Study design and setting
This study was approved by the Institutional Review Board of the Catholic University of Korea (UC20RISI0091). The need to obtain informed consent was waived because of the retrospective nature of the study. This retrospective observational cohort study was performed in a single center, Uijeongbu St. Mary’s Hospital, Catholic University of Korea, which is a regional emergency medical center and regional trauma center. The annual emergency department volume is approximately 80,000 visits, providing post-cardiac arrest care with hypothermic TTM to more than 45 patients annually.
From December 2011 to December 2019, postcardiac arrest (PCAS) patients who had undergone hypothermic TTM were included. Adults (≥ 18 years old) who maintained ROSC for longer than 20 minutes were eligible for hypothermic TTM. Patients who did not receive hypothermic TTM and those for whom blood HbA1c levels at admission were not available were excluded from the analysis. Patients did not receive hypothermic TTM for the following reasons: recovery of consciousness after ROSC; past history of irreparable brain damage (cerebral performance categories (CPC) scale 3–4); suspected hemorrhagic shock; suspected intracranial hemorrhage; known terminal illness; and refusal of the patient's family.
The primary outcome was 6-month mortality, while the secondary outcome was the 6-month neurological outcome. Good neurological outcomes were defined as CPC scores of 1–2, while poor neurological outcomes were defined as CPC scores of 3–5. Patient demographics and cardiac arrest variables were collected according to the Utstein style guidelines . We recorded the following baseline clinical data: age, sex, previous medical history (e.g., acute myocardial infarction, previous cardiac arrest, angina, congestive heart failure, hypertension (HTN), DM, lung disease, cerebrovascular accident (CVA), renal disease, liver cirrhosis, malignancy), initial cardiac arrest rhythm (shockable or non-shockable), presence of a witness, bystander cardiopulmonary resuscitation (CPR), time from collapse to ROSC, and glucose and HbA1c levels at admission. Blood samples for the determination of the HbA1c and glucose levels were collected immediately after ROSC. We collected medical data from the medical database. We obtained the survival time from the National Health Insurance Service database. We obtained the neurologic status of the patients by directly calling the patient’s caregiver 6 months after ROSC. We determined an optimal HbA1c cutoff of 6% for predicting 6-month mortality and the neurologic outcome. The guidelines recommend an HbA1c ≥ 6.5% to diagnose diabetes and an HbA1c between 5.7 and 6.4% for identifying prediabetes [17–19]. These cutoff values for HbA1c were derived in part from outpatient studies and were based on populations of those not acutely ill at the time of testing. Silverman et al. suggested that in an acute-care setting such as the emergency department, an HbA1c of 5.7% was the optimal screening cutoff for prediabetes, and 6% was the optimal screening cutoff for diabetes . The South Korea health system does not permit the withdrawal of life-sustaining treatment (WLST) from patients; therefore, we did not use the collected data in the present study to make any decisions regarding the withdrawal of life support from any patient. However, do-not-resuscitate (DNR) orders are legal and socially acceptable. Therefore, if the family did not want to escalate treatment after the prognosis was made, it was not performed.
The post-cardiac arrest care performed on the study subjects was based on the CPR guidelines from the American Heart Association and Korean CPR Association [21, 22]. To reach the target temperature, induction was started immediately after ROSC with ice packs and an automatic surface cooling device using hydrogel pads (Arctic Sun 5000, Medivance Inc., Louisville, CO, USA); the target temperature was 33 °C for 24 hours, followed by 12 hours of rewarming at the rate of 0.25 °C per hour. After reaching the target rewarming temperature of 36.8 °C, we continued normothermic TTM for an additional 36 hours. We continuously infused midazolam (0.04–0.2 mg/kg/hr) and rocuronium (0.3–0.6 mg/kg/hr) to control shivering during the hypothermic period. All patients were admitted to the intensive care unit and received standard intensive care. The following clinical parameters were used to achieve hemodynamic optimization, ventilator management, and glucose management: SaO2 94–96%, PaCO2 35 to 45 mmHg, mean arterial pressure greater than or equal to 70 mmHg, urine output greater than or equal to 0.5 mL/kg per hour, and glucose level 144 to 180 mg/dL. In addition, we monitored amplitude-integrated electroencephalography. If there was evidence of epileptic discharges, we administered anti-epileptic drugs (valproic acid, levetiracetam, clonazepam).
This study was conducted in accordance with the strengthening the reporting of observational studies in epidemiology statement .
As there were no preliminary data, we assumed that the group with HbA1c ≤ 6% would have twice as many patients as the group with HbA1c > 6%, according to our clinical experience. We calculated the sample size to detect a difference between survival rates of 0.3 (HbA1c ≤ 6%) and 0.15 (HbA1c > 6%). Finally, a total of 302 subjects was needed to achieve a power of 80% at a significance level of 0.01.
We present categorical variables as absolute numbers with percentages; these variables were compared with the chi-square test or Fisher's exact test. Continuous variables are presented as median values with interquartile ranges (IQR) and were compared with the Mann-Whitney U test because the continuous variables had nonparametric distributions.
We compared the survival rates between the group with HbA1c ≤ 6% and the group with HbA1c > 6% by the log-rank test. Kaplan-Meier analysis survival curves were created to analyse 6-month survival.
A multivariate logistic regression analysis was used to assess the effects of the predictors. All variables with a significance level less than 0.01 according to univariate analysis and cardiac arrest characteristics (non-shockable rhythm, absence of witness, no bystander CPR, time to ROSC) were included in the multivariate logistic regression model. The goodness of fit of the model was evaluated by the Hosmer-Lemeshow test. The results of the logistic regression analysis are presented as odds ratios (ORs) and 95% confidence intervals (CIs). All of the statistical analyses were performed using MedCalc version 19.1.5. (MedCalc software, Mariakerke, Belgium). P values < 0.01 were considered statistically significant (two-sided).