Methods\ud
Objective\ud
To test the efficacy of hydrocortisone therapy in trauma patients.\ud
\ud
Design\ud
Multicenter randomized, double blind, placebocontrolled study.\ud
\ud
Setting\ud
Seven intensive care units (ICUs) in France during November 2006 to August 2009.\ud
\ud
Subjects\ud
150 patients with severe trauma who required ICU stay for at least 48 hours were included in the study.\ud
\ud
Intervention\ud
Patients were randomly assigned to a continuous intravenous infusion of either hydrocortisone (200 mg/day for 5 days, followed by 100 mg on day 6 and 50 mg on day 7) or placebo. The treatment was stopped if patients had an appropriate adrenal response.\ud
\ud
Outcomes\ud
Hospital-acquired pneumonia within 28 days. Secondary outcomes included the duration of mechanical ventilation, ICU length of stay, hyponatremia, and death.\ud
\ud
Results\ud
An intention-to-treat (ITT) analysis included 149 patients and the modified ITT analysis included 113 patients with corticosteroid insufficiency. In the ITT analysis, 26 of 73 patients (35.6%) treated with hydrocortisone and 39 of 76 patients (51.3%) receiving placebo developed hospital -acquired pneumonia by day 28 (hazard ratio (HR), 0.51; 95% confidence interval (CI), 0.30-0.83; P = 0.007). In the modified ITT analysis, 20 of 56 patients (35.7%) in the hydrocortisone group and 31 of 57 patients (54.4%) in the placebo group developed hospital-acquired pneumonia by day 28 (HR, 0.47; 95% CI, 0.25-0.86; P = 0.01). Mechanical ventilation-free days increased with hydrocortisone use by 4 days (95% CI, 2-7; P = 0.001) in the ITT analysis and 6 days (95% CI, 2-11; P < 0.001) in the modified ITT analysis. Hyponatremia was observed in 7 of 76 (9.2%) in the placebo group vs. none in the hydrocortisone group (absolute difference, −9%; 95% CI, −16% to −3%; P = 0.01). Four of 76 patients (5.3%) in the placebo group and 6 of 73 (8.2%) in the hydrocortisone group died (absolute difference, 3%; 95% CI, −5% to 11%; P = 0.44).\ud
\ud
Conclusions\ud
In intubated trauma patients, the use of an intravenous stress-dose of hydrocortisone, compared with placebo, resulted in a decreased risk of hospital-acquired pneumonia

