Sage Journals: Discover world-class research

Abstract

Inflammatory, neurologic, and cardiac biomarkers appear to have varying significance in the prognostication of patients with cardiac arrest. Post-cardiac arrest syndrome is a condition characterized by systemic ischemia with reperfusion injury, neurologic damage, and myocardial dysfunction. The relative significance of these biomarkers remains unclear and is an area of active investigation. In this narrative review, we aim to describe what is currently known about the role of inflammatory, neurologic, and cardiac biomarkers in cardiac arrest. A PubMed review was performed for relevant articles. Articles that studied inflammatory, neurologic, and cardiac biomarkers in adult cardiac arrest were included. This narrative review determined that biomarkers play a key role in facilitating prognostication of patients with cardiac arrest. The release of inflammatory, neurologic, and cardiac biomarkers mediates inflammation, ischemic brain injury, and myocardial dysfunction. Inflammatory and neurologic biomarkers appear to have more clinical utility than cardiac biomarkers. When combined with physical exam, imaging and electroencephalograph findings, blood biomarkers can be useful in making predictions of patient outcomes post-cardiac arrest. Despite this utility, no single biomarker has sufficient power to predict patient outcomes independently. Ongoing research investigating these biomarkers remains an area of strong clinical interest. In conclusion, inflammatory, neurologic, and cardiac biomarkers all play a role in understanding both the short-term and long-term outcomes in patients with cardiac arrest. To date, no single parameter has been shown to reliably predict outcome in cardiac arrest patients. Such biomarkers remain an area of active investigation.

Keywords

cardiac arrest biomarkers inflammation inflammatory cytokines

Introduction

There are estimated to be over 436,000 cardiac arrests annually in the United States. In those patients who achieve return of spontaneous circulation (ROSC), the rate of survival to hospital discharge remains relatively low.¹ Post-cardiac arrest syndrome (PCAS) may be contributing to this low survival rate. PCAS is characterized by systemic ischemia with reperfusion injury, neurologic damage, and myocardial dysfunction.² Following the ischemic state that results from cardiac arrest, many biomarkers are released into circulation resulting in ongoing injury to the brain and other vital organs.^3,4 These diffuse injuries trigger the activation of metabolic cascades, subsequently leading to the release of inflammatory, neurologic, and cardiac biomarkers. The abundant systemic inflammation is followed by endothelial activation and damage which further exacerbates injury to the brain and other organs. The management of PCAS involves intensive care support of multiple organ systems in a coordinated fashion.⁵ Refer to Figure 1 for a schematic outlining the basic pathophysiology of PCAS.

Figure 1.

Post-cardiac arrest syndrome. Basic pathophysiology of post-cardiac arrest syndrome (PCAS). IL-6, interleukin 6; IL-10, interleukin-10; TNF-α, tumor necrosis factor-α; CRP, C reactive protein; NSE, neuron-specific enolase; NFL, neurofilament light; UCH-L1, ubiquitin C-terminal hydrolase L1; CK-MB, creatinine kinase-MB.

Current guidelines recommend the use of biomarkers as part of a multimodal approach to prognostication in patients with cardiac arrest. Recent research has explored the role of biomarkers in observational studies conducted in the cardiac arrest population. Large-scale studies may be helpful in addressing clinical challenges associated with cardiac arrest.⁶ In addition, the advent of omics technology has opened new avenues for exploring the molecular mechanisms underlying cardiac arrest.⁷

A standard methodology and the establishment of clinically appropriate cut-off levels for various biomarkers have previously been proposed as potential areas for further investigation.⁸ Since cardiac arrest can have devastating clinical and economic consequences, it is thought that the use of biomarkers as an adjunctive tool may help alleviate any potential cost burden.

In this narrative clinical review, we discuss the role of inflammatory cytokines, neurologic biomarkers, and cardiac biomarkers in the setting of cardiac arrest.

Materials and Methods

An initial search of inflammatory, cardiac, and neurologic biomarkers was conducted. Once identification of biomarkers from each of the aforementioned categories was done, PubMed searches were performed for each individual biomarker using the keywords of each biomarker followed by the keyword cardiac arrest. Articles were selected based on their association to cardiac arrest outcomes. Additional cited articles were also taken from within the original studies.

Articles that did not relate to cardiac arrest were excluded. Pediatric and non-English language studies were also excluded from this review. All listed authors (RS, CS, and JP) were involved in the selection of relevant references.

Study characteristics, including lead authors, year of study, and study design were collected. Population data from relevant studies was extracted to assess for potential bias. Primary outcomes were also examined. Refer to Figure 2 for a visual representation of research background, methodology, conclusions, and future perspective of research in the field related to this narrative review.

Figure 2.

Narrative review summary. Graphical representation of research background, methodology, conclusions, and future perspective of research in the field.

The quality of the narrative review studies was evaluated using the scale for the assessment of non-systematic review articles (SANRA).

Inflammatory Biomarkers

Interleukin-6 and Interleukin-10

Following a cardiac arrest, systemic inflammation occurs and leads to a significant increase in the levels of cytokines. Prolonged ischemia results in tissue and organ damage;^3,9 however, reperfusion-induced injury may be even more harmful than the initial ischemic insult.^3,10 As part of the reperfusion injury seen in PCAS, leukocytes and endothelial cells release pro-inflammatory cytokines interleukin-6 (IL-6) and interleukin-10 (IL-10).⁹ In two studies of the inflammatory profile of patients resuscitated from out-of-hospital cardiac arrest (OHCA), the levels of IL-6 and IL-10 were noted to be significantly higher among patients who did not survive compared to those who did survive.^3,11 In a separate study of adults with in-hospital cardiac arrest (IHCA) receiving ACLS-guided resuscitative and post-resuscitative care, IL-6 and IL-10 levels were found to be significantly lower in patients with favorable outcomes compared to those who had an unfavorable outcome. In multivariable analysis, IL-10 levels measured within 6 h of IHCA were found to be an independent predictor of favorable neurologic outcomes.¹² These findings from both OHCA and IHCA patients suggest that IL-6 and IL-10 may have some predictive value for mortality and neurologic prognostication. Furthermore, higher IL-6 levels were associated with an increased need for vasopressor support. Since IL-6 has the capability to trigger endothelial activation and damage, it is thought that this may explain hemodynamic instability in this context.³ It has been suggested that IL-6 may promote neuronal survival, but may also increase the permeability of the blood–brain barrier.¹³ The exact mechanism of IL-6 in brain injury is still yet to be fully elucidated.

With the association of IL-6 elevation with PCAS severity, the IL-6 receptor antagonist tocilizumab has been studied as a potential therapeutic intervention. Tocilizumab was found to result in a significant reduction in systemic inflammation and myocardial injury in patients resuscitated from OHCA.¹⁴ This data suggests that there may be specific targets with which to treat PCAS and to potentially improve prognosis.

