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. Author manuscript; available in PMC: 2025 Dec 1.
Published in final edited form as: Curr Opin Crit Care. 2024 Sep 27;30(6):611–617. doi: 10.1097/MCC.0000000000001219

Cardiac Arrest and Microcirculatory Dysfunction: A narrative review

Max S Kravitz 1,*, John H Lee 1,*, Nathan I Shapiro 1
PMCID: PMC11540727  NIHMSID: NIHMS2024589  PMID: 39377652

Abstract

Purpose of review

This review provides an overview of the role of microcirculation in cardiac arrest and post-cardiac arrest syndrome through handheld intravital microscopy and biomarkers. It highlights the importance of microcirculatory dysfunction in post-cardiac arrest outcomes and explores potential therapeutic targets.

Recent findings

Sublingual microcirculation is impaired in the early stage of post-arrest and is potentially associated with increased mortality. Recent work suggests that the proportion of perfused small vessels is predictive of mortality. Microcirculatory impairment is consistently found to be independent of macrohemodynamic parameters. Biomarkers of endothelial cell injury and endothelial glycocalyx degradation are elevated in post-arrest settings and may predict mortality and clinical outcomes, warranting further studies. Recent studies of exploratory therapies targeting microcirculation have shown some promise in animal models, but still require significant research.

Summary

While research continues to suggest the important role that microcirculation may play in post-cardiac arrest syndrome and cardiac arrest outcomes, the existing studies are still limited to draw any definitive conclusions. Further research is needed to better understand microcirculatory changes and their significance to improve cardiac arrest care and outcomes.

Keywords: cardiac arrest, microcirculation, post-cardiac arrest syndrome, endothelial glycocalyx, endothelium

INTRODUCTION

Despite continued effort and recent advances, cardiac arrest is still associated with poor survival with an out-of-hospital survival rate of around 9% and an in-hospital survival rate of around 19% in the United States (1–3). Although there have been improvements in the rate of return of spontaneous circulation (ROSC), mortality after ROSC remains high in part due to pathophysiological processes of post-cardiac arrest syndrome (4).

During cardiac arrest, global ischemia-reperfusion injury damages endothelial cells and the endothelial glycocalyx, disrupting physiological functions at the microcirculatory level (5,6). These disruptions are early steps in the development of post-cardiac arrest syndrome, which ultimately leads to organ dysfunction and poor clinical outcomes (7,8).

This review provides an overview of the role of microcirculation in cardiac arrest, focusing on the assessment of microcirculatory dysfunction and its association with outcomes. Through a contemporary review of microcirculation assessment techniques in cardiac arrest, we highlight the clinical importance of the microcirculation as a prognostic indicator and potential therapeutic target.

MICROCIRCULATION PATHOPHYSIOLOGY

The microcirculation is a critical component of the cardiovascular system, consisting of arterioles, capillaries, and venules that facilitate the exchange of oxygen, nutrients, and waste products between the intravascular compartment and the tissues (9–11). A healthy microcirculation is essential for maintaining cellular homeostasis, supporting the metabolic demands of tissues, and ensuring proper functioning of the immune response by facilitating the movement of leukocytes to sites of infection or injury.

Microcirculatory dysfunction in cardiac arrest begins with global ischemia from the cessation of blood flow and is followed by reperfusion injury during ROSC (4,12). The production of reactive oxygen species and inflammatory cytokines leads to endothelial cell injury, and the activation of proteases degrade the endothelial glycocalyx. Shedding of the negatively charged endothelial glycocalyx, systemic inflammation, and the upregulation of thrombin creates a prothrombotic environment in the microcirculation which contributes to the development of microvascular thrombosis (13,14). Endotheliopathy from global ischemia-reperfusion, sympathoadrenal hyperactivation, and inflammation leads to loss of tight junctions between endothelial cells, which causes capillary leakage (15–17).

