Prediction of return of spontaneous circulation in out-of-hospital cardiac arrest with non-shockable initial rhythm using point-of-care testing: a retrospective observational study

Abstract

BACKGROUND:

Out-of-hospital cardiac arrest (OHCA) is a public health concern, and many studies have been conducted on return of spontaneous circulation (ROSC) and its prognostic factors. Rotational thromboelastometry (ROTEM^®), a point-of-care testing (POCT) method, has been useful for predicting ROSC in patients with OHCA, but very few studies have focused on patients with non-shockable rhythm. We examined whether the parameters of POCT could predict ROSC in patients with OHCA and accompanying non-shockable rhythm.

METHODS:

This is a single-center, retrospective observational study. Complete blood count, blood gas, and ROTEM POCT measurements were used. This study included patients with non-traumatic OHCA aged 18 years or older who were transported to the emergency department and evaluated using POCT between January 2013 and December 2021. The patients were divided into the ROSC and non-ROSC groups. Prehospital information and POCT parameters were compared using receiver operating characteristic (ROC) curve analysis, and further logistic regression analysis was performed.

RESULTS:

Sixty-seven and 135 patients were in the ROSC and non-ROSC groups, respectively. The ROC curves showed a high area under the curve (AUC) for K⁺ of 0.77 (95% confidence interval [CI]: 0.71–0.83) and EXTEM amplitude 5 min after clotting time (A5) of 0.70 (95%CI: 0.62–0.77). The odds ratios for ROSC were as follows: female sex 3.67 (95%CI: 1.67–8.04); K⁺ 0.64 (95%CI: 0.48–0.84); and EXTEM A5 1.03 (95%CI: 1.01–1.06).

CONCLUSION:

In OHCA patients with non-shockable rhythm, K⁺ level and the ROTEM parameter EXTEM A5 may be useful in predicting ROSC.

INTRODUCTION

Out-of-hospital cardiac arrest (OHCA) occurs from multiple causes, is frequent, and is a major public health concern.[1,2] Return of spontaneous circulation (ROSC) in patients with OHCA indicates successful early resuscitation efforts.[3] Early knowledge of whether ROSC can be obtained for patients with OHCA may be important for healthcare providers and patient families in making decisions about medical interventions.[4] The proportion of patients with OHCA and non-shockable rhythm is increasing,[5-7] and such patients tend to have a poor prognosis.[8] Therefore, the importance of characterizing and optimizing treatment for patients with OHCA accompanied by non-shockable rhythm has been recognized.[9]

Factors that predict ROSC and long-term survival in patients with OHCA have been studied, including prehospital information, such as age, sex, witnesses, bystander cardiopulmonary resuscitation (CPR), cause leading to cardiac arrest, and initial rhythm.[10] According to blood tests, various factors, such as levels of K⁺,[11,12] Na⁺,[13] blood glucose,[13] ammonia,[14] brain natriuretic peptide,[15] lactate,[16-18] and free thyroxine 4,[19] have been reported to affect the prognosis of OHCA. Moreover, significant activation of coagulation occurs as a part of the pathogenesis after cardiac arrest.[20] Progressive coagulation abnormalities have also been reported as the duration of cardiopulmonary arrest increases.[21] There are scattered studies using rotational thromboelastometry (ROTEM^®; TEM International, GmbH, Germany) to elucidate the coagulation state after cardiac arrest and to understand its pathophysiology.[21-23] ROTEM is a viscoelasticity measurement device using whole blood samples. The standard laboratory test may detect coagulation disorders that cannot be detected by self-learning training.[24,25] In addition, ROTEM is a point-of-care testing (POCT) method, and its results can be obtained quickly at the bedside. Taking advantage of its rapidity, a previous study has applied ROTEM to predict ROSC in patients with OHCA.[26] To the best of our knowledge, no studies have examined the predictors of ROSC by POCT focused on OHCA patients with non-shockable rhythm. In this study, we focused on coagulopathy occurring in OHCA patients with non-shockable rhythm and considered the possibility that ROTEM parameters could predict ROSC more quickly and accurately than other approaches. We used the parameters of POCT, including ROTEM, to determine the predictors of ROSC in patients with non-shockable rhythm OHCA.

