In septic shock, refractory hypotension is very common and most of the time responsible for serious multi-organ failure disorders even after recent advancements in modern medical practice. Septic shock is a distributive type of vasodilatory shock, and the first line of a vasopressor is noradrenaline to keep mean arterial blood pressure greater than 65 mmHg. Severe stress conditions may lead to hyposynthesis of cortisol. In septic shock cases, decreased levels of cortisol are noted. Recent surviving sepsis guidelines recommend a low dose of corticosteroids for the treatment of vasopressor-dependent septic shock. The use of corticosteroids is not strongly recommended, but they may be useful, as they have anti-inflammatory properties and maintain cardiovascular homeostasis through salt and water retention. Hydrocortisone plays an important role and is effective in reducing the time length of shock when included in the standard treatment protocol. The recommended hydrocortisone daily dosage ranges from 200 to 300 mg in 3–4 divided doses. Continuous infusion of hydrocortisone may be an alternative method of administration. Hyperglycemia is one of the most common side effects of corticosteroid treatment. Hyperglycemia is associated with a higher incidence of mortality in critically ill patients. Few studies showed a higher incidence of hyperglycemia with hydrocortisone given as intermittent boluses when compared to continuous infusion. However, only a small number of cases were taken for these studies and they were retrospective. In this study, we evaluated prospectively the risk of hyperglycemia of intermittent boluses versus continuous infusion of hydrocortisone on a relatively large sample size of critically ill patients with septic shock.
MATERIALS AND METHODS
After approval from the institutional ethical committee (letter no: 84/IEC/IGIMS/2021 dated: March 23, 2021), 140 patients were selected for the study at a tertiary care teaching hospital and the study was conducted between June 2021 and May 2022. Written informed consent was obtained for participation in the study and the use of the patient data for research and educational purposes. Patients were randomly assigned to two groups by computer-generated number. Group 1 was intermittent bolus group containing 70 patients and Group 2 was continuous infusion group containing 70 patients. The inclusion criteria include all patients who were admitted to the trauma intensive care unit (TICU) with septic shock and those who were started on norepinephrine and received hydrocortisone either as intermittent boluses or as continuous infusion. The exclusion criteria were patients who exceeded 200 mg per day of hydrocortisone. The principles of the Declaration of Helsinki were followed during the conduct of the study.
The following parameters were collected: age, sex, history of hypertension, diabetes, coronary artery disease, chronic kidney disease, chronic respiratory disease and cancer recent use of corticosteroids, source of infection, on the basis of type of admission (medical or surgical), individual parameters of the Sequential Organ Failure Assessment (SOFA) score, length of stay in hospital, length of stay in intensive care unit (ICU), blood glucose level readings, and mortality.
The primary outcome was mean blood glucose. The secondary outcomes were the incidence of hypoglycemia, hyperglycemia, mortality, total duration until reversal from shock (defined as the duration of vasopressor therapy), length of hospital stays, length of ICU stay, and glycemic variability estimated as the glucose coefficient of variation (standard deviation/mean × 100). All blood glucose levels were included in the analysis of the study.
Sample size and statistical analysis
The sample size of 140 patients (70 patients in each group) was required for the study to have 90% power to show a 50% relative reduction of blood sugar level with continuous hydrocortisone infusion at a one-sided alpha level of 0.05. Baseline data were described as mean with standard deviation for continuous variables, median with interquartile range for ordinal variables and nonnormally distributed continuous variables, and frequencies with percentages for categorical variables. To evaluate multiple blood glucose measurements for each patient, a linear mixed regression model with an unstructured covariance matrix assuming independence between patients was considered. The data analysis was considered for history of diabetes, median baseline of random glucose level, and history of longstanding use of steroid and the duration of hydrocortisone therapy as a random effect. The estimated means of blood glucose and the mean difference between the two groups were calculated by a linear mixed model. The mortality was compared between the groups using multiple factors such as baseline age, SOFA score, surgical status, and preexisting diseases such as diabetes, hypertension, chronic kidney disease, coronary artery disease, and respiratory diseases. Their results were reported as crude odds ratios and adjusted odds ratios with corresponding 95% confidence intervals (CIs). Qualitative variables were compared between the two groups with the Chi-square of the Fisher's exact test when needed, and continuous variables were compared using the Student's t-test or the Wilcoxon rank-sum test as appropriate. SAS statistical software version 9.4 (SAS Institute, Cary, NC, USA) was used for statistical analysis. All P values were one-sided, and P < 0.05 was considered statistically significant.
Out of 140 patients, a total of 112 patients were included in the final analysis of the study. Twenty-eight patients were excluded from the study. Twenty-two patients died and six patients withdraw their consent to participate in the study. Fifty-four (48.2%) patients received intermittent bolus of hydrocortisone, and 58 (51.8%) patients received continuous infusion [Figure 1]. A total of 200 mg per day of hydrocortisone was received by all patients in both the groups. In the intermittent bolus group, all patients received 50 mg hydrocortisone every 6 hourly, and in the continuous infusion group, all patients received 200 mg hydrocortisone infused over 24 h. The mean ages of the intermittent infusion and continuous infusion groups were 60 and 58 years, respectively. Other baseline characteristics were similar in both the groups [Table 1]. A higher number of patients received hydrocortisone as a continuous infusion in the TICU (58 patients [51.8%]) than the intermittent bolus group, but it was not significant (P < 0.12). There was no difference between the two groups in hydrocortisone duration until recovery from sock.