Tumor Necrosis Factor-α

In addition to interleukins, tumor necrosis factor-alpha (TNF-α) is also thought to play a role in PCAS. Levels of TNF-α have been shown to be markedly increased in the brain following cardiac arrest in animal models.¹⁵ TNF-α is thought to be a mediator of disease following global ischemia and has shown the capability to induce apoptosis.¹⁶ However, other studies have suggested that TNF-α can promote tissue repair and regeneration in the long term.^17,18

TNF-α is also thought to mediate cardiovascular dysfunction seen in PCAS; the increase in TNF-α following cardiac arrest has been shown to be temporally related to a dramatic decline in cardiac function.¹⁹ It has also been shown that TNF-α has the capability to decrease systemic vascular resistance when acting synergistically with IL-1 β.²⁰ In a porcine model of cardiac arrest, the administration of a monoclonal antibody against TNF-α was found to reduce early myocardial contractile dysfunction,¹⁹ suggesting that TNF-α may potentially serve as a therapeutic target for future use. TNF-α is also known to induce expression of selectins on endothelium, promoting local inflammation and further organ dysfunction,⁴ likely contributing to hemodynamic instability and the subsequent need for vasopressor support. The exact role of TNF-α in PCAS remains unknown and is an area for further investigation.

C-Reactive Protein

C- reactive protein (CRP) is a relatively inexpensive and widely available biomarker that is often used in clinical practice. In addition to its clinical utility, CRP has also been investigated in the setting of PCAS. During the acute phase response following an inciting inflammatory event, CRP is released by the liver into the bloodstream. Once the primary inflammatory stimulus is removed, CRP levels will typically decrease.²¹ A prior study has shown that in patients successfully resuscitated from cardiac arrest, CRP levels on admission were significantly higher in patients with IHCA and non-shockable rhythms at presentation than in other cardiac arrest patients.²¹ Another parameter that may have some clinical value is the CRP to albumin ratio (CAR). Prior studies have reported that the CAR can have prognostic value in cases of traumatic brain injury, myocardial infarction, and stroke.²² Conversely, low levels of albumin are also thought to be predictive of poor prognosis in various disease states. CAR at 72 h after cardiac arrest was an independent predictor of long-term mortality in patients with PCAS.²³ CRP has also been studied with respect to neurologic outcomes. High CRP levels at the time of admission are associated with unfavorable neurologic outcomes 30 days after OHCA.²⁴ Based on these findings, CRP could be used to assess the severity of ischemia-reperfusion injury and ultimately prognosis.

Lactic Acid

Lactate elevation commonly occurs under conditions of ischemia and other forms of critical illness.^25,26 Patients with PCAS often experience shock and elevated lactate as a result of the ischemia-reperfusion injury.²⁵ A study by Cocchi et al showed that a post-ROSC elevation in lactate was associated with an increased risk of mortality in patients with OHCA; when combined with a post-ROSC vasopressor requirement, the mortality risk increased further.²⁷ This same group performed a similar but larger prospective study, which also showed high discrimination between survivors and non-survivors.²⁸ Further studies have explored if such results could be extrapolated to IHCA patients.

In a retrospective study of patients with IHCA, elevated lactate level post-ROSC was associated with mortality. When combined with the need for vasopressors post-ROSC, mortality was significantly higher in the elevated lactate group. However, the ability to discriminate between survivors and non-survivors appeared to be only moderate in this IHCA cohort.²⁶ One key difference between the respective study populations is that the IHCA study was limited to those requiring mechanical ventilation after ROSC. By limiting to a population that may be more critically ill at baseline, this may account for the discrepancy in predictive value between the two groups.²⁶

In addition to lactate levels, the decrease in lactate has been investigated as a potential surrogate marker for adequate tissue perfusion after ROSC. A retrospective observational cohort study examined the prognostic strength of lactate clearance measured as early as 3 h post-arrest. This showed that lactate clearance at the third hour post-arrest was significantly higher in patients who survive the first 24, 48, and 72 h.²⁹ Lactate clearance was not significantly different between survivors and non-survivors in the long term (1 month and 3 months post-cardiac arrest). When combined with other factors such as bystander cardiopulmonary resuscitation (CPR), age, and initial shockable rhythm, lactate clearance may allow for a more accurate prediction of long-term survival.²⁹

A prospective multicenter trial of patients with OHCA demonstrated that a greater percent lactate reduction over the first 12 h post-cardiac arrest was associated with lower mortality and a good neurologic outcome among patients who survived to hospital discharge.²⁵ The use of lactate clearance as an endpoint of resuscitation may show some utility in prognostication and warrants further investigation.

In a post hoc analysis of the FINNRESUSCI study, investigators studied whether lactate levels predict long-term outcomes after OHCA. Time-weighted mean lactate values for the entire intensive care unit (ICU) stay and the last measured lactate value in the ICU were independent predictors of poor outcome at 1 year.³⁰ It is thought that an elevated lactate in the immediate aftermath of a cardiac arrest is likely associated with ischemia and reperfusion injury which may be improved with hemodynamic optimization in the early phases post-ROSC. A persistently elevated lactate in later phases may be associated with organ failure, which may be more difficult to treat and associated with a worse outcome.³⁰ It is important to note that factors other than hypoperfusion may also cause an elevated lactate, thus making it more difficult to use as a marker of resuscitation.

Procalcitonin

PCAS, the inflammatory response observed in post-ROSC cardiac arrest patients, includes the production of procalcitonin, a protein often produced in response to pro-inflammatory stimuli.^31–35 While procalcitonin has historically been used in the evaluation of sepsis, its use in cardiac arrest has also been investigated. In a prospective cohort of adult patients with cardiac arrest treated with targeted temperature management (TTM), serum procalcitonin elevations in the first 24 to 48 h after cardiac arrest were found to correlate with the severity of PCAS and with worse neurologic outcomes. In addition, in this study, early elevated procalcitonin levels were not associated with early onset infections.³¹ Early elevation of procalcitonin may help with identifying patients at higher risk for cardio-circulatory failure and PCAS-related organ dysfunction. It may also help identify patients that may benefit from more aggressive vasoactive therapy. Similar findings have also been supported in a meta-analysis on procalcitonin in cardiac arrest.³⁴ Annborn et al conducted a study on the release profile of procalcitonin and its association to PCAS and long-term outcomes. In patients resuscitated from cardiac arrest, serum procalcitonin levels demonstrated an early release pattern and were significantly higher in patients with poor outcomes.³¹ One potential confounder is that the aforementioned study populations consisted of patients who had undergone TTM. It is difficult to know if the practice of TTM impacts the kinetics of procalcitonin release.³⁵

In a study examining both procalcitonin and S100B, the combination of both biomarkers improved prognostic performance compared to the use of either biomarker alone.³⁶ This finding further supports using a multimodal approach to prognostication. In a post hoc analysis of the FINNRESUSCI study, elevated procalcitonin was an independent predictor of hemodynamic instability.³³ This suggests that the inflammatory response following cardiac arrest likely plays a role in circulatory shock and that early elevated procalcitonin levels may help identify patients who can benefit from vasoactive therapy. Whereas some biomarkers are not readily available in clinical practice, procalcitonin levels are widely available and easy to obtain in a hospital setting. Procalcitonin shows some practical promise as a useful biomarker for prognostication in patients following cardiac arrest.³²

Refer to Table 1 for a summary of studies investigating inflammatory biomarkers.