METHODS TO ASSESS MICROCIRCULATION

Overview

Various methods of assessing microcirculation have been investigated ranging from direct visualization of the microcirculation through handheld intravital microscopy (18,19), confocal microscopy (20), and capillaroscopy to indirect measurement of microcirculatory function and capacity through capillary refill time (CRT) (21,22), and near-infrared spectroscopy (NIRS) with vascular occlusion test (VOT) (23–25). Of these methods, handheld intravital microscopy is likely the most studied method and the gold standard method for assessing sublingual microcirculation (26).

Handheld intravital microscopy is typically performed using a small handheld video microscope that allows direct visualization of microcirculation at the bedside using specific wavelengths of light to capture high-contrast images of red blood cells flowing through the microvasculature. Earlier devices were based on orthogonal polarization spectral imaging, which were subsequently succeeded by sidestream dark field imaging and incident dark field imaging, both of which offered enhanced image clarity and resolution. The microscopes also have dedicated automated analysis software (e.g. GlycoCheck (27,28), Automated Vascular Analysis (29)) for extracting microcirculatory parameters; however, the accuracy of the software is still evolving. While studies have historically assessed sublingual microcirculation, other areas such as cerebral, conjunctival, and intestinal regions have been studied (30,31). Intravital microscopy is noninvasive and performed at the bedside, making it possible to assess microcirculation in real-time. There are a number of studies that have utilized intravital microscopy in critical illnesses such as cardiac arrest, sepsis and trauma (32–34). However, there are important challenges, most notably issues with reproducibility due to its operator dependence as well as pressure artifacts (pushing too hard when trying to obtain images such that flow is occluded and interpreted as falsely impaired) (18).

Another important area of research is in the identification of blood biomarkers that measure degradation of the endothelial glycocalyx, endotheliopathy, and tissue hypoperfusion to assess microcirculatory health. Various biomarkers have been studied in critical illnesses such as cardiac arrest, sepsis, and trauma. Research into diverse methods of assessing microcirculation have enhanced our understanding of the pathophysiology of cardiac arrest.

Assessment of Microcirculation in Cardiac Arrest using Handheld Intravital Microscope

The first and only available report on microcirculation assessment during cardiac arrest in humans was performed by Elbers et al. in 2010 on a patient who suffered a cardiac arrest from a submersion trauma (35). They showed that mechanical cardiopulmonary resuscitation (CPR) was able to provide some microcirculatory flow albeit being significantly reduced (microcirculatory flow index [MFI] 1.8 and perfused vessel density [PVD] of 3.8/mm2). These parameters improved drastically after ROSC (MFI 3.0 and PVD 9.01/mm2). They also observed that microcirculatory flow was largely unrelated to macrohemodynamic parameters. However, this finding is on a single patient and the hypothermia (22°C) caused by submersion makes the findings difficult to interpret.

Other studies investigating microcirculatory changes in cardiac arrest and CPR have been performed in animal models. A 2018 study using 24 porcine models showed that microcirculatory flow in the sublingual region rapidly decreased during cardiac arrest and incompletely recovered during CPR (36). In contrast, both cerebral and peripheral oxygenation decreased gradually during cardiac arrest with cerebral oxygenation slightly recovering with CPR. Peripheral oxygenation did not improve significantly even with resuscitation. Notably, there was only a moderate amount of correlation between sublingual microcirculation parameters and oxygenation. These findings are broadly consistent with prior works where microcirculatory flow dramatically decreased during cardiac arrest with partial recovery during CPR (37–42).

A larger body of work has evaluated changes in microcirculation after resuscitation in an attempt to understand the role of microcirculation in post-cardiac arrest syndrome. The most recent study was performed by Voß et al. in 2021 on 25 patients after out-of hospital cardiac arrest (OHCA) and assessed sublingual microcirculation at time of admission and after 6, 12, and 24 hours (43). They found that the proportion of perfused vessels (PPV) for small vessels (< 20 μm) at 6 hours was higher in survivors compared to non-survivors (85 ± 7.9% vs 75 ± 6.6%; p=0.1). There was no significant difference in PPV at admission, 12 or 24 hours. PPV performed equally to initial serum lactate in predicting survival with an area under the curve of 0.84. Combination of PPV > 78.4% and initial serum lactate < 5.15 mmol/l were predictive of survival with positive predictive value of 100% and negative predictive value of 67%. Notably, PPV did not correlate with serum lactate. While the study is limited by a small number of patients, findings suggest that early PPV is a potential tool for short-term prognosis in OHCA.