METHODS

Study design and participants

This is a single-center, retrospective, observational study conducted at Saga University Hospital. It was approved by the Ethics Committee of Saga University Hospital (approval number: 2020-02-R-08) and conformed to the provisions of the Declaration of Helsinki, as revised in Fortaleza, Brazil, in October 2013. The need for informed consent was waived owing to the retrospective nature of the study.

This study included patients with non-traumatic OHCA aged 18 years or older who experienced OHCA and ongoing CPR evaluated with POCT upon emergency department arrival, including ROTEM, between January 2013 and December 2021. Patients with a shockable rhythm, those with cancer complications, those with in-hospital cardiac arrest, those with a do-not-resuscitate order, and those with a cadaveric rigidity on arrival were excluded. Patient information for the analysis referred to prehospital and post-arrival data was collected according to Utstein forms and our electronic medical records. Prehospital information included data related to witnesses, bystander CPR, initial rhythm by emergency medical service (EMS), prehospital intervention (advanced airway management and epinephrine administration), physician-staffed EMS, and the temporal record. Post-arrival information included POCT measurements and the cause of OHCA. The cause of the cardiac arrest was determined by the responding emergency physician. Causes of OHCA were classified based on a previous study as follows[27]: intrinsic (non-cardiac [respiratory, neurological, sepsis, and hemorrhage] and cardiac [unless otherwise indicated]), and extrinsic (neck hanging, choking, drowning, and drug addiction).

Prehospital treatment for out-of-hospital cardiac arrest in Japan

In the prehospital setting, CPR is performed by EMS. The EMS team connects the call to a physician in charge of the local medical system, who will secure the peripheral venous route, administer epinephrine, and use the advanced airway (tracheal intubation and supraglottic devices) under telephone instructions. In some areas, there are physician-staffed EMS that dispatch emergency physicians and nurses to the scene by helicopter or specialized vehicle at the request of the dispatcher. Physician-staffed EMS will intubate, administer medications, and search for the cause of cardiac arrest in the prehospital setting.

Point-of-care testing measurements in the emergency department

Three POCT measurements, complete blood count, blood gas, and ROTEM, were used in our emergency department. Blood specimens were collected promptly after the patient with OHCA was brought to the emergency department. Blood samples were also collected at the time of intravenous line placement or by puncturing the femoral artery or vein. White blood cell count, hemoglobin, and platelet levels were measured using Sysmex XN-9000 (Sysmex Corporation, Japan). The partial pressure of carbon dioxide (pCO₂), partial pressure of oxygen (pO₂), actual base excess, pH, Na⁺, K⁺, Cl^–, HCO₃ ^–, blood glucose, and lactate levels were measured using ABL825 and ABLS800 (Radiometer CO., LTD., Japan). ROTEM parameters were measured with ROTEM delta by well-experienced team physicians. Work shifts were randomly set regardless of the ROTEM measurement team membership. The hospital accepts patients at any given time, and there were no differences in patient severity by shift. In terms of measurements, the focus was on the extrinsic coagulation pathway (EXTEM), including clotting time (CT), amplitude 5–30 min after CT (A5–A30), and maximum clot firmness (MCF). There were no measurements in which CT exceeded 1,800 s and coagulation occurred. Therefore, other items were set as 0. All tests were performed according to the manufacturer’s recommendations. Measurements were taken immediately after blood collection. However, depending on the availability of hospital staff, measurements were taken after ROSC or after the abandonment of resuscitation to prioritize resuscitation.

Statistical analysis

All statistical analyses were performed using the JMP Pro version 14 software package (SAS Inc., USA). Normality and distribution of continuous variables were assessed using the Shapiro-Wilk test. The normally distributed data are presented as the means, whereas non-normally distributed data are presented as medians and interquartiles. The characteristics of the patients were compared using Chi-square test for categorical data as well as Student’s t-test and Wilcoxon rank-sum test for the continuous data, respectively. For all analyses, P < 0.05 was considered significantly different.

