venous Tube: citrate, EDTA + aprotinin + indomethacin	Described
Gando et al. 1997 ⁴⁰	Asia	Prospective cohort	Age: adult Subtype: none	Setting: ED, hospital Clinician: Ø	Stage: intra‐arrest, at ToR, post‐ROSC Serial: yes	Fibrinopeptide A, fibrinopeptide B, D‐dimer, tPA activity, tPA antigen, PAI‐1 activity, PAI‐1 antigen	Source: arterial Tube: citrate, heparin + aprotinin	Described
Gando et al. 1999 ⁴¹	Asia	Prospective cohort	Age: adult Subtype: none	Setting: ED, hospital Clinician: Ø	Stage: intra‐arrest, at ToR, post‐ROSC Serial: yes	Tissue factor, tissue factor pathway inhibitor	Source: arterial Tube: Ø	Described
Hostler et al. 2007 ⁴⁹	Americas	Prospective cohort	Age: adult Subtype: none	Setting: prehospital Clinician: physician	Stage: intra‐arrest Serial: no	TAT	Source: venous Tube: citrate	Described Time: Ø
Koami et al. 2017 ⁶⁰	Asia	Retrospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	Lactate, WBC, Hg, Plt count, PT‐INR, aPTT, fibrinogen, FDP, D‐dimer, TEM	Source: Ø Tube: Ø	Described
Schochl et al. 2013 ⁹⁹	Europe	Prospective cohort	Age: adult Subtype: none	Setting: prehospital Clinician: physician	Stage: intra‐arrest Serial: no	Hg, Hct, Plt count, PT‐INR, aPTT, fibrinogen, TEM	Source: venous Tube: EDTA, citrate	Described Time: 2 h

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Note: Symbol “Ø” denotes incomplete reporting of methods.

Abbreviations: aPTT, activated partial thromboplastin time; C3a, complement component C3a; ED, emergency department; EDTA, ethylenediaminetetraacetic acid; FDP, fibrin degradation products; FIXa‐AT, activated factor IX‐antithrombin; FXIa‐AT, activated factor XI‐antithrombin; Hct, hematocrit; Hg, hemoglobin; PGF1α, prostaglandin F1alpha; Plt, platelet; PT‐INR, prothrombin time and international normalized ratio; SC5b‐9, complement SC5b‐9 soluble membrane attack complex; sICAM‐1, soluble intercellular adhesion molecule‐1; sP‐selectin, soluble P‐selectin; TAFI, thrombin activatable fibrinolysis inhibitor; TAT, thrombin–antithrombin complex; TEM, thromboelastometry; tPA, tissue plasminogen activator; TXB2, thromboxane B2; WBC, white blood cell count.

^{^a}

Incomplete reporting to assess all inclusion and exclusion criteria.

^{^b}

^{^c}

^{^d}

For prehospital studies, time interval between blood collection and final processing.

TABLE 5.

Genetics, hormones, inflammation, and lipid studies.