Several other studies have investigated microcirculation after cardiac arrest in the past and found impaired microcirculation after cardiac arrest (44–46). The first study evaluating microcirculation in post-cardiac arrest was performed by Donadello et al. in 2011. They found that the initial sublingual MFI and PPV were lower in cardiac arrest patients compared to healthy controls, but improved after rewarming to values similar to control. The microcirculation parameters were not associated with macrohemodynamic parameters. However, the study did not look at survival. Similar findings were seen in later studies including a 2012 study by van Genderen et al. that showed that initial and persistent impairment in microcirculation after rewarming were predictive of mortality (45). They found that the initial impairment in microcirculation were not significantly different between the survivors and non-survivors. A 2013 study by Omar et al. did not find significant differences in MFI at 6 and 24 hours between survivors vs. non-survivors, although they did see higher MFI at 24 hours in those with better neurological outcomes (44). This finding is consistent with the most recent study by Voß et al. where the difference between survivors and non-survivors were seen in PPV for microvessels (< 20 μm).

Biomarkers of the Endothelial Glycocalyx

The endothelial glycocalyx is present on all blood vessels and serves key functions at the level of the microcirculation (47). Measurement of endothelial glycocalyx biomarkers in blood is an efficient indirect method for assessing microcirculation parameters. In a rat model of hemorrhagic shock, Torres Filho et al. demonstrated that circulating biomarkers of the endothelial glycocalyx degradation inversely correlate with microcirculation glycocalyx thickness: syndecan-1 (r = −0.937, p < 0.001) and heparan sulfate (r = −0.864, p < 0.006). These same biomarkers also correlated well with microvascular permeability: syndecan-1 (r = 0.793, p < 0.02) and heparan sulfate (r = 0.794, p < 0.03) (48).

The first evidence that endothelial glycocalyx degradation is associated with clinical outcomes post-cardiac arrest was described by Grundmann et al. in a 2012 prospective cohort study. They found that endothelial glycocalyx biomarkers in post-cardiac arrest patients were significantly elevated compared to controls: syndecan-1 (2.8 fold increase), heparan sulfate (1.7 fold increase), and hyaluronic acid (2 fold increase). Furthermore, heparan sulfate and syndecan-1 were elevated within the first 24 hours in eventual non-survivors compared to survivors. In this study, it is notable that syndecan-1 was most elevated within 6 hours after resuscitation and its level correlated to duration of CPR (R = 0.5, p < 0.05). Heparan sulfate and hyaluronic acid were elevated in an intermediate time period of 48 hours to 72 hours, and were not correlated with duration of CPR (6).

In a 2019 study by Bogner-Flatz et al, syndecan-1 and hyaluronan measured immediately after ROSC were associated with increased occurrence of multiple organ failure (49). In 2024, He et al., performed a retrospective study of 71 patients and found that heparan sulfate levels were associated with both 30-day mortality and poor neurologic outcomes. Hyaluronan was only associated with 30-day mortality, and syndecan-1 was not predictive of either outcome (50). Further clinical studies determining the accuracy of endothelial glycocalyx biomarkers for diagnosis of microcirculatory dysfunction and for clinical prognosis are needed.

Biomarkers of Endothelial Cell Injury

Similar to the endothelial glycocalyx, the endothelium is ubiquitous to all blood vessels and serves key functions at the level of the microcirculation (17). Biomarkers of endothelial cells have been studied in post-cardiac arrest patients; however, no specific endothelial cell biomarker has been proven to correlate significantly with parameters measured by direct visualization of the microcirculation (44).

