Hydrocortisone Therapy for Patients With Multiple Trauma. Part 2
Study drug infusion began within 36 hours of the trauma onset, immediately after the completion of a short corticotropin test. Hydrocortisone hemisuccinate (Upjohn, Serb laboratory, Paris, France) and placebo were prepared immediately before use in a syringe containing 48 mL of saline isotonic solution. In addition to standard of care, the study drugs were continuously administered intravenously as follows: 200 mg/d for 5 days, 100 mg on day 6, and 50 mg on day 7 for patients with corticosteroid insufficiency. After receiving the results of the short corticotropin test (in the first 48 hours following inclusion), the treatment was stopped if patients had an adapted corticosteroid function.
Each patient's general characteristics including demographics, injury severity score and abbreviated injury score, fluid infusions, vasopressors, antibiotic prophylaxis, etomidate use, surgery, infections, organ failures, length of ventilatory support, and ICU hospitalization and death at day 28 were recorded.
Immediately before beginning the treatment, but at least 8 hours after a bolus injection of etomidate,6 a short corticotropin test was performed: cortisolemia before and 30 and 60 minutes after an intravenous bolus of 0.25 mg of corticotropin (Novartis, Rueil-Malmaison, France). In patients with corticosteroid insufficiency, a second short corticotropin test was performed 24 hours after the end of treatment.
During the 28-day period after randomization, clinical assessments were performed twice a day in the ICU. Methods to enhance the quality of measurements included holding triannual telephone contact with investigators, sending e-mails, and conducting random quality assurance evaluations.
The study's primary outcome was occurrence of hospital-acquired pneumonia within 28 days of randomization. The secondary outcomes were duration of mechanical ventilation and length of ICU stay, rates of death, other infections, and organ failures, and duration of vasopressor support on day 28. Safety was assessed by recording adverse events.
Modifiable risk factors of hospital-acquired pneumonia18 were prospectively recorded. Clinical evaluation for diagnosis of pneumonia was performed twice a day in the ICU. A chest x-ray was taken as soon as pneumonia was suspected after clinical examination. A culture sample was collected immediately when radiographic infiltrates and antibiotic therapy was not modified.
Statistical Analysis
After verifying that the cumulative probability of hospital-acquired pneumonia on day 28 was significantly decreased in the hydrocortisone group compared with the placebo group using a stratified log-rank test (test initially planned for the primary end point), we decided a posteriori to perform complementary sensitivity analyses with an adjustment for etomidate use. The final a posteriori primary analysis consisted of evaluating the effect of hydrocortisone on the primary outcome (ie, pneumonia within 28 days), with adjustment by means of a Cox multivariate proportional hazards model that included 3 predefined covariates: the center, TBI (presence or absence), and the injury severity score (≤30 or >30). Corresponding hazard ratios (HRs) along with their 95% confidence intervals (CIs) were reported. If a significant difference was confirmed for the primary end point, then subgroup analysis for TBI (presence or absence) was performed. The hierarchical testing procedure allowed us to control the family-wise type I error rate. A second complementary analysis was a priori planned considering mortality as part of the outcome (composite outcome). We also reported the crude Kaplan-Meier estimator at day 28. Because the randomization process came before the corticotropin test, an intention-to-treat analysis (ITT) that includes the whole population was first performed followed by a modified ITT for patients with corticosteroid insufficiency.
Hydrocortisone Therapy for Patients With Multiple Trauma
Severe trauma is one of the leading causes of death and morbidity in the world. The overall rate of posttraumatic pneumonia reaches an incidence of 40% to 60%, mainly in patients with traumatic brain injury (TBI). Early posttraumatic pneumonia increases the duration of mechanical ventilation, hospitalization, and risk of death. Thus, prevention of posttrauma pneumonia is a major clinical and economical issue.
Stress-dose hydrocortisone was suggested as a means of improving outcome in septic patients with critical illness–related corticosteroid insufficiency.6 Recommendations advocate the use of long-term stress-dose hydrocortisone (200 mg/d) in patients with septic shock7 and with severe community-acquired pneumonia. Both experimental and clinical data suggest that corticosteroid use may decrease the occurrence and severity of nosocomial pneumonia in patients treated in intensive care units (ICUs).
Persistent systemic inflammatory response syndrome was predictive of nosocomial infection in trauma patients. Trauma-related corticosteroid insufficiency was also correlated with systemic inflammatory response syndrome. It has been suggested that hydrocortisone attenuates the overwhelming inflammatory response without immunosuppression, restoring an adequate immune response to infection. We postulated that treatment with stress-dose levels of hydrocortisone would diminish the prevalence of hospital-acquired pneumonia, the first cause of infection in trauma patients.
Study Design
This multicenter, randomized, double-blind, parallel, placebo-controlled study was approved by the institutional review board of Angers, France. Patients were enrolled from November 15, 2006, to August 4, 2009, when recruitment was completed at the 7 participating French ICUs. Patients were enrolled after a next-of-kin provided written informed consent. Retrospective consent, when available, was obtained from patients. The authors designed the study, but data were gathered and analyzed by an independent monitoring board.
Patients with multiple trauma who were older than 15 years 3 months and expected to require mechanical ventilation for more than 48 hours were included in the study. Those with previous adrenal insufficiency, previous immunosuppression, treatment with corticosteroids within the last 6 months, or were pregnant were excluded.
Multiple trauma was defined as having 2 or more traumatic injuries and an injury severity score higher than 15. Severe TBI was defined as a Glasgow Coma Scale score of less than or equal to 8 after initial care. Corticosteroid insufficiency was defined as basal cortisolemia level lower than 15 μg/dL (to convert to nanomoles per liter multiply by 27.588) or a maximal increase in the cortisol level lower than 9 μg/dL in the 60 minutes following a short corticotropin test.
Pneumonia was considered when at least 2 signs (body temperature >38°C; leukocytosis >12 000/mL, or leukopenia <4000/mL; purulent pulmonary secretions) associated with the appearance of a new infiltrate were present or when change occurred in an existing infiltrate on chest x-ray. The diagnosis needed to be confirmed by a lower respiratory tract sample using a quantitative culture with a predefined positive threshold of 104 colony-forming units per milliliter (CFU/mL) for a bronchoalveolar lavage or nonbronchoscopic sample and 103 CFU/mL for a protected specimen brush. Hospital-acquired pneumonia was defined as pneumonia that occurs 48 hours after admission that had not been incubating at the time of admission. The definitions of other infections as well as organ failure are provided as supplemental material. Patients were randomized in a 1:1 ratio in fixed blocks of 4 and stratified according to the treatment center, the presence of severe TBI, and injury severity score higher than 30 by a computerized number generator list provided by a statistician not involved in the determination of eligibility or in the assessment of outcomes. All assignments were made through a central randomization center. In each center, an unblinded pharmacist who was not involved in the determination of eligibility or in the assessment of outcomes prepared the study drug. Patients, investigators, and members of the monitoring board and medical and nursing staff were unaware of the patients' treatment assignment.