Aleti, Venkata S

Yende, Sachin

Critical Care

PubMed

D-Scholarship@Pitt

Expanded abstractCitationRoquilly A, Mahe PJ, Seguin P, et al.: Hydrocortisone Th erapy for Patients with Multiple Trauma: Th e Random-ized Controlled HYPOLYTE Study. JAMA 2011, 305: 1201-1209.Clinicaltrials.gov Identiﬁ er: NCT00563303BackgroundTh e role of stress-dose hydrocortisone in the manage-ment of trauma patients is currently unknown.MethodsObjective: To test the eﬃ  cacy of hydrocortisone therapy in trauma patients.Design: Multicenter randomized, double blind, placebo-controlled study.Setting: Seven intensive care units (ICUs) in France during November 2006 to August 2009.Subjects: 150 patients with severe trauma who required ICU stay for at least 48 hours were included in the study.Intervention: Patients were randomly assigned to a continuous intravenous infusion of either hydrocortisone (200 mg/day for 5 days, followed by 100 mg on day 6 and 50 mg on day 7) or placebo. Th e treatment was stopped if patients had an appropriate adrenal response.Outcomes: Hospital-acquired pneumonia within 28 days. Secondary outcomes included the duration of mechanical ventilation, ICU length of stay, hyponatremia, and death.ResultsAn intention-to-treat (ITT) analysis included 149 patients and the modiﬁ ed ITT analysis included 113 patients with corticosteroid insuﬃ  ciency. In the ITT analysis, 26 of 73 patients (35.6%) treated with hydro-cortisone and 39 of 76 patients (51.3%) receiving placebo developed hospital-acquired pneumonia by day 28 (hazard ratio (HR), 0.51; 95% conﬁ dence interval (CI), 0.30-0.83; P = 0.007). In the modiﬁ ed ITT analysis, 20 of 56 patients (35.7%) in the hydrocortisone group and 31 of 57 patients (54.4%) in the placebo group developed hospital-acquired pneumonia by day 28 (HR, 0.47; 95% CI, 0.25-0.86; P = 0.01). Mechanical ventilation–free days increased with hydrocortisone use by 4 days (95% CI, 2-7; P = 0.001) in the ITT analysis and 6 days (95% CI, 2-11; P  <  0.001) in the modiﬁ ed ITT analysis. Hyponatremia was observed in 7 of 76 (9.2%) in the placebo group vs. none in the hydrocortisone group (absolute diﬀ erence, −9%; 95% CI, −16% to −3%; P = 0.01). Four of 76 patients (5.3%) in the placebo group and 6 of 73 (8.2%) in the hydrocortisone group died (absolute diﬀ erence, 3%; 95% CI, −5% to 11%; P = 0.44).ConclusionsIn intubated trauma patients, the use of an intravenous stress-dose of hydrocortisone, compared with placebo, resulted in a decreased risk of hospital-acquired pneumonia.CommentarySevere trauma is a leading cause of death, especially in younger adults. Patients who survive the initial trauma are at high risk for infections, which often increases subsequent morbidity and mortality. Pneumonia is a common infection, occurring in 40-60% of trauma patients. Shock and resuscitation following trauma may lead to an exaggerated immune response [1]. Th e “two hit hypothesis” states that an initial less severely injured patient may eventually develop worsening of multi-organ failure as a result of reactivation of their inﬂ ammatory response due to minor intercurrent event [2], such as an infection. Th us, preventing infection in trauma patients is important.Th e eﬀ ect of glucocorticoid therapy on susceptibility to infections is controversial. Several lines of evidence suggest that glucocorticoid therapy may reduce risk of infection. For example, higher circulating levels of pro-inﬂ ammatory cytokines, such as tumor necrosis factor (TNF) and interleukin (IL)-6, may increase risk of © 2010 BioMed Central LtdGlucocorticoid therapy for trauma – ready for prime time?Venkata S Aleti and Sachin Yende*University of Pittsburgh Department of Critical Care Medicine: Evidence-Based Medicine Journal Club, edited by Sachin YendeJ O U R N A L  C LU B  C R I T I Q U E*Correspondence: yendes@upmc.eduDepartment of Critical Care Medicine, University of Pittsburgh, 606D Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USAAleti and Yende Critical Care 2012, 16:301 http://ccforum.com/content/16/1/301© 2012 BioMed Central Ltdinfection in animal models and human studies [3,4]. Gluco corticoids inhibit nuclear factor-kB and trans crip-tion of genes that code for pro-inﬂ ammatory cytokines, includ ing TNF, IL-1, IL-6, IL-8, and interferon (IFN)-γ [5,6], and may therefore prevent infection. Th e acute pro-inﬂ ammatory response following trauma is followed by a compensatory anti-inﬂ ammatory response, where immune cells may experi ence tolerance (immuno paralysis). Although immuno paralysis may be important to dampen the deleterious eﬀ ects of the pro-inﬂ ammatory response, patients may be at higher risk for secondary infections during this phase. By reducing the early inﬂ ammatory response, gluco corticoids may reduce the magnitude of the subse quent anti-inﬂ ammatory response, thereby reduc ing risk of secondary infections. However, some studies suggest that glucocorticoid therapy could have deleter ious eﬀ ects on infection risk. For instance, the risk of secondary infections was higher in patients who received gluco corticoid therapy in the CORTICUS [7] trial. No large randomized clinical trial has examined the eﬃ  cacy of glucocorticoids to prevent