A retrospective, observational, single-center study was performed in the tertiary hospital of Shanghai Jiao Tong University Affiliated Sixth People's Hospital (Shanghai PA; 1766 beds) from January 2011 to December 2017. Patient data were collected from the hospital's electronic record database. The Ethics Committee of Shanghai Jiao Tong University Affiliated Sixth People's Hospital (Approval No. 2018-ky-033k) and the Chinese Clinical Trial Registry (Approval No. ChiCTR1800017004) approved this study.

The diagnosis of IHCA was identified according to the International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-10-CM) code I46.9. For all the patients in the database, the inclusion criteria were as follows: patients older than 18 years; patients who underwent chest compression for at least 2 min during hospital treatment; and patients with the recovery and maintenance of spontaneous circulation > 48 h. The exclusion criteria were as follows: patients with cerebral trauma before admission; patients with a documented do-not-resuscitate order; patients with two or more cardiac arrests; patients with an admission temperature >38°C or <35.5°C; patients with missing temperature records or covariate information; patients with known infection on admission, such as sepsis or pneumonia; patients with antibiotic use before admission; and pregnant patients (Figure 1).

To ensure validity, the data were reviewed by two trained researchers. The following data were collected from each patient: age, sex, preexisting illness, first monitored rhythm, location of arrest, duration of cardiopulmonary resuscitation (CPR), hospital admission temperature, chest X-ray, highest procalcitonin (PCT) level, and white blood cell count within 48 h following ROSC, sputum cultures obtained within 48 h following ROSC, and vital status at hospital discharge (alive or dead). The length of hospital stay was calculated from the date of ROSC to the date of death or hospital discharge. We reviewed all available temperature data after ROSC from the medical record, and the total duration of a body temperature higher than 38°C and the initial onset of fever were collected.

IHCA was defined as the absence of pulse or hypoperfusion resulting in ventricular fibrillation, pulseless ventricular tachycardia, pulseless electrical activity, or asystole in in-hospital patients who required extra chest compressions. ROSC was defined as no chest compressions for at least 20 min. According to current guidelines, a positive chest X-ray was defined as detectable infiltrate, and a positive sputum culture was defined as the presence of gram-negative bacilli or gram-positive bacteria (16). Severe brain injury was defined as a Glasgow Coma Scale (GCS) score ≤ 8 at 24 h postresuscitation (17). A cardiovascular event was defined as the occurrence of myocardial infarction requiring coronary angiography during hospitalization. The time of day referred to the occurrence of IHCA during work hours (7:00 a.m. to 5:00 p.m. and day of the week). Antibiotic use was defined as the administration of an antibiotic after ROSC. The outcome was survival to hospital discharge. Fever duration was defined as the total duration of an axillary temperature higher than 38°C during hospitalization, converted into days. The IDF for each patient was calculated by dividing the total duration of a body temperature higher than 38°C by the duration of hospitalization (18). No fever was defined as no episodes of temperature ≥ 38.0°C, prolonged fever was defined as fever longer than 5 days (15, 19), and early fever was defined as fever occurring in the first 2 days after CA (4).

Categorical variables are presented as counts and percentages. For continuous variables, normality was assessed, and non-normally distributed continuous variables are expressed as medians and 25th and 75th percentiles. Variables related to IDF were evaluated by linear regression, and multivariate logistic regression models were used to determine the potential risk factors of fever on survival to hospital discharge. Model 1 adjusted covariates included the following: diabetes mellitus, GCS ≤ 8, CPR interval, epinephrine dosing, and renal replacement therapy. Model 2 adjusted covariates included model 1 plus the potential confounders of procalcitonin, positive chest X-ray, endotracheal intubation, and central venous catheter. Model 3 adjusted covariates included model 2 plus the potential confounders of neuromuscular blockers, corticosteroids, and antibiotic therapy. Model 4 adjusted covariates included model 3 plus the potential confounders of NSAIDs, acetaminophen and physical cooling (Table 3). Subsequently, the logistic regression models, which contained other variables that may affect discharge survival, were included in these models. The variables in the logistic regression model are shown in Table 4. By using the mediation package in R, we detected whether the relevant variables affected the survival outcome via IDF (20). For each analysis, the null hypothesis was assessed at a two-sided significance level of 0.05, and all analyses were analyzed using PASW/SPSSTM software version 25 (IBM Inc., Chicago, IL, USA) or R version 3.6.2. A probability value of P < 0.05 was considered significant.