For the primary outcome, the blood glucose estimated marginal mean was 154.48 mg.dL−1 (95% confidence interval [CI]: 144.56–165.88) for the intermittent bolus group and 160.80 mg.dL−1 (95% CI: 142.64–172.66) for the continuous infusion group with a mean difference of 6.32 mg.dL−1 (95% CI: −12.44–23.38) [Table 2]. For the secondary outcomes, 12 (22.2%) of 54 in the bolus group and 10 (17.2%) out of 58 in the infusion group died with an adjusted odds ratio of 0.62 (0.19–2.04). No statistically significant difference was observed between the two groups with regard to hospital length of stay, ICU length of stay, or vasopressor duration [Table 3]. The incidence of hyperglycemia, hypoglycemia, or glucose coefficient of variation between the two groups was not statistically significant.
The evaluation of the safest method of hydrocortisone administration in septic shock patients was the main objective of this study. Methods of hydrocortisone administration in this study was either intermittent boluses or continuous infusion. The primary outcome neither causes changes in an increase in mean blood glucose nor increase in incidence of hyperglycemic events. The difference between the blood glucose means was 6.32 mg.dL−1 more in the continuous infusion group, which is not a statistically or clinically significant difference. There were no significant differences found between the two groups regarding the secondary outcome in rate of mortality, incidence of hypoglycemia or hyperglycemia, total duration until recovery from shock, length of hospital stays, length of ICU stays, and glycemic variability estimated as the glucose coefficient of variation. Most of the patients in TICU received hydrocortisone as a continuous infusion than intermittent bolus; however, the difference was not significant. In a small randomized control trial (RCT), Weber-Carstens et al. reported that hydrocortisone was associated with a significant increase in blood glucose readings within 6 h after bolus doses when compared to continuous infusion. This study was conducted on very small (only 16 patients), and the baseline characteristic report was also missing.
Another RCT conducted by Loisa et al. They had reported that bolus doses of hydrocortisone increased the risk of hyperglycemia in 48 patients. This was statistically significant, but the results were not clinically significant, as the difference in mean blood glucose was only 0.2 mmol.L−1 (3.6 mg.dL−1). The baseline comorbidities of the two groups were also missing in that study. 7 mmol.L−1 (126 mg.dL−1) was used as a cutoff for defining hyperglycemia in Loisa et al.'s study although the 2021 surviving sepsis guideline updates accept up to 10 mmol.L−1.
A retrospective cohort study by Hoang et al. reported a higher incidence of hyperglycemia with intermittent bolus doses of hydrocortisone. However, this study was conducted on 51 patients only, and the results were not clinically satisfactory in coexisting comorbid patients such as diabetes. A higher prevalence of diabetic patients in the bolus group was also noted, which may have affected the results. A recent RCT was conducted on 29 patients by Tilouche et al., and they found no significant difference between intermittent bolus and continuous infusion; however, the sample size was small, and hyperglycemia was not the primary outcome. Gibbison et al. conducted a meta-analysis among different regimens of steroids in septic shock patients including hydrocortisone intermittent bolus and continuous infusion; however, they did not find the difference in hyperglycemia between different regimens due to significant variation in defining hyperglycemia between trials. This study reports no difference in mortality between the two groups. These findings correlate with previous studies comparing boluses and continuous infusion. Tilouche et al. found that hydrocortisone boluses ideal for the faster reversal of shock than continuous infusion, but their study showed no significant difference in the times until shock reversal between the two groups. Although they did discover a trend toward decreased vasopressor duration in the bolus group by a median of 0.6 days, it was not statistically significant. Mitwally et al. concluded in their study that intermittent boluses of hydrocortisone were not associated with a higher risk of hyperglycemia than continuous infusion in septic shock patients.
The strength of this study includes its relatively larger sample size than previous studies and prospective study design. All previous studies were including the same clinical question and the adjustment of the results to baseline characteristics [Table 1]. Several patient factors other than hydrocortisone may affect blood glucose readings. The prime benefit of this study is the study's design. Being prospective rather than retrospective might have excluded bias to the results. Direct data obtained from patients may have decreased the risk of bias.
One of the limitations was the use of multiple methods of blood glucose measurement (laboratory, blood gases, and point of care). We accept that the readings from different methods might be slightly different. However, a larger study group may be nullified these limitations. These findings will support the administration of different techniques of hydrocortisone administration, and the clinician will not require to change their administration methods. Some practitioners may prefer to give hydrocortisone as boluses based on the studies, which showed that boluses may cause an early reversal of shock and also ease administration more than continuous infusion. The use of corticosteroids in refractory hypotension in septic shock is not supported by many studies. This may raise controversies to this study. Future research directions include larger sample size prospective randomized control trials that are required to confirm these results.
The risk of hyperglycemia is almost equal in both intermittent and continuous infusions of hydrocortisone in septic shock patients. Larger sample size prospective randomized control trials are required to confirm these results.
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Conflicts of interest
There are no conflicts of interest.
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