Study ^a	Region	Design	Population ^b	Setting and clinician drawing blood	Sample timing ^c	Blood biomarker(s)	Sample collection	Laboratory methods ^d
Gando et al. 1999 ⁴²	Asia	Prospective cohort	Age: adult Subtype: none	Setting: ED, hospital Clinician: Ø	Stage: intra‐arrest, at ToR, post‐ROSC Serial: yes	sL‐selectin, sP‐selectin, neutrophil elastase, thrombomodulin, TNFα, IL‐1β	Source: arterial Tube: Ø	Described
Gando et al. 2000 ⁴³	Asia	Prospective cohort	Age: adult Subtype: none	Setting: ED, hospital Clinician: Ø	Stage: intra‐arrest, at ToR, post‐ROSC Serial: yes	sICAM‐1, sVCAM‐1, sE‐selectin, neutrophil elastase, thrombomodulin	Source: arterial Tube: Ø	Described
Havmoeller et al. 2014 ⁴⁷	Americas	Prospective cohort	Age: adult Subtype: VF	Setting: Ø Clinician: Ø	Stage: intra‐arrest Serial: no	Non‐esterified free fatty acids	Source: Ø Tube: plain	Described Time: Ø
Ichikawa et al. 2021 ⁵⁰	Asia	Prospective cohort	Age: Ø Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	Epinephrine, norepinephrine, dopamine, vasopressin,	Source: Ø Tube: Ø	Described
Kim et al. 2019 ⁵⁸	Asia	Retrospective cohort	Age: adult Subtype: cardiac	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	Total cholesterol	Source: Ø Tube: Ø	Ø
Koizumi et al. 2020 ⁶¹	Asia	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pH, pO₂, pCO₂, Bicarb, lactate, Na, K, WBC, glucose, TSH, free T3, free T4, ACTH, cortisol, GH, IGF‐1, renin, aldosterone	Source: Ø Tube: Ø	Described
Lindner et al. 1992 ⁷⁰	Europe	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest, at ROSC, post‐ROSC Serial: yes	ACTH, cortisol, vasopressin, renin	Source: venous Tube: plain	Described
Lindner et al. 1996 ⁷¹	Europe	Prospective cohort	Age: adult Subtype: VF, witness	Setting: ED Clinician: Ø	Stage: intra‐arrest, at ROSC, post‐ROSC Serial: yes	Endothelin, epinephrine, norepinephrine, vasopressin, ACTH, cortisol	Source: venous Tube: EDTA, heparin, glutathione	Described
Longstreth et al. 1996 ⁷³	Americas	Retrospective cohort	Age: adult Subtype: none	Setting: prehospital Clinician: paramedic	Stage: at ROSC, at ToR Serial: no	Total T4, total T3, free T3, reverse T3, TSH, free T4 index	Source: Ø Tube: EDTA	Described Time: Ø
Morisaki et al. 1991 ⁸⁰	Asia	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	pH, K, epinephrine, norepinephrine, cortisol	Source: Ø Tube: EDTA	Ø
Narayanan et al. 2014 ⁸²	Americas	Prospective cohort	Age: adult Subtype: cardiac	Setting: prehospital Clinician: paramedic	Stage: intra‐arrest Serial: no	Testosterone, estradiol	Source: venous Tube: Ø	Described Time: Ø
Oshima et al. 2019 ⁹²	Asia	Prospective cohort	Age: adult Subtype: cardiac	Setting: ED Clinician: Ø	Stage: intra‐arrest, at ROSC Serial: no	Epinephrine, dopamine, norepinephrine, vasopressin	Source: Ø Tube: Ø	Described
Paradis et al. 1991 ⁹³	Americas	Interventional	Age: adult Subtype: refractory	Setting: ED Clinician: physician	Stage: intra‐arrest Serial: yes	Epinephrine	Source: arterial, venous Tube: glutathione	Described
Schultz et al. 1993 ¹⁰⁰	Americas	Prospective cohort	Age: adult Subtype: none	Setting: ED, hospital Clinician: Ø	Stage: intra‐arrest at ROSC, post‐ROSC, at ToR Serial: yes	Cortisol, ACTH	Source: venous Tube: plain, EDTA	Described
Strohmenger et al. 1995 ¹¹⁰	Europe	Prospective cohort	Age: adult Subtype: cardiac	Setting: ED Clinician: Ø	Stage: intra‐arrest, at ROSC, post‐ROSC Serial: yes	Prolactin, PGF2α, 15‐keto‐13,14‐dihydro‐PGF2α, 6‐keto‐PGF1α, TXB2	Source: venous Tube: EDTA + indomethicin	Described
Sumiyoshi et al. 2021 ¹¹³	Asia	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest, post‐ROSC Serial: yes	sPD‐L1	Source: arterial Tube: Ø	Described
Wander et al. 2016 ¹²² ^a	Americas	Retrospective cohort	Age: adult Subtype: VF/pVT	Setting: prehospital Clinician: paramedic	Stage: Ø Serial: no	Micro‐RNA	Source: venous Tube: Ø	Described Time: 48 h
Wortsman et al. 1993 ¹²⁵	Americas	Prospective cohort	Age: adult Subtype: refractory	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: yes	Epinephrine, norepinephrine	Source: arterial, venous Tube: heparin + glutathione	Described

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Note: Symbol “Ø” denotes incomplete reporting of methods.

Abbreviations: ACTH, adrenocorticotropic hormone; Bicarb, bicarbonate; ED, emergency department; GH, growth hormone; IGF‐1, insulin‐like growth factor‐1; IL‐1β, interleukin‐1 beta; K, potassium; Na, sodium; pCO₂, partial pressure of carbon dioxide (arterial or venous); PGF1α, prostaglandin F1alpha; PGF2α, prostaglandin F2alpha; pO₂, partial pressure of oxygen (arterial or venous); sE‐selectin, soluble E‐selectin; sICAM‐1, soluble intercellular adhesion molecule‐1; sL‐selectin, soluble L‐selectin; sP‐selectin, soluble P‐selectin; sPD‐L1, soluble programmed cell death‐1 ligand; sVCAM‐1, soluble vascular cell adhesion molecule‐1; T3, triiodothyronine; T4, thyroxine; TNFα, tumor necrosis factor alpha; TSH, thyroid‐stimulating hormone; TXB2, thromboxane B2; WBC, white blood cell count.

