We retrospectively analyzed the medical information of patients admitted the ICUs of a tertiary university hospital between 2006 and 2018. These ICUs included surgical, medical, and emergency ICUs. The study included 104 critically ill patients who underwent two rapid cosyntropin stimulation tests during hospitalization, all of whom underwent the first test during ICU admission. Cosyntropin stimulation test was performed in patients with suspected relative adrenal insufficiency (RAI). Since there are no definite diagnostic criteria for RAI, stimulation test was performed when the clinician suspected the disease. Usually the affected patients had clinical signs such as hyponatremia or refractory shock, fever or general weakness. The test was conducted in the following method. Basal ACTH and cortisol levels were measured by collecting the blood sample of the patient before the injection of cosyntropin. The blood used for ACTH measurement was collected in a pre-chilled lithium-heparin tube and carried in an ice box for minimizing degradation of ACTH. The patient was injected intravenously with 250 μg of tetracosactrin (Synacthen). After 30 and 60 minutes after the injection of the drug, the patient’s blood sample was collected separately and the cortisol level was measured.

Demographic data including age, sex, and body mass index were collected. The clinical variables included comorbidities, vital signs at the time of admission to the ICU, and blood test results. The severity of patient illness was assessed by Acute Physiology and Chronic Health Evaluation (APACHE) II score on the first day of ICU admission based on vital signs and laboratory results. The management in the ICU included invasive mechanical ventilation (MV), continuous renal replacement therapy (CRRT), and use of vasoactive agents. We also investigated the presence of septic shock and bacteremia at the time of the cosyntropin stimulation test and whether the patient had acquired a nosocomial infection during their ICU stay. Information was collected to determine if there was a history of steroid use and whether the patient received etomidate before ICU admission. The clinical outcomes of the patients included 30-day ICU mortality, ICU mortality, in-hospital mortality, ICU length of stay (LOS), and hospital LOS. This study was approved by the Institutional Review Board of Seoul National University Hospital (IRB No. 1802-006-918) and patient consent was waived with retrospective design of the study.

Adrenocortical dissociation refers to a condition in which the ACTH concentration is decreased while the cortisol concentration is increased. There remains no consensus regarding the cutoff value to define this condition; therefore, the definition of adrenocortical dissociation used in the present study was an ACTH concentration of <22 pmol/L (100 pg/ml), 25th percentile and cortisol concentration >600 nmol/L (21.75 μg/dl), 75th percentile of total population. We compared the clinical outcomes of patients who were evaluated as having adrenocortical dissociation and patients without dissociation in the first cosyntropin stimulation test.

Statistical analyses were performed using STATA ver. 13.0 (StataCorp., College Station, TX, USA). Categorical variables were described as number (percent) and continuous variables as mean and standard deviation. For univariate analysis, continuous variables were assessed by Student t-tests, while categorical variables were assessed by Pearson chi-square or Fisher exact tests. Patient survival in the hospital was compared using Kaplan-Meier analysis and log-rank tests. Cox regression analysis was performed for the multivariate analysis of factors affecting hospital mortality. The P-values <0.05 were considered statistically significant.

Table 1 shows the baseline and clinical characteristics of these 94 patients. Their mean age was 64.6±16.1 years and 33% were female. The mean APACHE II score was 25.0±8.3 and 53.2% of the patients had septic shock. Among 87 total patients requiring MV, 19.5% of patients (n=17) were administered etomidate during rapid sequence intubation, and 80.5% (n=70) cases used midazolam during the intubation procedure. During ICU admission, 92.6% of the patients required invasive MV and 30.9% received CRRT. Patients with hypertension showed higher hospital mortality (17.2% vs. 53.3%, P<0.001) and patients who received CRRT also showed higher mortality (23.4% vs. 46.7%, P=0.023).

Adrenocortical Responses of Study Population in Cosyntropin Stimulation Tests

We also compared the rapid ACTH stimulation test results of survivors and non-survivors. There was no significant difference in ACTH and cortisol basal levels between the two groups when comparing the first test. However, in the second test, the baseline cortisol level and the cortisol level after 30 minutes for the non-survivor group were statistically significantly higher. Similar results were obtained when comparing cortisol levels after correcting for serum albumin levels (Table 2).

We compared the clinical outcome between patients with and without ACTH cortisol dissociation in first stimulation test, as shown in Table 3. The dissociation and no-dissociation groups had similar demographic and clinical characteristics (Supplementary Table 1), the overall hospital mortality was 31.9% and the ICU mortality rate was 14.9% (14/94, data not shown). The hospital mortality rates were 55% and 25.7% in the dissociation and control groups, respectively. The mortality rate was higher in the dissociation group compared to the 28-day mortality rate only in patients who underwent two tests within 28 days. There was no difference in hospital LOS between the two groups although the mean value of the dissociation group was lower. The 90-day mortality rate in patients who underwent two cosyntropin tests within 90 days was also higher in the dissociation group and consistent with the analysis of patients who underwent two cosyntropin tests during the ICU period (Table 3). These results were consistent in patients without etomidate (Supplementary Table 2).

We also compared the clinical outcomes of the CIRCI group defined by the 2017 SCCM/ESICM criteria but found no statistically significant difference. The outcomes were similar between patients with decreased and increased cortical response in the second test (Supplementary Table 3). Kaplan-Meier time series analysis showed a higher mortality rate in the dissociation group than that in the control group (P=0.009, log-rank test) (Figure 2). A Cox regression univariate analysis of factors determining hospital mortality revealed that ACTH-cortisol dissociation was associated with higher hospital mortality. Furthermore, ACTH-cortisol dissociation was significantly associated with higher hospital mortality in multivariate analysis adjusted for age, sex, presence of cancer, APACHE II score, hypertension and medical history of malignancy (Table 4).

To analyze the effect of ACTH-cortisol dissociation on clinical prognosis, we divided the patients into four groups. The first group consisted of patients without ACTH-cortisol dissociation in both tests, the second group showed dissociations in both tests, the third group showed dissociation in the first test only, and the fourth group showed dissociation in only the second test. Three patients had ACTH-cortisol dissociation in both cosyntropin stimulation tests (group 2); they comprised 3.2% of the total patient population and had 100% hospital mortality. Fifteen patients showed dissociation in the only first test (group 3) and had a hospital mortality rate of 53.3%. The patients with dissociation in the second test (group 4), had a 44.4% in-hospital mortality. Groups 1, 3, and 4 had an overall hospital mortality rate of 31.3%. The hospital mortality rate of patients without dissociation in two tests was the lowest, at 24.2%. These differences between groups were similar for 90-day and ICU mortality (Table 5).