Regardless of the duration of ROSC, the ROSC group was defined as patients who achieved ROSC even once during resuscitation in the emergency department, and the non-ROSC group was defined as patients who did not achieve ROSC. Univariate analysis was performed to compare prehospital information and POCT measurements at hospital arrival. Receiver operating characteristic (ROC) curve analysis was performed for the significant factors between the two groups. Youden’s index was used to calculate the cutoff value, the area under the curve (AUC), sensitivity, and specificity. Based on univariate analysis, logistic analysis was performed to identify factors affecting ROSC. Spearman’s test was performed on the factors used in the logistic analysis to confirm multicollinearity.

RESULTS

Participant characteristics

During the study period, 1,197 patients with OHCA were transported to the hospital as emergencies. ROTEM measurements were performed on patients with OHCA transported during the hours when emergency physicians who were members of the ROTEM measurement team were on duty. These emergency physicians worked 44.4% of the day shift and 25.7% of the night shift. ROTEM measurements were performed on 268 patients with OHCA. After excluding patients with ROSC before hospital arrival (n=29), those with trauma (n=20), those with shockable initial rhythm (n=12), those with cancer complications (n=3), and those with missing data (n=2), a total of 202 patients were included in the analysis. The ROSC and non-ROSC groups comprised 67 and 135 patients, respectively (Figure 1). A comparison of the characteristics of patients in the ROSC and non-ROSC groups is shown in Table 1. There were significant differences between the two groups in sex and witness (female: 39 [58.2%] vs. 45 [33.3%], P= 0.0009; and witness: 34 [50.8%] vs. 30 [22.2%], P< 0.001). There were no significant differences in age or bystander CPR. Regarding initial rhythms, 49 and 153 patients had pulseless electrical activity (PEA) and asystole, respectively, and there was no significant difference between the two groups. Although there was no significant difference, there was a higher proportion of physician-staffed EMS in the ROSC group. Prehospital epinephrine administration was not significantly different between groups; however, prehospital interventions tended to be more frequent in the ROSC group. Although there was no significant difference in the time from call the EMS to EMS arrival at the scene, there was a significant difference in the time from EMS arrival at the scene to hospital arrival (25 min [20–34 min] vs. 22 min [17–30 min]). Regarding the cause of OHCA, there were significant differences in neurological and choking factors (neurological: 3 [4.5%] vs. 0 [0.0%], P=0.0354; and choking: 17 [25.4%] vs. 5 [3.7%], P<0.001).

Figure 1.

Patients with OHCA during the study period and those included in the analysis. OHCA: out-of-hospital cardiac arrest; ROTEM: rotational thromboelastometry; ROSC: return of spontaneous circulation.

Table 1.

Characteristics of patients with OHCA in the ROSC and non-ROSC groups

Outcomes

A comparison of POCT measurements in the ROSC and non-ROSC groups is shown in Table 2. Significant differences were observed in the levels and/or values of platelets, pH, pCO₂, K⁺, lactate, and all of the ROTEM parameters between the two groups. The results of ROC analyses are shown in Table 3. The highest AUC in blood gas analysis was for K⁺, with an AUC of 0.77 (95% confidence interval [CI]: 0.70–0.83). The highest AUC in ROTEM parameters was for EXTEM A5, with an AUC of 0.70 (95%CI: 0.62–0.77). The odds ratios (OR) and their 95%CIs from logistic regression analysis for ROSC, adjusted for confounding factors, are shown in Table 4. Female sex (OR=3.67, 95% CI: 1.67–8.04); K⁺ (OR=0.64, 95% CI: 0.48–0.84) and EXTEM A5 (OR=1.03, 95% CI: 1.01–1.06) are the predictive factors for the ROSC in patients with OHCA accompanied with non-shockable rhythm.

Table 2.

POCT parameters of patients with OHCA in the ROSC and non-ROSC groups, median (interquartile)

Table 3.

ROC analysis in measurement items

Table 4.

Logistic regression analysis for ROSC

DISCUSSION

In the emergency setting, effective resuscitative care requires rapid decision-making and a comprehensive understanding of the patient’s condition. Therefore, POCT, which provides rapid results, is useful. This study suggests that EXTEM A5 is valuable for predicting ROSC in patients with non-shockable OHCA, along with female sex and K⁺, which have been reported to be significant factors in other studies.

Previous studies have reported significant associations between ROSC and the sex of patients,[10] K⁺ level,[11,12] and lactate level.[16,18,28] Similar results were obtained in the patient population of the present study.

