In-hospital cardiac arrest (IHCA) occurs in approximately 9–10 out of 1000 hospitalized patients [1]. Outcome-related factors of IHCA patients can help develop critical care plans for both patients and their families. These factors can help narrow the range of medical resources required for treatment [2]. Therefore, research analyzing factors related to neurological outcomes in IHCA patients could improve their prognosis through the appropriate distribution of medical resources.

There are differences in management between IHCA and out-of-hospital cardiac arrest (OHCA) patients. Survival rates and neurological outcomes in OHCA patients are significantly influenced by factors directly related to cardiac arrest management, such as high-quality cardiopulmonary resuscitation (CPR), the presence of a witness, appropriate application of defibrillation, and professional airway management [3, 4]. In contrast, in IHCA patients, most outcomes can be determined by the preexisting illness or the reason for hospitalization rather than the etiology of the cardiac arrest [5]. Therefore, pathological changes such as underlying conditions or alterations in laboratory tests during hospitalization might play a more crucial role in predicting future outcomes for IHCA patients.

When cardiac arrest patients experience the return of spontaneous circulation (ROSC), the resulting systemic ischemia-reperfusion response can induce increased systemic inflammation and coagulation, leading to disseminated intravascular coagulation (DIC) [6]. In addition to tissue hypoxia, this causes coagulation and immune dysfunction, potentially resulting in multiple organ failure and increased inflammation. In OHCA patients, altered DIC profiles and elevated DIC scores were associated with mortality or poor neurological outcomes [7, 8]. In contrast, the relationship between DIC profiles and neurological outcomes in IHCA patients remains unclear. Therefore, we sought to examine the correlation between DIC profiles and neurological outcomes in IHCA patients.

This study demonstrated that IHCA patients with poor neurological outcomes had lower levels of fibrinogen and ATIII compared to those with good neurological outcomes. Furthermore, fibrinogen and ATIII levels were strongly associated with poor neurological outcomes. ATIII level was weakly associated with poor neurological outcomes at 6 months, while fibrinogen level was not associated with poor neurological outcomes at 6 months.

ATIII, a single-chain protein found in plasma, is synthesized in the liver. It inhibits the coagulation system and is rapidly consumed in conditions such as systemic inflammatory response syndrome, sepsis, and DIC, leading to an early decrease in plasma levels [13]. In a study investigating the relationship between thrombin-antithrombin (TAT) levels and survival rates in patients resuscitated from cardiac arrest, the majority of patients exhibited elevated TAT levels [12]. Furthermore, increased TAT levels over the 24 hours following resuscitation were independently associated with survival [14]. Several studies assessed ATII levels in OHCA patients. In a study by Park et al. [15], ATIII levels did not differ between the good and poor outcome groups until 72 hours after ROSC [15]. In another study, when the normal cutoff value for ATIII was 20 mg/dL [16], the ATIII levels immediately after ROSC showed a normal range of over 75% in both good and poor outcome groups [7]. However, in the present study, the ATIII levels in the poor outcome group was 65.7%, which was lower than normal. Unlike in OHCA, the reason for hospitalization is closely related to the prognosis in IHCA. The reason for hospitalization in the poor outcome group might be more serious than in the good outcome group, which is reflected by the different GO-Far scores between the two groups. Low ATIII levels are associated with severity and mortality in critically ill patients [17, 18, 19]. Furthermore, ATIII activity might decrease with older age [20]. In the present study, the poor outcome group was older, and older age is a significant factor for prognosis following cardiac arrest. Therefore, the ATIII levels in the poor outcome group would be decreased before cardiac arrest compared to the good outcome group. Furthermore, the decrease in ATIII would be further accelerated due to the ischemic reperfusion injury from the cardiac arrest.

In OHCA patients, there was no difference in fibrinogen levels immediately after ROSC between good and poor outcome groups [21, 22]. In the present study, fibrinogen levels tended to be normal. In contrast to OHCA patients, the fibrinogen level in the poor outcome group was higher than that in the good outcome group, and this relationship continued following the multivariate analysis. Several studies [23, 24, 25] showed that mildly high fibrinogen levels are associated with the prognosis of critically ill patients. In patients with chronic heart failure, a high fibrinogen level ($\ge$284 mg/dL) was associated with increased 90-day mortality [23]. Fibrinogen levels $\ge$350 mg/dL were associated with exacerbations of chronic obstructive pulmonary disease (COPD) and death in COPD patients [24]. Fibrinogen $\ge$280 mg/dL was associated with major adverse cardiovascular events, including death after percutaneous coronary intervention [25]. Fibrinogen plays a distinct role in arterial thrombosis through platelet aggregation, plasma viscosity, and fibrin formation, which increases cardiovascular risk [26, 27].

Unlike previous studies on OHCA, our study did not show a difference in DIC scores between good and poor outcomes groups of IHCA patients. The components of the ISTH score are platelet count, prothrombin time, fibrinogen, and D-dimer. In the present study, these elements did not differ between good and poor outcomes groups, except for fibrinogen levels. Fibrinogen exceeded 1.0 g/L in both groups; thus, no meaningful distinction could be made regarding the DIC score. In contrast to previous studies, D-dimer was significantly increased in both groups depending on the DIC score.

The present study has some limitations. First, this is a single-center retrospective study which is susceptible to bias. Therefore, future studies, including multi-center trials, are necessary to further validate our conclusions. Second, we did not directly compare patients who received TTM with those who did not, which could have affected the neurological outcomes. Previous study suggested that TTM might affect the prognosis of IHCA patients [28]. In the present study, we measured the DIC profile immediately after ROSC to minimize the interference of TTM, but future studies are needed to explore the effect of TTM on the DIC profile in both TTM and non-TTM groups of IHCA patients. Third, our study group consisted of only 29 patients. Thus, the ratio of the number of events per variable in the multivariate logistic regression model was lower than the desired ratio of $>$10 suggested by Peduzzi et al. [29]. The variables considered in the analysis were carefully selected. Additionally, the main purpose of this study was to examine the prognostic significance of DIC profiles, rather than to create a multivariable model to predict the outcome of IHCA patients. Therefore, the number of patients in the study group was limited. Fourth, there may be an interaction of major trauma, stroke, and septicemia for DIC profiles. However, all three diseases accounted for approximately 10% of the total patients and had no significant relationship with poor outcomes. Therefore, we believe that the three diseases had little effect on the relationship between prognosis and DIC profile in IHCA patients. Fifth, we did not investigate the relationship between the serial change of DIC profiles and the prognosis of IHCA patients. Finally, we did not consider blood transfusions or direct oral anticoagulants that could influence the DIC profile during post-cardiac arrest care. Therefore, the relationship with prognosis was investigated using only variables obtained after ROSC, and the DIC profile after ROSC was included in the regression model.

Decreased fibrinogen and ATIII levels after ROSC were independent risk factors for poor neurological outcomes in IHCA. Unlike OHCA, the DIC score is unlikely to play a significant prognostic role in IHCA. Future research is needed on the relationship between serial changes in the DIC profile after ROSC and neurological prognosis in IHCA patients.

All data generated or analyzed during this study are included in this article and its supplementary material files. Further enquiries can be directed to the corresponding author.

DL and BL designed the research study. DL, BL, SR, and JL performed the research. SB and YC provided help and advice on the study. DL and BL analyzed the data. DL and BL wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

This study was approved by the Chonnam National University Hospital Institutional Review Board (CNUH-2022-135). Due to the study’s retrospective nature, informed consent was not obtained.

Not applicable.

This research received no external funding.

The authors declare no conflict of interest.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/j.rcm2509340.