^{^a}

Incomplete reporting to assess all inclusion and exclusion criteria.

^{^b}

^{^c}

^{^d}

For prehospital studies, time interval between blood collection and final processing.

TABLE 6.

Oxidative stress and neurologic studies.

Study ^a	Region	Design	Population ⁽	Setting and clinician drawing blood	Sample timing ^c	Blood biomarker(s)	Sample collection	Laboratory methods ^d
Ishikawa et al. 2021 ⁵¹ ^a	Asia	Prospective cohort	Age: adult Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest, post‐ROSC Serial: no	Biological antioxidant potential, Diacron‐reactive oxygen metabolites	Source: Ø Tube: Ø	Described
Kim et al. 2018 ⁵⁷ ^a	Americas	Interventional	Age: adult Subtype: none	Setting: ED Clinician: paramedic	Stage: Ø Serial: yes	Nitrite	Source: Ø Tube: nitrite preservation solution	Ø
Song et al. 2010 ¹⁰⁶	Asia	Prospective cohort	Age: Ø Subtype: witness	Setting: ED Clinician: Ø	Stage: intra‐arrest, at ROSC Serial: yes	S100B	Source: Ø Tube: serum	Described
Turedi et al. 2009 ¹¹⁸ ^a	Asia	Prospective cohort	Age: Ø Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	Ischemia‐modified albumin, malondialdehyde	Source: venous Tube: serum	Described
Turkdogan et al. 2012 ¹¹⁹ ^a	Asia	Prospective cohort	Age: Ø Subtype: none	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	Matrix metalloproteinase‐9	Source: venous, arterial Tube: Ø	Described
Vitturi et al. 2020 ¹²¹ ^a	Americas	Interventional	Age: Ø Subtype: none	Setting: ED Clinician: Ø	Stage: Ø Serial: no	Nitrite, cGMP, nitrated conjugated linoleic acid	Source: Ø Tube: nitrite preservation solution, heparin	Described
Yokobori et al. 2018 ¹²⁷	Asia	Prospective cohort	Age: Ø Subtype: cardiac	Setting: ED Clinician: Ø	Stage: intra‐arrest Serial: no	NSE, S100B, pNF‐H, IL‐6	Source: Ø Tube: Ø	Described

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Note: Symbol “Ø” denotes incomplete reporting of methods.

Abbreviations: cGMP, cyclic guanosine monophosphate; ED, emergency department; IL‐6, interleukin‐6; NSE, neuron‐specific enolase; pNF‐H, phosphorylated neurofilament heavy subunit; S100B, S100 calcium‐binding protein beta.

^{^a}

Incomplete reporting to assess all inclusion and exclusion criteria.

^{^b}

^{^c}

^{^d}

For prehospital studies, time interval between blood collection and final processing.

The studies evaluated a total of 105 blood‐based biomarkers. The median number of studies per blood‐based biomarker was 2, with an interquartile range of 1–4. Qualitative summaries for each biomarker are provided in Table S1.

Synthesis of the 118 studies is provided in Table 7. Most of the studies were conducted in Asia (63 studies, 53%). Only 22 studies (19%) had blood samples collected in the prehospital setting, and only six studies (5%) had intra‐arrest blood samples collected by paramedics in the prehospital setting. ¹² , ¹³ , ¹⁴ , ²⁰ , ⁸² , ⁸³ Only three studies (3%) enrolled any pediatric patients. ²⁴ , ⁹⁰ , ¹¹⁴ Out of the eight categories of use for biomarkers defined by the BEST Resource, only two were routinely assessed: prognostic (97 out of 105 biomarkers, 92%) and diagnostic (61 out of 105 biomarkers, 58%). ¹⁰ The “predictive” category was assessed for only one biomarker, while the “susceptibility,” “safety,” and “surrogate endpoint” categories were never assessed in the field of resuscitation science.

TABLE 7.

Summary of studies and biomarkers.