In a prospective cohort study of OHCA, Gando et al. demonstrated that biomarkers of endothelial cell activation (ICAM, VCAM, E-selectin, and thrombomodulin) were elevated after cardiac arrest compared to controls, which is likely a response to endothelial activation from global ischemia-reperfusion injury (51). Johansson et al. showed that biomarkers of endothelial cell injury correlated with biomarkers of sympathoadrenal activation (adrenaline and noradrenaline) in post-cardiac arrest patients and were predictive of increased mortality, which suggests a relationship between sympathoadrenal hyperactivation and endothelial cell activation (16). Bro-Jeppsen et al. performed a study of endothelial activation in OHCA and correlated biomarkers of endothelial activation with sequential organ failure assessment (SOFA) score. They found that only the baseline thrombomodulin was predictive of SOFA score at 24 – 72 hours. At 24 hours thrombomodulin, syndecan-1 and E-selectin correlated with SOFA score, but only thrombomodulin correlated with SOFA at 48 and 72 hours (52). A 2024 cohort study by Katsandres et al. examined endothelial injury biomarkers in OHCA and found that angiopoietin-2, in addition to endothelial glycocalyx biomarkers heparan sulfate and chondroitin sulfate, were elevated in post-cardiac arrest patients. Angiopoietin-2 was also associated with worse neurologic outcomes (54).

Lactate

In post-cardiac arrest patients, lactate may be elevated from an underlying pathology that led to cardiac arrest or it may rise from hyperperfusion and ischemia-reperfusion injury. Persistent lactate elevation in post-cardiac arrest syndrome can result from various causes, including microcirculatory dysfunction and cardiogenic shock (4,55–57). These pathophysiological conditions lead to anaerobic metabolism, resulting in glycolysis where lactate is produced as the end product. Lactate is then metabolized primarily through the liver through gluconeogenesis, and lactate clearance is decreased in the setting of liver failure.

Lactate levels have not been shown to correlate with microscopic parameters following cardiac arrest, (43) though elevated lactate levels are associated with increased mortality in post-cardiac arrest (57,58). Additionally, decreased lactate clearance is linked to higher mortality in these conditions (57). Lactate is a useful prognostic biomarker and can guide resuscitation post-cardiac arrest, but likely due to multiple possible etiologies which causes lactate to remain elevated, it is not a specific biomarker to microcirculation.

CARDIAC ARREST INTERVENTIONS AND MICROCIRCULATION

Intra-arrest Epinephrine

Early administration of epinephrine is recommended by the American Heart Association guideline (59,60). Epinephrine improves the rate of ROSC and survival, but whether this extends to improved neurologic outcomes remains unclear. Prior studies by Ristagno et al. in pig models showed that cerebral microcirculatory blood flow and oxygen tension were decreased with epinephrine administration (61,62). A recent study by Choi et al. evaluated the relationship between cerebral microcirculation and epinephrine administration timing in pig models and found that early epinephrine administration was associated with improved cortical cerebral blood flow and improved cerebral perfusion pressure. However, the study did not compare to placebo (63). The use of epinephrine during arrest results in increasing cerebral perfusion pressure but at the cost of vasoconstriction. The effects on the microcirculation in humans during arrest is still yet to be answered definitively.

Targeted Temperature Management

The role of targeted temperature management (TTM) or therapeutic hypothermia to 32 – 36°C after cardiac arrest is controversial, (64,65) with a recent large randomized trial showing no difference compared to normothermia (65). The impact of therapeutic hypothermia on microcirculation is especially of interest given the possible detrimental effect of vasoconstriction induced by hypothermia. A recent randomized trial looking at the effect of therapeutic hypothermia on microcirculation was performed by Koopmans et al. involving 22 patients. They compared the sublingual microcirculation and vascular reactivity between therapeutic hypothermia and normothermia (66). They found no significant difference in MFI or vascular reactivity between the groups at all timepoints. Tissue oxygenation was higher in the hypothermia group initially, but the difference disappeared over time. This seems to conflict with other earlier studies such as the one by Donadello et al. who found that initial sublingual microcirculation during the early stage of post-arrest period while the patients were undergoing therapeutic hypothermia had more impaired microcirculation. They hypothesized that the impairment is related to hypothermia. A similar finding was seen in a pediatric study (median age 2.3 years) by Buijs et al. (67) who assessed the microcirculation in buccal mucosa in 22 patients receiving therapeutic hypothermia and found that microcirculation parameters (MFI, PVD) were lower compared to healthy control. The difference went away once patients were normothermic. While these studies are limited by small sample size, the findings by Koopmans et al. appear to suggest that microcirculation impairment seen during the early stage of post-arrest period is potentially more related to the arrest itself rather than temperature management.