Table 1.

Inflammatory biomarkers.

Study	Biomarker	Study details	Main findings
Adrie, C., et al (2002) ³	IL-6IL-10TNF-αLactate	Prospective study61 OHCA patientsAge >16 yearsYears of inclusion: 1999–2000Country: FranceSingle center	High levels of circulating cytokines and the dysregulated production of cytokines contribute to a “systemic inflammatory response syndrome” in patients who were successfully resuscitated after cardiac arrest.Levels of IL-6 and IL-10 were higher in non-survivors after cardiac arrest, especially among those requiring vasopressors.TNF-α and lactate were related to mortality.In sepsis, measurement of sustained plasma pro-inflammatory cytokines, such as TNF-α and IL-6, rather than their peak concentrations identifies those patients who develop multiple organ dysfunction and death.
Peberdy, MA.; National Post Arrest Research Consortium (NPARC) Investigators (2016) ¹¹	IL-6IL-10TNF-α	Prospective study102 OHCA patientsAge ≥18 yearsYears of inclusion:2011–2012Country: United StatesMulticenter	Early inflammatory markers, especially IL-6, are higher in patients with a poor outcome after OHCA.Non-survivors and patients with poor functional outcome had statistically significant higher IL-6 and IL-10 levels at all time points (0, 12 and 24 h) compared to survivors.Baseline IL-6 levels were a good predictor of mortality.
Patel, JK. (2021) ¹²	IL-6IL-10TNF-α	Prospective study105 IHCA patientsAge > 18 yearsYears of inclusion:2014–2019Country: United StatesSingle center	Early levels of IL-6, IL-10, and TNF-α were significantly lower in patients with favorable neurologic outcome compared with those who had an unfavorable neurologic outcome.Lower levels of early IL-10 were noted to be independently associated with higher rates of survival with favorable neurologic outcomes.
Schriefl, C. (2021) ²⁴	CRP	Prospective study832 OHCA patientsAge ≥18 yearsYears of inclusion:2013–2018Country: AustriaSingle center	Admission CRP levels are associated with unfavorable neurological outcome and mortality 30days after OHCA.
Cocchi, MN. (2020) ²⁸	Lactate	Prospective study352 OHCA patientsAge > 18 yearsYears of inclusion:2008–2016Country: United StatesSingle center	The combination of lactate and vasopressors in the immediate post-arrest period is predictive of mortality.
Shin, H. (2019) ³⁴	Procalcitonin	Meta-analysis (10 studies: nine full publications and one conference abstract)1065 OHCA & IHCA patientsAge ≥ 18 yearsYears of inclusion:2007–2017Country: Multiple in Europe and United StatesMulticenter	An elevated procalcitonin level at an early phase of PCAS (0–24 h during hospital admission) is associated with poor outcomes including in-hospital mortality.Measurement of procalcitonin levels in adult patients with ROSC could be a valuable marker for prognosis.

Inflammatory biomarkers—A summary of studies evaluating different inflammatory cytokines as biomarkers in cardiac arrest. IL-6, interleukin 6; IL-10, interleukin-10; TNF-α, tumor necrosis factor-α; CRP, C reactive protein; LA, lactate; OHCA, out-of-hospital cardiac arrest; IHCA, in-hospital cardiac arrest; PCAS, post-cardiac arrest syndrome; ROSC, return of spontaneous circulation.

Neurologic Biomarkers

Neuron-Specific Enolase

Neuron-specific enolase (NSE) is a biomarker that is primarily found in neurons and neuroendocrine cells.^37–42 Elevated NSE levels following cardiac arrest can result from multiple mechanisms, including necrosis and damage to the blood–brain barrier.^37,39–42 Currently, NSE is the only blood-based biomarker recommended by guidelines as part of post-cardiac arrest care.^37,42–45

NSE has shown an ability to discriminate between survivors and non-survivors of cardiac arrest.⁴⁶ In a retrospective analysis of patients admitted to a tertiary center critical care unit, a change in NSE over 9.4 ng/ml was associated with poor prognostic factors such as asystolic arrest, long downtime before ROSC, and more rapid deterioration before death. NSE level at 48 h post-admission and the change in baseline to 48 h post-admission have also been suggested to be good predictors of outcome.⁴⁵ Data from the HYPERION trial showed that NSE values at 72 h post-cardiac arrest with a non-shockable rhythm were associated with a 90-day outcome.⁴³ Results from the prospective COMMUNICATE study showed that NSE levels measured on day 3 post-cardiac arrest significantly improved clinical risk scores for outcome prediction.⁴⁷ Based on such results, NSE has also shown the ability to distinguish fatality rates and neurological outcomes at various intervals following cardiac arrest. Another potential advantage of using NSE is that levels are not significantly affected by TTM, which is often used in the management of patients post-cardiac arrest.^{40,41,43,44,47,48}

Based on prior observational studies, higher mean arterial pressure (MAP) has been associated with better outcomes. The COMACARE trial assessed the feasibility and the effect on NSE of targeting low-normal or high-normal MAP after OHCA and successful resuscitation. However, the relative blood pressure level did not appear to have a significant effect on levels of NSE.⁴⁹

One important limitation to note in the interpretation of NSE is that hemolysis of any degree can substantially inflate lab results.^{39,44,50–52} Fortunately, modern laboratory techniques have been developed to minimize such risk. In addition to hemolysis, however, extraneuronal release from red blood cells and malignant tumors can also limit its interpretation.⁴²

Protein S100B

Protein S100B is a calcium-binding protein that is specific to the central nervous system and is normally found in astroglial and Schwann cells.^36,53 Given that protein S100B has a relatively short half-life compared to NSE, studies have been performed to assess its clinical utility in the early phase after ROSC.⁵³

In a prospective single-center study of non-traumatic successfully resuscitated cardiac arrest patients, an increasing value of S100B from admission to the first 24 h after ROSC was significantly associated with a poor outcome. When compared with other biomarkers, early levels of protein S100B were independently correlated with outcome after cardiac arrest.⁵³

In a separate prospective observational study of OHCA patients, early S100B levels were assessed at the start of CPR and immediately following CPR. When S100B was measured early around the time of initial CPR, it was found that higher levels were significantly associated with lower survival to admission. Despite this negative correlation, it was also found that higher levels of S100B were not associated with long-term survival. It is thought that the extracranial release of S100B and the time dependency of S100B release may partially account for this discrepancy.⁵⁴

As S100B lacks specificity, using it in isolation may present some limitations. To avoid these limitations, when S100B is combined with other parameters, the subsequent increase in specificity may be more useful in predicting outcomes.