In this retrospective cohort study, a total of 2,427 patients suffered from IHCA and ROSC after cardiopulmonary resuscitation, of whom 605 were eligible for inclusion in our study. The flow diagram of patient inclusion is shown in Figure 1. The median age of the patients was 69 years old [interquartile range (IQR) 60–80], of whom 48.8% were male (n = 297). The median duration of cardiopulmonary resuscitation was 19 min [(IQR) 10–28.5 min]. The location of cardiac arrest was as follows: 45.8% in the general wards, 16% in emergency departments, and 38.2% in intensive care units. Positive chest X-ray was identified in 42% (255/605) of the patients, and positive sputum culture was found in 31.7% (192/605). More than half of the patients had undergone endotracheal intubation, and 67.2% (407/605) and 23.6% (143/605) of the patients had received central venous catheterization. The median IDF was 0 [(IQR) 0–0.42], and the total rate of survival to hospital discharge was 26.9% (164/605) (Table 1). Prolonged fever and short-term fever were noted 16% (97/605) and 28.1% (170/605) of the patients, respectively. Early fever and delayed fever patients were noted in 17.2% (104/605) and 26.9% (163/605) of the patients, respectively. Antipyretic therapy including acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, ketoprofen, diclofenac, and physical cooling were indicative of the ice cap. Of these, acetaminophen controlled 32.6% (197/605) and NSAIDs and physical cooling controlled 3.5% (21/605) and 10.6% (64/605) of these cases, respectively.

To determine the risk factors associated with IDF, linear regression was adopted, and basic characteristics, infectious factors, and non-infectious factors were taken into account. Our results showed that positive chest X-ray (Beta = 0.07, 95% CI, 0.02–0.12, P = 0.008), central venous catheter (Beta = 0.06, 95% CI, 0.003–0.123, P = 0.04), GCS ≤ 8 (Beta = 0.20, 95% CI, 0.12–0.29, P < 0.001), and IHCA in the emergency ward (Beta = 0.11, 95% CI, 0.04–0.23, P = 0.008) were significant factors related to IDF (Table 2).

The impact of fever on the survival of patients discharged from the hospital was analyzed from multiple perspectives. IDF was defined as the fever duration divided by the hospitalization duration, while fever was divided into short-term fever and prolonged fever according to the duration of fever and early fever and delayed fever according to the onset of fever. At the same time, four regression models were established. Model 1 adjusted covariates of patients' basic disease characteristics; model 2 added procalcitonin, positive chest X-ray, endotracheal intubation and central venous catheter as potential infection confounders; model 3 added factors such as neuromuscular blockers, corticosteroids, renal replacement therapy and antibiotic therapy, which may affect body temperature; and model 4 added antipyretic treatments such as NSAIDs, acetaminophen and physical cooling. The results indicated that IDF (OR = 0.36, 95% CI, 0.13–0.97, P = 0.04) was an independent risk factor associated with survival to hospital discharge. After adjusting for fever-related confounding factors for prolonged fever, the results remained significant (adjusted OR = 0.13, 95% CI, 0.06–0.29, P < 0.001) (Table 3). While short-term fever, early fever and delayed fever did not show a significant impact on patient survival, the results were adjusted OR = 0.94, 95% CI, 0.74–1.38, P = 0.34, adjusted OR = 1.28, 95% CI, 0.60–2.72, P = 0.52, adjusted OR = 0.82, 95% CI, 0.42–1.60, P = 0.56, respectively. Therefore, the results of our study show that the initial onset time of fever and a shorter duration of fever have no significant effect on patient prognosis, while a fever lasting more than 5 days or a higher IDF are negatively associated with hospital discharge.

To further determine the risk factors associated with survival to hospital discharge, we performed univariate and multivariate analyses for the whole cohort. A total of 20 potential risk factors were included (Table 4), and the results revealed that arrest location, epinephrine dose, blood transfusion, endotracheal intubation, central venous catheter, and positive chest X-ray were statistically significant in the univariate logistic regression analysis. Variables associated with survival to hospital discharge with P values ≤ 0.2 in the univariate analysis were included in the multivariate logistic regression. In the multivariate logistic regression analyses, endotracheal intubation (adjusted OR = 0.47, 95% CI, 0.33–0.69, P < 0.001), central venous catheter placement (adjusted OR = 0.54, 95% CI, 0.34–0.89, P = 0.01), and positive chest X-ray (adjusted OR = 0.67, 95% CI, 0.46–0.98, P = 0.04) were found to be independent risk factors associated with survival to hospital discharge (Table 4).

To explore the underlying causal mechanism, a causal mediation analysis was performed, and the IDF was designated as the mediator. This analysis divided the total effect into direct effects and indirect effects (20), in which indirect effects represented the causal mechanism through IDF and direct effects represented all other mechanisms. As shown in Table 5, a positive chest X-ray influenced the survival to hospital discharge through the mediating effect of IDF, where the average causal mediation effect (ACME) was −0.01 (95% CI −0.03 to 0.00; P < 0.001), the average direct effect (ADE) was −0.06 (95% CI −0.13 to 0.00; P = 0.12), and the proportion of the mediated effect was 19% (95% CI 0.02–1.14; P = 0.04) (Figure 2). Central venous catheter had an impact on the partially mediated outcome, with an ACME of −0.01 (95% CI −0.03 to 0.00; P < 0.001) and an ADE of −0.09 (95% CI −0.16 to −0.01; P = 0.04), and the proportion of the mediated effect was 10% (0.01–0.52, P = 0.02) (Figure 3). Endotracheal intubation had a non-significant average indirect effect of 0.01 (95% CI 0.00–0.02; P = 0.06) (Figure 4).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.