EXPLORATORY THERAPIES

There have been several studies of novel therapeutics targeting different aspects of microcirculatory dysfunction. These studies have been primarily in animal models. Although some have shown promise, no therapy thus far has demonstrable clinical benefit.

Anti-inflammatory

MCC950, a selective NLRP3 inflammasome inhibitor, was studied in a rat model of cardiac arrest. They found that the treatment group had improved myocardial function and sublingual microcirculation as well as improved 48 hour survival (68). Methylprednisolone was studied in rat models and was shown to improve myocardial function and microcirculation (cerebral, sublingual, and intestinal). The treatment group had decreased levels of pro-inflammatory cytokines pointing to the role of anti-inflammatory in improving microcirculation in post-cardiac arrest syndrome (69).

Vasodilation

A randomized controlled trial of iloprost (a cytoprotective, vasodilatory, prostacyclin analog) in humans showed no difference in 48 hour endothelial biomarkers and did not an increase in endothelial biomarkers at the 96 hour mark showing a rebound effect after cessation of iloprost (70). Inhaled nitric oxide, another vasodilatory agent, has demonstrated improved outcomes in animal models of post-cardiac arrest syndrome (71). In addition, intrathecal administration of sodium nitroprusside was studied in pig models to reduce postischemic cerebral hypoperfusion. Treatment with intrathecal sodium nitroprusside was associated with improved tissue oxygen tension as well as cerebral microcirculation, faster recovery of electrical activity. Intravenous administration of sodium nitroprusside was not associated with improvement in cerebral parameters (72).

Vascular space

The potential for polyethylene glycol-20k (PEG-20k) in expanding the microvascular space and preventing no-flow state in several studies (73–75). The studies showed that treatment with PEG-20k was associated with improved myocardial function, microcirculation (MFI and PVD) as well as cerebral function and survival rate. When compared to epinephrine, PEG-20k was as effective in increasing the coronary perfusion pressure while reducing duration of arrhythmia (74). Notably, combination treatment of PEG-20k and MCC950 was associated with further improvement (75).

Nutrients

An animal study assessing the effect of hydrogen gas on endothelium and endothelial glycocalyx against ischemia-reperfusion injury showed no difference in syndecan-1 and sublingual microcirculation although treatment reduced metabolic changes (76). Treatment with ω−3 polyunsaturated fatty acid (ω−3 PUFA) and ascorbic acid (vitamin C) was studied to assess the effect of myocardial protection from damage from reduced lipid metabolism and oxidative damage after cardiac arrest in rat models. They found that treatment with ω−3 PUFA or ascorbic acid reduced myocardial dysfunction and improved sublingual microcirculation. The effect was larger when treated with both agents (77).

CONCLUSION

Studies have consistently demonstrated that microcirculatory dysfunction is associated with increased mortality and poor neurological outcomes following cardiac arrest. Early and/or persistent microcirculatory impairment assessed using intravital microscopy and biomarkers is associated with lower survival and worse neurological outcomes. However, these studies are limited by small sample sizes and infrequent measurements. Further research is needed to complete the understanding of microcirculatory impairment in cardiac arrest.

KEY POINTS.

  • Microcirculation parameters assessed through proportion of perfused vessels for small vessels (< 20 μm) early after cardiac arrest (6 hours) may be associated with lower survival.

  • Biomarkers of endothelial glycocalyx and endothelial cell injury have been found to be elevated in post-cardiac arrest and may predict mortality, but there is mixed evidence regarding correlation of biomarkers with microscopic parameters.

  • Several exploratory therapies targeting microcirculation have shown promising results in animal models warranting further studies.

Financial support and sponsorship

MSK and JHL are supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (grant number T32HL155020). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health

Footnotes

Conflict of interest

None.

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