In a study of patients with OHCA, a dual marker approach of S100B and NSE together allowed for early identification of patients with poor clinical outcomes with a specificity of 100%.⁵²

In a prospective cohort study of cardiac arrest patients treated with TTM, protein S100B and procalcitonin were analyzed. The combination of 24-h S100B and procalcitonin values improved sensitivity compared with S100B alone. In patients treated with TTM, the combination of both biomarkers improved prognostic performance compared to the use of either biomarker alone. It is evident that the prognostic utility of S100B appears to be more useful when used in combination with other biomarkers.³⁶

Neurofilament Light

Neurofilament light (NFL) is a biomarker in which elevated levels in the blood can indicate axonal injury. Historically, it has been an active area of investigation in degenerative diseases of the nervous system:^46,50,51,55 however, NFL has also been shown to have some implications in cardiac arrest.

When measured with an ultrasensitive immunoassay, serum NFL concentrations were a reliable and highly sensitive predictor of poor neurologic outcome at 6 months following cardiac arrest. NFL also demonstrated the ability to differentiate between various degrees of neurologic impairment, offering a more detailed assessment.⁵⁶ It also performed better than other serum biomarkers including NSE, S100B, and tau. One reason that may account for this difference is that NFL is less sensitive to hemolysis than NSE.⁵⁶ Despite its advantages, one important limitation to note is that ultrasensitive immunoassays have limited availability in routine laboratories so these findings cannot currently be extrapolated to clinical practice.

Elevated NFL at 24-72 h after OHCA has been shown to be predictive of a poor outcome. A meta-analysis of nine studies examined an association between NFL level and neurologic outcomes at 24 h, 48 h, and 72 h after cardiac arrest. Higher levels of NFL were suggestive of poorer prognosis, especially at the 72-h mark.⁵⁷

Notwithstanding the assets of NFL, the prognostic value of NFL at earlier time points post-cardiac arrest and in IHCA has been less studied. In a retrospective, multicenter observational study of patients after cardiac arrest, despite NFL at 12 and 48 h after OHCA reliably predicting both good and bad neurologic outcomes, predicting outcomes after IHCA was less reliable.⁵⁸ Earlier prediction of neurological recovery may facilitate decision-making and provide insight into appropriate limitations of care within an in-hospital setting; NFL's lack of reliability in predicting outcomes at earlier time points and in IHCA patients is a drawback to its use.

As described earlier, the use of TTM can sometimes affect levels of certain biomarkers. In a post hoc analysis of the COMCARE trial, there was no significant difference in the prognostic accuracy of NFL with respect to the TTM target used. Targeting a high MAP was associated with lower levels of NFL. This finding suggests that maintaining a higher blood pressure after cardiac arrest may mitigate the effects of ischemic brain injury.⁵⁵

Tau

Tau is a microtubule protein found in gray matter axons.^50,51,59 Prior studies have demonstrated that tau may have prognostic value in ischemic stroke and traumatic brain injury.⁵¹ Such studies have also extended to explore its use in prognostication of patients with cardiac arrest. In a small pilot study, a late increase in tau protein appeared to be associated with a worse outcome after cardiac arrest. Tau levels were significantly different between poor and good outcome groups at both 48 h and 96 h after ROSC.⁶⁰ In a separate study examining kinetics of tau release, delayed elevations at 24-48 h post-ROSC in tau peak were more predictive of outcome than early elevations within 24 h of ROSC.^61,62 Other evidence suggests that the optimal time for predictive ability for tau may be later on, at the 72-h mark post-ROSC.⁶³

In a cohort of 689 patients taken from the TTM trial, tau levels were measured and compared with neurologic outcomes at 6 months by the cerebral performance category (CPC) scale and modified Rankin scale. In this study, increased levels of tau were associated with a poor outcome at 6 months after cardiac arrest. Its accuracy for predicting outcome was equally high for patients randomized to 33 degrees Celsius versus 36 degrees Celsius target temperature.⁶² This study suggests that the use of TTM should not confound the interpretation of tau levels. Additionally, tau levels were found to be significantly higher in patients with CPC 5 compared with lower CPC scales. This suggests that tau may be useful in predicting the degree of neurologic impairment following cardiac arrest. Another potential advantage of tau is that it is more resistant to hemolysis than NSE.⁶²

Ubiquitin Carboxyl-Terminal Hydrolase

Ubiquitin carboxyl-terminal hydrolase (UCH-L1) is a biomarker that reflects neuronal cell body injury. It is mostly found in the neurons of the cerebral cortex and has been linked to formation of neurodegeneration, stroke, and traumatic brain injury.^64,65 UCH-L1 has previously been studied in animal models. In a study involving hypothermic circulatory arrest and cardiopulmonary bypass, canines undergoing prolonged hypothermic circulatory arrest had significant increases in serum UCH-L1 compared with those who underwent cardiopulmonary bypass.⁶⁴ These findings paved the way for further research on UCH-L1 involving human subjects.

In a post hoc analysis of the FINNRESUSCI study, UCH-L1 levels were measured and its ability to predict unfavorable neurologic outcome at 1 year was assessed; investigators then compared utility of UCH-L1 to utility of NSE. Concentrations of UCH-L1 were found to be higher in those with an unfavorable outcome than in those with a favorable outcome. However, the ability of UCH-L1 to predict outcome was not superior to that of NSE. The power of UCH-L1 to discriminate between patients with good and poor prognosis was also moderate. These results suggest that UCH-L1 may have limited ability to predict outcome.⁶⁶

In a separate study of TTM trial data, Ebner et al found that UCH-L1 was accurate in predicting a poor neurologic outcome after cardiac arrest. In addition, UCH-L1 was significantly better than NSE at predicting a poor neurologic outcome at 24 h and 48 h after cardiac arrest. This may be explained by the shorter half-life of UCH-L1 compared to NSE. The results from Ebner et al clearly differed from the aforementioned FINNRESUSCI post hoc analysis data. Such differences may be accounted for by baseline patient characteristics. In particular, the TTM trial only included patients with a presumed cardiac cause of cardiac arrest with most patients having an initial shockable rhythm.^66,67 Further studies may be needed to discern if UCH-L1 may be more clinically applicable to a particular patient population. In addition, proposed cut-offs for reference UCH-L1 levels would need to be validated in other studies as there is yet to be a defining universal cut-off value established.

