Materials and Methods
This was a retrospective study performed in a cohort of patients with septic shock admitted to the medical ICU of Samsung Medical Center (a 1,960-bed, university-affiliated, tertiary referral hospital in Seoul, South Korea), which has 30 beds providing care for approximately 860 critically ill patients per year. The study was approved by the institutional review board of Samsung Medical Center to review and publish information from the patients' records. Informed consent was waived because of the retrospective nature of the study.
Study Population
All consecutive patients with septic shock admitted to the medical ICU between January 2008 and December 2009 were screened for inclusion in this study if they had received low-dose corticosteroid therapy (≤ 300 mg/day of hydrocortisone or equivalent) for septic shock. Patients were excluded if they were less than 18 years old, had received systemic corticosteroid therapy within the last 3 months before septic shock, had received high-dose steroid therapy (> 300 mg/day of hydrocortisone or equivalent), or did not receive low-dose corticosteroid therapy for septic shock. Additionally, immunocompromised patients, such as those with HIV infection and those who had undergone stem cell or solid organ transplantations, were excluded from the study.
Initial Resuscitation and Hemodynamic Management for Septic Shock
A specific protocol for early recognition and management of patients with severe sepsis or septic shock has been implemented in our center since 2004. Additionally, to improve the compliance with the initial resuscitation bundle and management for sepsis, we revised, approved, and promoted our early goal-directed therapy (EGDT) protocol with an educational program named 'Emergency Approach to Sepsis Treatment (EAST)' in early 2008. Our EGDT protocol is an adaptation of the protocol reported by Rivers et al.. Fluid resuscitation and hemodynamic monitoring were initiated in patients fulfilling the criteria for severe sepsis or septic shock, with placement of a central venous catheter via the internal jugular or subclavian vein approach for central venous pressure (CVP) and central venous oxygen saturation (ScvO2) monitoring. Broad-spectrum antibiotics were administered as soon as possible. Hemodynamic resuscitation was conducted according to a predetermined treatment plan. First, isotonic crystalloid was administered in boluses to target CVP ≥ 8 mmHg. Second, systolic blood pressure ≥ 90 mmHg or mean arterial pressure (MAP) ≥ 65 mmHg, if not achieved with fluid administration, was targeted by initiating and titrating vasopressors (preferably norepinephrine as a first-line agent) to achieve this desired blood pressure. Finally, ScvO2 ≥ 70% was targeted after CVP and blood pressure goals were met. If ScvO2 was lower than 70% and the hematocrit was lower than 30%, packed red blood cells were transfused to achieve a hematocrit of at least 30%. If ScvO2 remained lower than 70% when hematocrit was 30% or higher, dobutamine was initiated at the treating physician's discretion and titrated in attempts to reach ScvO2 ≥ 70%. When the patient remained hypotensive after at least one hour of resuscitation with fluids and vasopressor, low-dose corticosteroid therapy was recommended as soon as possible after sampling for adrenocorticotropic hormone (ACTH) test if possible. However, the time to initiation of low-dose corticosteroid therapy was decided by the treating physician in the emergency department or ICU. Hydrocortisone was administered intravenously every 6 hours as a 50-mg bolus for 5 days and then tapered (50 mg intravenously every 12 hours for 3 days, followed by 50 mg intravenously daily for 3 days). Fludrocortisone was not to be administered in conjunction with hydrocortisone. If hemodynamic stabilization was achieved, the vasopressor was tapered based on the decision of the attending physician, keeping MAP above 65 mmHg and urinary output higher than 0.5 mL/kg/hour.
Definitions
Septic shock was defined as sepsis with acute circulatory failure characterized by persistent arterial hypotension (systolic arterial pressure < 90 mmHg in 156 patients (88%), mean arterial pressure < 60 mmHg in 147 (83%)], or a reduction in systolic blood pressure > 40 mmHg from baseline in 21 (12%)) despite adequate volume resuscitation. Organ dysfunction was defined as Sequential Organ Failure Assessment (SOFA) score ≥ 2 for each organ system. Critical-illness-related corticosteroid insufficiency (CIRCI) was diagnosed by a delta serum cortisol level of < 9 μg/dL after ACTH (250 μg) administration (relative adrenal insufficiency) or random total serum cortisol < 10 μg/dL. Appropriate antibiotic therapy was considered if the initially prescribed antibiotics were active against the identified pathogens, based on in vitro susceptibility testing. The time to initiation of antibiotic therapy relative to the onset of septic shock was defined as the time from the initial onset of septic shock-related hypotension to the initiation of antibiotics. Time to initiation of low-dose corticosteroid therapy was defined as the time from the initial onset of septic shock-related hypotension to the initiation of corticosteroid. Reversal of shock was defined as the maintenance of a systolic blood pressure of at least 90 mmHg without vasopressor support for at least 24 hours.
Data Collection
The following data recorded at the time of initiation of low-dose corticosteroid therapy were collected from the electronic medical records: general characteristics of the patients including demographic data, infection source, laboratory measurements including initial lactate, amount of fluid administered before initiation of vasopressor, doses of vasopressor (norepinephrine or equivalent), and organ dysfunction. The severity of illness was assessed by Simplified Acute Physiology Score 3 (SAPS 3) and SOFA scores. SAPS 3 was calculated as the worst value for that variable during the first one hour of ICU admission, and SOFA scores were calculated from the data on admission. On ICU admission, the following conditions were evaluated: the need for mechanical ventilation and renal replacement therapy, appropriateness of empirical antibiotic therapy, and presence of bacteremia.
The primary outcome was 28-day mortality. To address the primary research question of whether mortality and time to initiation of low-dose steroid therapy are associated, we considered age, gender, time to initiation of antibiotic therapy and severity of illness as potential confounders. The secondary outcomes were reversal of shock, ICU mortality, in-hospital mortality and the duration of ICU and hospital stay.
Statistical Analysis
Data are presented as medians and interquartile range (IQR) for continuous variables and as numbers (percentages) for categorical variables. Data were compared using the Mann-Whitney U-test for continuous variables and the χ or Fisher's exact test for categorical variables. To assess whether there was an association between 28-day mortality and the time to initiation of low-dose corticosteroid therapy, the Mantel-Haenszel test was used to examine trends across the quintiles of time.
A logistic regression model was used to adjust for potential confounding factors in the association between the time to initiation of low-dose corticosteroid therapy and 28-day mortality. Three models were constructed: model 1 was adjusted for age and gender, model 2 was additionally adjusted for time to initiation of antibiotic therapy and severity of illness, and model 3 additionally included factors with P < 0.25 in univariate analysis as confounding factors. Data are presented as odds ratios (OR) with 95% confidence intervals (CI).
The baseline characteristics and outcome measures of interest were then compared between the patients receiving low-dose corticosteroid therapy within versus after six hours from the initial onset of septic shock-related hypotension. Kaplan-Meier estimation was used to determine the 90-day survival curves for these two times to initiation of low-dose corticosteroid therapy, which were then compared using the log-rank test for survival data. Statistical analyses were performed using SAS version 9.1 (SAS Institute, Cary, NC), and two-sided P < 0.05 was considered significant.