A previous study concerning the prognosis of OHCA has reported better outcomes in patients with lower serum K⁺ levels.[29] Compared to the findings of existing studies, the results of the present study demonstrated that the serum K⁺ levels in OHCA were also lower in patients who achieved ROSC. The initial rhythms in this study were asystole and PEA, and most of the cases had unclear onset time. Some of the cases had a long time waiting for EMS after cardiac arrest, which may have resulted in high serum K⁺ levels.

However, in this study, bystander CPR was not significantly different between the ROSC and non-ROSC groups. Patients in this study were limited to individuals with PEA and asystole; furthermore, asystole was observed in 76% of all cases. This may suggest that some of the patients have been found a long time after cardiac arrest.

Skorko et al[30] reported that insufficient coagulation function and abnormal ROTEM measurements in OHCA. In the present study, lower platelet counts and significant differences in many ROTEM measurements were observed in the non-ROSC patients with OHCA. This may be due to more advanced coagulopathy in patients with a poorer prognosis.

In patients with OHCA, a prothrombotic state can also occur due to the promotion of inflammation with the expression of inflammatory mediators[31] and the activation of the procoagulant pathway.[23] Moreover, activation of the extrinsic coagulation pathway causes fibrin clot formation and hyperfibrinolysis due to hypoperfusion.[21,26] In this study, we focused on EXTEM, which mainly reflects the extrinsic coagulation pathway, as a ROTEM parameter with reference to previous studies.[23,26]

Most of the EXTEM items showed significant differences between the ROSC and non-ROSC groups, which may reflect coagulopathy in patients with OHCA. Koami et al[26] reported that among the ROTEM items, EXTEM A30 is useful for predicting ROSC. Although this existing study did not focus on EXTEM A5, the ROC analysis in this study confirmed a higher AUC in EXTEM A5. Focusing on EXTEM A5 in terms of more rapid results may be appropriate for the resuscitation of patients with OHCA, who require rapid decision-making.

Schöchl et al[23] also reported that significant differences occurred only in EXTEM CT between the ROSC and non-ROSC groups of patients with OHCA. They included the patients with a shockable rhythm, with a 32% rate of asystole. The high percentage of asystole suggests that the study included a large number of cases in which time had elapsed since the cardiac arrest. Therefore, coagulopathy may have progressed in the study population, leading to significant differences in many ROTEM parameters.

End-tidal carbon dioxide (EtCO₂) is useful in assessing the quality of CPR during resuscitation of OHCA patients and is considered a prognostic indicator. However, POCT, such as ROTEM, used to predict OHCA prognosis in this study may be costly. In addition, ROTEM measurements require practice. Non-invasive tools such as EtCO₂ may be useful as an alternative. However, ROTEM measuring can help to understand the coagulation pathology of OHCA and may assist in exploring the pathogenic mechanism.

During the study period, the resuscitation guidelines primarily used in Japan were revised twice, with the main changes being slight modifications to the speed and depth of chest compressions. After the outbreak of the COVID-19 epidemic, chest compression interruption during intubation was recommended (available at: https://www.jrc-cpr.org/jrc-guideline-2020/). We do not consider that this change will have a significant impact on the coagulation pathophysiology of OHCA, but it may have decreased the rate of ROSC. However, efforts were made by clinicians to minimize the interruption of chest compressions as recommended in the guidelines.

This study has some limitations. First, this was a single-center, retrospective study with a small number of patients and ROTEM evaluators. Therefore, we were not able to perform the measurement on all patients and conduct an in-depth analysis of the long-term prognosis. Second, it is unclear whether the POCT parameters in our institution are available in another environment. Meanwhile, some POCT methods are not available in our institution, and some potentially useful parameters may have been overlooked. In addition, the blood samples used for blood tests and ROTEM measurements may have been a mixture of arterial and venous blood. Third, patients administered epinephrine prior to hospital admission also received a prehospital infusion, but the volume of infusion and effect on coagulation are not known. Future studies with large sample size might help confirm our findings.

CONCLUSIONS

In summary, there is reason to propose the ROTEM parameter EXTEM A5, along with the K⁺ level, as a predictor of ROSC in patients with non-shockable OHCA.