In a 2021 retrospective analysis of prospectively collected serum samples at 24, 48, and 72 h post-arrest within the TTM trial data, authors concluded that low levels of brain injury markers in blood, including UCH-L1, NSE, NFL, tau, and S100B were associated with good neurological outcomes after CA.⁶⁸ Authors importantly noted that incorporating these biomarkers into neuroprognostication may help prevent premature withdrawal of life-sustaining support.

Refer to Table 2 for a summary of studies investigating neurologic biomarkers.

Table 2.

Neurologic biomarkers.

Biomarkers related to neurological injury
Study	Biomarker	Study details	Main findings
Song, H. (2023) ⁴⁶	NSETauNFLUCH-L1S100-B	Prospective study100 OHCA patientsAge >18 yearsYears of inclusion:2018–2020Country: South KoreaMulticenter (2)	Median serum levels of NSE and S100B were lower in patients with the good outcome group than in the poor outcome group at all time points.Novel serum biomarkers are a reliable predictor of poor neurological outcomes at six months after CA with high accuracy.
Wang, SL. (2023) ⁵⁷	NFL	Meta-analysis (nine studies)1296 OHCA & IHCA patientsAge >18 yearsAnalyzed studies published between: 2013–2022Country: Multiple in Europe and United StatesMulticenter	Serum NFL level was independently associated with neurologic outcomes and might be valuable as a biomarker for the prognosis post-ROSC following CA, especially 72 h post-arrest.
Mattsson, N. (2017) ⁶²	TauNSE	Prospective study689 OHCA patientsAge ≥ 18 yearsYears of inclusion:2010–2013Country: Multiple in Europe and AustraliaMulticenter	When combining tau, NSE, and clinical information, both tau and NSE were significant predictors of poor outcome.Higher serum tau correlated with poor neurological outcome and short survival after cardiac arrest.
Moseby-Knappe, M. (2021) ⁶⁸	UCH-L1NSENFLTauS100B	Prospective study717 OHCA patientsAge > 18 yearsYears of inclusion:2010–2013Country: Multiple in Europe and AustraliaMulticenter	Low levels of UCH-L1, NSE, NFL, tau, and S100B in the blood are associated with good neurological outcomes after CA.

Biomarkers related to neurological injury—A summary of studies evaluating different biomarkers related to neurological injury in cardiac arrest. NFL, neurofilament light; UCH-L1, ubiquitin carboxyl hydrolase; NSE, neuron-specific enolase; OHCA, out-of-hospital cardiac arrest; IHCA, in-hospital cardiac arrest; CA, cardiac arrest; ROSC, return of spontaneous circulation.

Cardiac Biomarkers

Creatine Kinase-MB

Elevation of serum creatine kinase-MB (CK-MB) in patients after non-traumatic cardiac arrest is common. In addition to acute myocardial infarction, CK-MB elevations may be associated with myocardial ischemia as well as physical trauma to the chest.^69,70 One study showed a positive correlation of CK-MB elevation with both the number of chest compressions given as well as the number of joules delivered during defibrillation.⁷¹ In patients with cardiac arrest, these factors may complicate the biochemical diagnosis of underlying myocardial infarction. The use of CK-MB appears to lead to more diagnostic error due to the variability of muscle CK release after resuscitation.⁷² When a comparison was made between myocardial ischemia and non-acute myocardial ischemia patients, no significant changes of CK-MB could be found over time; there also appeared to be a relative lack of sensitivity and specificity.^70,71 Based on this review, there does not appear to be as much of a role for CK-MB in the assessment of patients post-cardiac arrest compared with other biomarkers.

Troponin T

Troponin T, a type of cardiac troponin, is frequently obtained in patients following cardiac arrest. In patients without ST-segment elevations after ROSC, there can be uncertainty on the clinical utility of high troponin values. In addition to acute coronary syndrome (ACS), other factors may be associated with the release of troponin during cardiac arrest. Some of these may include defibrillation, chest compressions, or the global myocardial ischemia-reperfusion state that ensues following ROSC.^{69–71,73,74}

In a post hoc analysis of the Coronary Angiography after Cardiac Arrest trial of OHCA patients without ST-segment elevation, troponin T release during the first 72 h after ROSC was found to be predictive of survival and neurologic outcome. All troponin T measures were found to be independent prognostic factors for mortality and poor neurologic outcomes.⁷³

Cardiac troponin has also been analyzed for its utility in identifying ischemic etiology and for predicting subsequent left ventricular systolic dysfunction. At both current and higher thresholds, cardiac troponin did not perform well enough to guide identifying ischemic etiology or to predict left ventricular systolic dysfunction. Troponin T also performed poorly for predicting survival to discharge.⁷⁵

While Troponin T may have some diagnostic and prognostic utility in post-cardiac arrest patients, the evidence for said utility appears mixed and warrants further investigation.

Refer to Table 3 for a summary of studies investigating cardiac biomarkers.

Table 3.

Cardiac biomarkers.

Biomarkers related to myocardial dysfunction
Study	Biomarker	Study details	Main findings
Spoormans, EM. (2024) ⁷³	Troponin T	Post hoc analysis352 OHCA patientsYears of inclusion:2015–2018Country: NetherlandsMulticenter	The performance of troponin T values in predicting survival was poor. However, in a specific group of patients, OHCA patients without ST-segment elevation, troponin T release during the first 72 h after ROSC was an independent predictor for survival, neurologic outcome, and acute unstable lesions.
Agusala, V. (2019) ⁷⁵	Troponin T	Retrospective study145 OHCA & IHCA patientsYears of inclusion: N/ACountry: United StatesSingle center	Troponin T does not perform sufficiently well to guide clinical decision-making or predict patient outcomes in patients who achieve ROSC following cardiac arrest.

Biomarkers related to myocardial dysfunction—A summary of studies evaluating different biomarkers related to myocardial injury in cardiac arrest. CK-MB, creatinine kinase-MB; OHCA, out-of-hospital cardiac arrest; IHCA, in-hospital cardiac arrest; ROSC, return of spontaneous circulation.

Refer to Table 4 for a summary of all biomarkers, including inflammatory, neurologic, and cardiac biomarkers which were discussed above.

Table 4.

Cardiac arrest biomarker summary.