Characteristic	All studies (n = 118)	Studies with full reporting of inclusion‐exclusion criteria (n = 87)
Year of publication, n (%)
1970–1979	1 (1%)	1 (1%)
1980–1989	9 (8%)	7 (8%)
1990–1999	17 (14%)	16 (18%)
2000–2009	20 (17%)	13 (15%)
2010–2011	40 (34%)	28 (32%)
2020–present	31 (26%)	22 (25%)
Region, n (%)
Americas	24 (20%)	16 (18%)
Europe	28 (24%)	25 (29%)
Asia	63 (53%)	45 (52%)
Australia	3 (3%)	1 (1%)
Study design, n (%)
Retrospective cohort	43 (36%)	29 (33%)
Prospective cohort	68 (58%)	54 (62%)
Interventional	7 (6%)	4 (5%)
Patient age, n (%) ^a
Adult	100 (85%)	76 (87%)
Pediatric	3 (3%)	1 (1%)
Not reported	17 (14%)	11 (13%)
Subtype ^b , n (%) ^a
VF/pVT	5 (4%)	4 (5%)
Cardiac	16 (14%)	12 (14%)
ECPR	4 (3%)	3 (3%)
Refractory	3 (3%)	2 (2%)
PE	2 (2%)	0 (0%)
Witness	4 (3%)	3 (3%)
CKD	1 (1%)	0 (0%)
Cold	2 (2%)	1 (1%)
TTM	1 (1%)	0 (0%)
Elderly	1 (1%)	1 (1%)
None	80 (68%)	62 (71%)
Setting of sample collection, n (%) ^a
Prehospital	22 (19%)	20 (23%)
Emergency department	94 (80%)	66 (76%)
Hospital	14 (12%)	12 (14%)
Not reported	3 (3%)	2 (2%)
Clinical provider collecting sample, n (%) ^a
Paramedics	11 (9%)	7 (8%)
Nurse	2 (2%)	1 (1%)
Physician	17 (14%)	14 (16%)
Not reported	92 (78%)	67 (77%)
Timing of sample collection ^c , n (%) ^a
Intra‐arrest	90 (76%)	84 (97%)
At ROSC	12 (10%)	12 (14%)
Post‐ROSC	20 (17%)	18 (21%)
At ToR	11 (9%)	11 (13%)
At ECPR	2 (2%)	1 (1%)
Post‐ECPR	1 (1%)	1 (1%)
Not reported	25 (21%)	0 (0%)
Serial samples, n (%)
Yes	36 (31%)	31 (36%)
No	82 (69%)	56 (64%)
Blood source, n (%) ^a
Venous	37 (31%)	26 (30%)
Arterial	43 (36%)	36 (41%)
Intraosseous	1 (1%)	0 (0%)
Capillary	2 (2%)	1 (1%)
Not reported	52 (44%)	35 (40%)
Blood tube additive described, n (%)
Yes	45 (38%)	33 (38%)
No	73 (62%)	54 (62%)
Laboratory methods and timing described, n (%)
Yes	71 (60%)	55 (63%)
No	47 (40%)	32 (37%)
Biomarker category ^d , n (%) ^a , ^e
Diagnostic	61 (58%)	–
Monitoring	40 (38%)	–
Response	15 (14%)	–
Predictive	1 (1%)	–
Prognostic	97 (92%)	–
Safety	0 (0%)	–
Surrogate endpoint	0 (0%)	–
Susceptibility	0 (0%)	–

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^{^a}

Options not mutually exclusive (sum can be >100%).

^{^b}

^{^c}

^{^d}

Biomarker category—diagnostic: presence of disease or subtype; monitoring: draw repeatedly to assess disease status; response: demonstrate biologic response to medical intervention; predictive: predict favorable or unfavorable effect from medical intervention; prognostic: predict likelihood of clinical outcome; safety: adverse event after medical intervention; surrogate endpoint: predicts a specific clinical benefit; susceptibility: potential for developing a disease not currently present.

^{^e}

Denominator is the total number of biomarkers (n = 105).

4. LIMITATIONS

The work described here, and scoping review methodology in general, has the following limitations. No specific clinical questions were asked, and a quantitative critical appraisal of study quality was not indicated, so results are not directly applicable to clinical medicine. Missing data may have affected results, and the likelihood of publication bias could not be assessed. Finally, novel blood‐based biomarkers, especially those that have been investigated in animal studies but not human studies, are absent from this review.

5. DISCUSSION

This scoping review encompasses over 45 years of resuscitation science on intra‐arrest blood‐based biomarkers for OHCA. Despite this large volume of research, heterogeneity of study design and gaps in the body of literature are widespread. Recommendations for future research are provided.