A summary of biomarkers in cardiac arrest
Biomarker	Function	Potential treatment to modify levels	Advantages/disadvantages of use	Relevant references
Interleukin-6	Innate and adaptive immunity, acute phase response	Tocilizumab	Readily available	3, 9, 11, 12, 13, 14
Interleukin-10	Anti-inflammatory, enhances B cell and antibody production	No specific target	Readily available	3, 9, 11, 12, 13, 14
TNF-α	Innate immunity	Infliximab	Readily available	4, 15–20
C-reactive protein	Acute phase response, complement activation	Tocilizumab	Readily available, but nonspecific	21–24
Lactic acid	Anaerobic metabolism, gluconeogenesis	Hemodynamic support	Readily available, but nonspecific	25–30
Procalcitonin	Inflammation, exact mechanism unknown	Treat sepsis if present, hemodynamic support	Readily available	31–36
Neuron-specific enolase	Neural maturation	Targeted temperature management was not found to modify levels	Sensitive to hemolysis	37–52, 68
Protein S100B	Cell cycle progression and differentiation	No specific target	Short half-life, nonspecific	36, 52–54, 68
Neurofilament light	Major structural protein	Hemodynamic support	Resistant to hemolysis, requires ultrasensitive assay	46, 50, 51, 55–58, 68
Tau	Axonal microtubule stability	No specific target	Resistant to hemolysis, can predict degree of neurologic impairment	50, 51, 59–63, 68
Ubiquitin C-terminal hydrolase L1	Cleave ubiquitin from proteins, regulate protein degradation	No specific target	Short half-life, not readily available	64–68
Creatine kinase—MB	Catalyzes phosphorylation of creatine by ATP	Cardiac revascularization (in cases of ACS), tocilizumab	Nonspecific, levels affected by chest compressions and defibrillation	69–72
Troponin T	Regulates calcium and cardiac muscle contraction	Cardiac revascularization (in cases of ACS), tocilizumab	Easy to obtain, nonspecific	69–71, 73–75

A summary of biomarker functions, potential treatments, and advantages/disadvantages of use associated with relevant reference numbers.

ACS, acute coronary syndrome.

Conclusion

Inflammatory cytokines, neurologic biomarkers, and cardiac biomarkers all play a role in the evaluation and prognostication in patients following cardiac arrest. Following cardiac arrest, the inflammatory response mediates ischemia and reperfusion injury, brain dysfunction and myocardial injury. Inflammatory biomarkers play a role in PCAS. In terms of neurologic biomarkers, NSE is the only one currently recommended to use in clinical practice; however, other biomarkers such as UCH-L1, S100B, NFL, and tau have also shown potential to be useful adjuncts in prognostication. Cardiac-specific biomarkers such as CK-MB and troponin T do not appear to perform as well as inflammatory or neurologic biomarkers in prognostication. This remains an ongoing area of research. The implication for inflammatory, neurologic, and cardiac biomarkers in both short-term and long-term outcomes is an important area for further investigation.

Footnotes

Ethics Approval

This article does not contain any studies with human or animal participants. Informed consent is not required.

Consent to Participate

Not Applicable.

Consent for Publication

Not Applicable.

Acknowledgements

Not applicable.

Author Contribution(s)

Rohin Singla: Investigation; Methodology; Writing – original draft; Writing – review & editing.

Chelsey Sidaras: Methodology; Resources; Validation; Visualization; Writing – review & editing.

Jignesh K. Patel: Conceptualization; Investigation; Methodology; Supervision; Writing – review & editing.

Funding

The authors received no financial support for the research, authorship and/or publication of this article.

Conflict of Interest Statement

Dr Singla, Dr Sidaras, and Dr Patel have no direct or indirect conflicts of interest to disclose.

Availability of Data and Materials

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

ORCID iD

Jignesh K. Patel

References

Meaney

Bobrow

Mancini

, et al. Cardiopulmonary resuscitation quality: (corrected) improving cardiac resuscitation outcomes both inside and outside the hospital: A consensus statement from the American Heart Association. Circulation. 2013;128(4):417–435.

Nolan

Neumar

Adrie

, et al. Post-cardiac arrest syndrome: Epidemiology, pathophysiology, treatment, and prognostication. A scientific statement from the international liaison committee on resuscitation; the American Heart Association emergency cardiovascular care committee; the council on cardiovascular surgery and anesthesia; the council on cardiopulmonary, perioperative, and critical care; the council on clinical cardiology; the council on stroke. Resuscitation. 2008;79(3):350–379.

Adrie

Adib-Conquy

Laurent

, et al. Successful cardiopulmonary resuscitation after cardiac arrest as a “sepsis-like” syndrome. Circulation. 2002;106(5):562–568.

Bro-Jeppesen

Johansson

Hassager

, et al. Endothelial activation/injury and associations with severity of post-cardiac arrest syndrome and mortality after out-of-hospital cardiac arrest. Resuscitation. 2016;107:71–79.

Binks

Nolan

. Post-cardiac arrest syndrome. Minerva Anestesiol. 2010;76(5):362–368.

D'Andria Ursoleo

Bugo

Losiggio

, et al. Characteristics of out-of-hospital cardiac arrest trials registered in ClinicalTrials.gov. J Clin Med. 2024;13(18):5421.

Stopa

Lileikyte

Bakochi

, et al. Multiomic biomarkers after cardiac arrest. Intensive Care Med Exp. 2024;12(1):83.

Moseby-Knappe

Levin

Blennow

, et al. Biomarkers of brain injury after cardiac arrest; a statistical analysis plan from the TTM2 trial biobank investigators. Resusc Plus. 2022;10:100258.

Jou

Shah

Figueroa

Patel

. The role of inflammatory cytokines in cardiac arrest. J Intensive Care Med. 2020;35(3):219–224.

10.

Ar'Rajab

Dawidson

Fabia

. Reperfusion injury. New Horiz. 1996;4(2):224–234.

11.

Peberdy

Andersen

Abbate

, et al. Inflammatory markers following resuscitation from out-of-hospital cardiac arrest-A prospective multicenter observational study. Resuscitation. 2016;103:117–124.

12.

Patel

Sinha

Hou

, et al. Association of post-resuscitation inflammatory response with favorable neurologic outcomes in adults with in-hospital cardiac arrest. Resuscitation. 2021;159:54–59.

13.

Morganti-Kossman

Lenzlinger

Hans

, et al. Production of cytokines following brain injury: Beneficial and deleterious for the damaged tissue. Mol Psychiatry. 1997;2(2):133–136.

14.

Meyer

MAS

Wiberg

Grand

, et al. Treatment effects of interleukin-6 receptor antibodies for modulating the systemic inflammatory response after out-of-hospital cardiac arrest (the IMICA trial): A double-blinded, placebo-controlled, single-center, randomized, clinical trial. Circulation. 2021;143(19):1841–1851.

15.

Janata

Magnet

Uray

, et al. Regional TNFalpha mapping in the brain reveals the striatum as a neuroinflammatory target after ventricular fibrillation cardiac arrest in rats. Resuscitation. 2014;85(5):694–701.

16.

Shohami

Ginis

Hallenbeck

. Dual role of tumor necrosis factor alpha in brain injury. Cytokine Growth Factor Rev. 1999;10(2):119–130.

17.

Scherbel

Raghupathi

Nakamura

, et al. Differential acute and chronic responses of tumor necrosis factor-deficient mice to experimental brain injury. Proc Natl Acad Sci U S A. 1999;96(15):8721–8726.

18.

Nawashiro

Martin

Hallenbeck

. Neuroprotective effects of TNF binding protein in focal cerebral ischemia. Brain Res. 1997;778(2):265–271.

19.

Niemann

Rosborough

Youngquist

, et al. Cardiac function and the proinflammatory cytokine response after recovery from cardiac arrest in swine. J Interferon Cytokine Res. 2009;29(11):749–758.

20.

Cain

Meldrum

Dinarello

, et al. Tumor necrosis factor-alpha and interleukin-1beta synergistically depress human myocardial function. Crit Care Med. 1999;27(7):1309–1318.

21.

Dell'anna

Bini Viotti

Beumier

, et al. C-reactive protein levels after cardiac arrest in patients treated with therapeutic hypothermia. Resuscitation. 2014;85(7):932–938.

22.

Kim

Lee

. Association between C-reactive protein-to-albumin ratio and 6-month mortality in out-of-hospital cardiac arrest. Acute Crit Care. 2022;37(4):601–609.

23.

Bingol Tanriverdi

Patmano

Bozkurt

, et al. Prognostic value of C-reactive protein to albumin ratio in patients resuscitated from out-of-hospital cardiac arrest. Int J Clin Pract. 2021;75(7):e14227.

24.

Schriefl

Schoergenhofer

Poppe

, et al. Admission C-reactive protein concentrations are associated with unfavourable neurological outcome after out-of-hospital cardiac arrest. Sci Rep. 2021;11(1):10279.

25.

Donnino

Andersen

Giberson

, et al. Initial lactate and lactate change in post-cardiac arrest: A multicenter validation study. Crit Care Med. 2014;42(8):1804–1811.

26.

Issa

Grossestreuer

Patel

, et al. Lactate and hypotension as predictors of mortality after in-hospital cardiac arrest. Resuscitation. 2021;158:208–214.

27.

Cocchi

Miller

Hunziker

, et al. The association of lactate and vasopressor need for mortality prediction in survivors of cardiac arrest. Minerva Anestesiol. 2011;77(11):1063–1071.

28.

Cocchi

Salciccioli

Yankama

, et al. Predicting outcome after out-of-hospital cardiac arrest: Lactate, need for vasopressors, and cytochrome c. J Intensive Care Med. 2020;35(12):1483–1489.

29.

Lonsain

De Lausnay

Wauters

, et al. The prognostic value of early lactate clearance for survival after out-of-hospital cardiac arrest. Am J Emerg Med. 2021;46:56–62.

30.

Laurikkala

Skrifvars

Backlund

, et al. Early lactate values after out-of-hospital cardiac arrest: Associations with one-year outcome. Shock. 2019;51(2):168–173.

31.

Annborn

Dankiewicz

Erlinge

, et al. Procalcitonin after cardiac arrest - an indicator of severity of illness, ischemia-reperfusion injury and outcome. Resuscitation. 2013;84(6):782–787.

32.

Engel

Ben Hamouda

Portmann

, et al. Serum procalcitonin as a marker of post-cardiac arrest syndrome and long-term neurological recovery, but not of early-onset infections, in comatose post-anoxic patients treated with therapeutic hypothermia. Resuscitation. 2013;84(6):776–781.

33.

Pekkarinen

Ristagno

Wilkman

, et al. Procalcitonin and presepsin as prognostic markers after out-of-hospital cardiac arrest. Shock. 2018;50(4):395–400.

34.

Shin

Kim

, et al. Procalcitonin as a prognostic marker for outcomes in post-cardiac arrest patients: A systematic review and meta-analysis. Resuscitation. 2019;138:160–167.

35.

Varon

Polderman

. Procalcitonin for prognostication after cardiac arrest: Another piece of the puzzle? Resuscitation. 2013;84(6):718–719.

36.

Jang

Park

Lim

, et al. Combination of S100B and procalcitonin improves prognostic performance compared to either alone in patients with cardiac arrest: A prospective observational study. Medicine (Baltimore). 2019;98(6):e14496.

37.

Kurek

Swieczkowski

Pruc

, et al. Predictive performance of Neuron-Specific Enolase (NSE) for survival after resuscitation from cardiac arrest: A systematic review and meta-analysis. J Clin Med. 2023;12(24):7655.

38.

Isgro

Bottoni

Scatena

. Neuron-specific enolase as a biomarker: Biochemical and clinical aspects. Adv Exp Med Biol. 2015;867:125–143.

39.

Stammet

. Blood biomarkers of hypoxic-ischemic brain injury after cardiac arrest. Semin Neurol. 2017;37(1):75–80.

40.

Stammet

Collignon

Hassager

, et al. 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. J Am Coll Cardiol. 2015;65(19):2104–2114.

41.

Calderon

Guyette

Doshi

, et al. Combining NSE and S100B with clinical examination findings to predict survival after resuscitation from cardiac arrest. Resuscitation. 2014;85(8):1025–1029.

42.

Hoiland

Rikhraj

KJK

Thiara

, et al. Neurologic prognostication after cardiac arrest using brain biomarkers: A systematic review and meta-analysis. JAMA Neurol. 2022;79(4):390–398.

43.

Lascarrou

Miailhe

le Gouge

, et al. NSE as a predictor of death or poor neurological outcome after non-shockable cardiac arrest due to any cause: Ancillary study of HYPERION trial data. Resuscitation. 2021;158:193–200.

44.

Czimmeck

Kenda

Aalberts

, et al. Confounders for prognostic accuracy of neuron-specific enolase after cardiac arrest: A retrospective cohort study. Resuscitation. 2023;192:109964.

45.

Gillick

Rooney

. Serial NSE measurement identifies non-survivors following out of hospital cardiac arrest. Resuscitation. 2018;128:24–30.

46.

Song

Bang

You

, et al. Novel serum biomarkers for predicting neurological outcomes in postcardiac arrest patients treated with targeted temperature management. Crit Care. 2023;27(1):113.

47.

Luescher

Mueller

Isenschmid

, et al. Neuron-specific enolase (NSE) improves clinical risk scores for prediction of neurological outcome and death in cardiac arrest patients: Results from a prospective trial. Resuscitation. 2019;142:50–60.

48.