5.1. Heterogeneity of study design

Although each study shared the common element of intra‐arrest sampling for blood‐based biomarkers, the collection of studies meeting inclusion and exclusion criteria demonstrated substantial variability in many aspects of study design. The fundamental structure of emergency medical services (EMS) in the geographic regions of Asia, Europe, and Americas vary with regards to the clinical provider leading the resuscitation (paramedic vs. physician) and the site of the resuscitation (on‐scene vs. rapid transport to a hospital). These variables affect the capability to draw/analyze blood samples and the timing of blood draws relative to the start of resuscitation. Not only does this affect the logistics of conducting the study, but it also affects the “context of use,” a concise description of how a biomarker is intended to be used, which is required by regulatory agencies such as the US FDA. ¹⁰ In addition, the pathophysiology of OHCA evolves throughout the resuscitation, so biomarker measurements occurring on‐scene versus in the hospital may vary, even within a single patient.

While variation in time between collapse and the start of resuscitative efforts is an unavoidable reality of OHCA, studies still had significant heterogeneity in whether they accounted for the exact timing of blood draws relative to the start of resuscitation, whether the arrest was witnessed or not, and whether bystander CPR occurred, all of which may affect biomarker levels. Heterogeneity in the electrical activity of the heart (ie, ventricular fibrillation/tachycardia vs. PEA/asystole) not only defines interventions that may affect biomarker levels and context of use, but may also represent different underlying etiologies of arrest. Some studies included small cohorts of in‐hospital cardiac arrest patients, which likely differ in underlying pathophysiology and whether biomarker levels are known prior to arrest. Finally, multiple evolutions of recommended intra‐arrest management have occurred over the past 45 years, especially regarding chest compressions, ventilation, and medication administration. As a result, the ability to compare results from two technically similar studies performed in different decades is limited.

5.2. Gaps in research

Few conclusions can be drawn from existing literature due to significant gaps that exist. The heterogeneity described above limits direct comparison between studies, and even when studies were relatively similar in study design, conflicting results were common. Missing data and lack of standardized reporting limits the reproducibility of many studies. This was especially true for the processes and methods used to collect, preserve, and measure blood‐based biomarkers, which were missing from a surprisingly large number of studies. Even when “routine” laboratory studies were reported, the lack of blood source, tube additive, assay method, and measurement device limits reproducibility and generalizability. Finally, the statistical methods used for analysis were both heterogenous, and at times, markedly flawed. For example, when adjusted analyses were performed, a linear relationship was often assumed, even though many “routine” biomarkers indicate pathophysiology when measured levels are high or low, with healthy levels in the middle.

This literature base also demonstrates a lack of recognition that the pathophysiology of a patient who is intra‐arrest is fundamentally different than one who is post‐ROSC or on extracorporeal support, as blood draws from these different cohorts were commonly combined into a single cohort. This issue was the main reason why we could not fully assess inclusion and exclusion criteria for 31 studies. Clinical guidelines recognize this difference by providing completely different treatment recommendations and flow diagrams. ¹ Although not explicitly defined in clinical guidelines, there may also exist a pathophysiological difference between the immediate post‐ROSC period that is dominated by cardiovascular instability and re‐arrest rates up to 40% (generally seen in the prehospital setting and emergency department), versus the post‐cardiac arrest syndrome of comatose patients that is dominated by metabolic failure and uncontrolled inflammatory response (generally seen in the intensive care unit). ⁶

Although this scoping review identified 105 different biomarkers that have been studied, the median number of studies per biomarker was only 2. Thus, for most biomarkers, it is not possible to draw conclusions regarding their utility in OHCA patients. Pediatrics is almost entirely absent from this field of research, with only three studies enrolling pediatric patients. Extrapolating adult literature to pediatric patients is problematic since the underlying etiologies of arrest likely differ in incidence and pathophysiology. Many studies seemed to evaluate what was readily available instead of actively looking for novel biomarkers, which may have resulted in observational bias (ie, “streetlight effect”). To date, there have been no systematic investigations designed to discover blood‐based biomarkers with utility during the intra‐arrest phase of OHCA. Two longitudinal studies have collected blood samples from OHCA patients in the prehospital settings, but both were focused on studying risk factors for OHCA, not intra‐arrest management, with blood samples frequently collected late in the resuscitation when the patient was “stable” or after termination of resuscitation. ¹²⁹ , ¹³⁰

5.3. Recommendations for future research

Blood‐based biomarkers play a central role in the diagnosis and treatment of essentially all critically ill patients, yet none are routinely measured during the intra‐arrest phase of OHCA resuscitations. This scoping review makes clear the need for careful planning of future studies on intra‐arrest blood‐based biomarkers for OHCA to advance this field of research.