Pfeifer

Franz

Figulla

. Hypothermia after cardiac arrest does not affect serum levels of neuron-specific enolase and protein S-100b. Acta Anaesthesiol Scand. 2014;58(9):1093–1100.

49.

Jakkula

Pettila

Skrifvars

, et al. Targeting low-normal or high-normal mean arterial pressure after cardiac arrest and resuscitation: A randomised pilot trial. Intensive Care Med. 2018;44(12):2091–2101.

50.

Gul

Huesgen

Wang

, et al. Prognostic utility of neuroinjury biomarkers in post out-of-hospital cardiac arrest (OHCA) patient management. Med Hypotheses. 2017;105:34–47.

51.

Humaloja

Ashton

Skrifvars

. Brain injury biomarkers for predicting outcome after cardiac arrest. Crit Care. 2022;26(1):81.

52.

Ryczek

Kwasiborski

Rzeszotarska

, et al. Neuron-specific enolase and S100B: The earliest predictors of poor outcome in cardiac arrest. J Clin Med. 2022;11(9):2344.

53.

Deye

Nguyen

Vodovar

, et al. Protein S100B as a reliable tool for early prognostication after cardiac arrest. Resuscitation. 2020;156:251–259.

54.

Song

Shin

Ong

Jeong

. Can early serum levels of S100B protein predict the prognosis of patients with out-of-hospital cardiac arrest? Resuscitation. 2010;81(3):337–342.

55.

Wihersaari

Ashton

Reinikainen

, et al. Neurofilament light as an outcome predictor after cardiac arrest: A post hoc analysis of the COMACARE trial. Intensive Care Med. 2021;47(1):39–48.

56.

Moseby-Knappe

Mattsson

Nielsen

, et al. Serum neurofilament light chain for prognosis of outcome after cardiac arrest. JAMA Neurol. 2019;76(1):64–71.

57.

Wang

Feng

. Serum neurofilament light chain as a predictive marker of neurologic outcome after cardiac arrest: A meta-analysis. BMC Cardiovasc Disord. 2023;23(1):193.

58.

Levin

Lybeck

Frigyesi

, et al. Plasma neurofilament light is a predictor of neurological outcome 12 h after cardiac arrest. Crit Care. 2023;27(1):74.

59.

Arctaedius

Levin

Thorgeirsdottir

, et al. Plasma glial fibrillary acidic protein and tau: Predictors of neurological outcome after cardiac arrest. Crit Care. 2024;28(1):116.

60.

Mortberg

Zetterberg

Nordmark

, et al. Plasma tau protein in comatose patients after cardiac arrest treated with therapeutic hypothermia. Acta Anaesthesiol Scand. 2011;55(9):1132–1138.

61.

Randall

Mortberg

Provuncher

, et al. Tau proteins in serum predict neurological outcome after hypoxic brain injury from cardiac arrest: Results of a pilot study. Resuscitation. 2013;84(3):351–356.

62.

Mattsson

Zetterberg

Nielsen

, et al. Serum tau and neurological outcome in cardiac arrest. Ann Neurol. 2017;82(5):665–675.

63.

You

Kang

Jeong

, et al. The early prognostic value and optimal time of measuring serum and cerebrospinal fluid tau protein for neurologic outcomes in postcardiac arrest patients treated with targeted temperature management. Ther Hypothermia Temp Manag. 2022;12(4):191–199.

64.

Arnaoutakis

George

Wang

, et al. Serum levels of neuron-specific ubiquitin carboxyl-terminal esterase-L1 predict brain injury in a canine model of hypothermic circulatory arrest. J Thorac Cardiovasc Surg. 2011;142(4):902–910. e1.

65.

Wang

Yang

Sarkis

, et al. Ubiquitin C-terminal hydrolase-L1 (UCH-L1) as a therapeutic and diagnostic target in neurodegeneration, neurotrauma and neuro-injuries. Expert Opin Ther Targets. 2017;21(6):627–638.

66.

Wihersaari

Reinikainen

Tiainen

, et al. Ubiquitin C-terminal hydrolase L1 after out-of-hospital cardiac arrest. Acta Anaesthesiol Scand. 2023;67(7):964–971.

67.

Ebner

Moseby-Knappe

Mattsson-Carlgren

, et al. Serum GFAP and UCH-L1 for the prediction of neurological outcome in comatose cardiac arrest patients. Resuscitation. 2020;154:61–68.

68.

Moseby-Knappe

Mattsson-Carlgren

Stammet

, et al. Serum markers of brain injury can predict good neurological outcome after out-of-hospital cardiac arrest. Intensive Care Med. 2021;47(9):984–994.

69.

Mullner

Sterz

Binder

, et al. Creatine kinase and creatine kinase-MB release after nontraumatic cardiac arrest. Am J Cardiol. 1996;77(8):581–585.

70.

Kim

, et al. Implication of cardiac marker elevation in patients who resuscitated from out-of-hospital cardiac arrest. Am J Emerg Med. 2012;30(3):464–471.

71.

Mattana

Singhal

. Determinants of elevated creatine kinase activity and creatine kinase MB-fraction following cardiopulmonary resuscitation. Chest. 1992;101(5):1386–1392.

72.

Grubb

Fox

Cawood

. Resuscitation from out-of-hospital cardiac arrest: Implications for cardiac enzyme estimation. Resuscitation. 1996;33(1):35–41.

73.

Spoormans

Lemkes

Janssens

, et al. The prognostic value of troponin-T in out-of-hospital cardiac arrest without ST-segment elevation: A COACT substudy. J Soc Cardiovasc Angiogr Interv. 2024;3(2):101191.

74.

Kruse

Enghard

Schroder

, et al. Weak diagnostic performance of troponin, creatine kinase and creatine kinase-MB to diagnose or exclude myocardial infarction after successful resuscitation. Int J Cardiol. 2014;173(2):216–221.

75.

Agusala

Khera

Cheeran

, et al. Diagnostic and prognostic utility of cardiac troponin in post-cardiac arrest care. Resuscitation. 2019;141:69–72.

Biomarkers in Cardiac Arrest: A Narrative Review

Abstract

Keywords

Introduction

Materials and Methods

Inflammatory Biomarkers

Interleukin-6 and Interleukin-10

Tumor Necrosis Factor-α

C-Reactive Protein

Lactic Acid

Procalcitonin

Neurologic Biomarkers

Neuron-Specific Enolase

Protein S100B

Neurofilament Light

Tau

Ubiquitin Carboxyl-Terminal Hydrolase

Cardiac Biomarkers

Creatine Kinase-MB

Troponin T

Conclusion

Footnotes

Ethics Approval

Consent to Participate

Consent for Publication

Acknowledgements

Author Contribution(s)

Funding

Conflict of Interest Statement

Availability of Data and Materials

ORCID iD

References