Specifically, we recommend in future studies that the timing of blood draws relative to key resuscitation events be reported, such as the time of collapse or recognition, EMS arrival, therapeutic interventions, ROSC, termination of resuscitation, and bystander interventions. Investigators should avoid phrases such as “after resuscitation,” “in survivors,” “on admission,” “post‐cardiac arrest,” and “as soon as possible,” as they have no uniform temporal or pathophysiological definition and can be interpreted differently depending on context and culture. The “context of use” for the biomarker under investigation should be explicitly stated, especially regarding whether it is to be used intra‐arrest, immediately post‐ROSC, or for post‐cardiac arrest syndrome. Biomarker categories other than “prognostic” and “diagnostic” should be investigated. For example, “response” and “predictive” biomarkers could help guide the development and specificity of novel interventions. Serial blood draws should be obtained when possible, to determine which biomarkers are rapidly changing (possibly due to the pathophysiology of OHCA) versus those that are static (may have existed pre‐arrest). Methods used to collect, process, preserve, and measure blood‐based biomarkers, including tube additive, assay method, and device used to measure levels, should be universally reported. Finally, statistical models should not assume a linear relationship between biomarker levels and pathophysiology, unless well defined in prior research.

Since OHCA occurs outside the traditional setting for blood‐based biomarker investigations, additional research is needed to develop novel processes and methods to collect, process, and analyze blood‐based biomarkers in the prehospital setting. Systematic investigations designed to discover novel blood‐based biomarkers for OHCA should also be undertaken. Finally, blood‐based biomarker research that specifically targets pediatric OHCA is needed.

In conclusion, over 45 years of resuscitation science on intra‐arrest blood‐based biomarkers for OHCA have been conducted, yet heterogeneity of study design and gaps in the body of literature are widespread. Recommendations for future research are provided.

AUTHOR CONTRIBUTIONS

Justin Benoit and Jason McMullan conceived the study and obtained research funding. Justin Benoit designed the study protocol. Justin Benoit and Andrew Hogan designed the data extraction templates. Justin Benoit, Andrew Hogan, and Katherine Connelly performed the literature search, data extraction, and data charting. Justin Benoit and Andrew Hogan performed data synthesis. Jason McMullan supervised the conduct of the study. Justin Benoit and Andrew Hogan drafted the manuscript, and all authors contributed substantially to its revision. Justin Benoit takes responsibility for the paper as a whole.

CONFLICT OF INTEREST STATEMENT

The authors declare they have no conflicts of interest.

Supporting information

Supporting Information

EMP2-5-e13131-s001.docx^{(53.3KB, docx)}

ACKNOWLEDGMENTS

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH).

Benoit JL, Hogan AN, Connelly KM, McMullan JT. Intra‐arrest blood‐based biomarkers for out‐of‐hospital cardiac arrest: A scoping review. JACEP Open. 2024;5:e13131. 10.1002/emp2.13131

Supervising Editor: Lara Goldstein, MD, PhD.

Presentation: National Association of EMS Physicians Annual Meeting, January 11, 2024, Austin, TX, USA.

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PERMALINK

Intra‐arrest blood‐based biomarkers for out‐of‐hospital cardiac arrest: A scoping review

Justin L Benoit, MD, MS

Andrew N Hogan, MD

Katherine M Connelly, MD

Jason T McMullan, MD, MS

Abstract

Objective

Methods

Results

Conclusions

1. INTRODUCTION

1.1. Background

1.2. Importance

1.3. Goals

2. METHODS

2.1. Protocol and eligibility criteria

2.2. Information sources, search strategy, and selection process

2.3. Data charting and synthesis

3. RESULTS

FIGURE 1.

TABLE 1.

TABLE 2.

TABLE 3.

TABLE 4.

TABLE 5.

TABLE 6.

TABLE 7.

4. LIMITATIONS

5. DISCUSSION

5.1. Heterogeneity of study design

5.2. Gaps in research

5.3. Recommendations for future research

AUTHOR CONTRIBUTIONS

CONFLICT OF INTEREST STATEMENT

Supporting information

ACKNOWLEDGMENTS

REFERENCES

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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