infections and the current study by Roquilly et al. remains one of the largest studies to test this hypothesis.In this study the author enrolled 150 patients with an injury severity score of 15 and above and included patients with traumatic brain injury (managed at a level 1 trauma center) and randomized them to cortisol and placebo treated arms. Baseline cortisol was measured and patients who were cortisol-deﬁ cient were given steroid treatment for 1  week. Th e author determined occurrence of pneumonia within 28 days of hospitali za-tion and found that patient who received steroid treat-ment had a signiﬁ cantly lower incidence of pneumonia compared to placebo (HR, 0.51; P = 0.007).Th e results of this study are in contrast with the results of the CRASH [8] study. Th e CRASH study was a large multicenter randomized clinical trial conducted in 10,000 patients with head injury, as evidenced by Glasgow Coma Score of 14 or less, to determine whether high dose glucocorticoids improve outcomes. However, there were important diﬀ erences between the HYPOLYTE and CRASH studies (Table 1). In contrast to CRASH, which focused on traumatic head injury patients alone, HYPOLYTE enrolled a broad population of patients with trauma and included a smaller subset (44.96%) with head injury. Both dose and duration of glucocorticoid therapy were diﬀ erent. CRASH used high dose steroids, which may lead to immunosuppression. HYPOLYTE used low-moderate dose glucocorticoids, which are less likely to cause immune suppression and may be important in patients who have critical illness-related corticosteroid insuﬃ  ciency (CIRCI). Th e CRASH study treated all patients with glucocorticoid therapy, whereas the HYPOLYTE study discontinued therapy in those who did not meet criteria for relative adrenal insuﬃ  ciency. Dura-tion of therapy also diﬀ ered between these studies and shorter course of steroids can be associated with rebound inﬂ ammation. Finally, the primary endpoint in these studies was also diﬀ erent. For example, the primary end-point was all-cause mortality at 2  weeks in the CRASH study, whereas the HYPOLYTE study examined eﬀ ect of steroids on hospital-acquired pneumonia. Th e CRASH study was stopped early due to higher mortality in the steroid treated arm, whereas the current study showed no diﬀ erence in mortality between the two treat ment groups.Th is study by Roquilly et al. has several limitations. First, cortisol levels drawn prior to administering steroids may be inﬂ uenced by the prior use of etomidate for intubation, (63% of patients in this study received etomidate prior to intubation), which can cause adrenal suppression for approximately 24 hours [9,10]. Th us, the high rate of adrenal insuﬃ  ciency may be inﬂ uenced by etomidate administration. Second, it is unclear whether steroid therapy should be targeted based on presence or absence of relative adrenal insuﬃ  ciency. Although the corticotropin stimulation test is recommended to diagnose CIRCI, results of the CORTICUS trial showed no diﬀ erence in the eﬃ  cacy of glucocorticoid therapy among those with and without relative adrenal insuﬃ  -ciency. Th ird, the investigators did not assess the long-term eﬀ ects of steroid use, such as myopathy and critical illness neuropathy, a potential complication of gluco-corticoid therapy. Finally, the study did not determine mechanisms of beneﬁ cial eﬀ ects of steroids. For example, whether steroids reduced risk of infection by reducing pro-inﬂ ammatory markers or improved immune cell function is not known.RecommendationAlthough results of this study are intriguing, gluco-corticoids cannot be recommended for routine use in trauma patients. Th ese results suggest a nee d to con duct a larger trial to understand whether a reduction in infection observed in this study translates into improved mortality.Table 1. Diff erences between HYPOLYTE and CRASH studies CRASH STUDY HYPOLYTE STUDYNumber of patients 10,000 150Primary end point Mortality Pneumonia incidenceTime to administration of  < 8 hours Within 36 hours offi rst dose of steroid  trauma; 25 hours   (median)Steroid loading dose 2 gms NoneDuration of Steroids 48 hours 1 weekAleti and Yende Critical Care 2012, 16:301 http://ccforum.com/content/16/1/301Page 2 of 3AbbreviationsCI, confi dence interval; CIRCI, critical illness-related corticosteroid insuffi  ciency; HR, hazard ratio; ICU, intensive care unit; IFN, interferon; IL, interleukin; ITT, intention-to-treat; TNF, tumor necrosis factor; Competing interestsThe authors declare that they have no competing interests.Published: 20 January 2012References1. Rotstein OD: Modeling the two-hit hypothesis for evaluating strategies to prevent organ injury after shock/resuscitation. J Trauma 2003, 54:S203-S206.2. Saadia R, Schein M: Multiple organ failure. How valid is the “two hit” model? J Accid Emerg Med 1999, 16:163-166.3. Hinojosa E, Boyd AR, Orihuela CJ: Age-associated infl ammation and toll-like receptor dysfunction prime the lungs for pneumococcal pneumonia. J Infect Dis 2009, 200:546-554.4. Yende S, Tuomanen EI, Wunderink R, et al.: Preinfection systemic infl ammatory markers and risk of hospitalization due to pneumonia. Am J Respir Crit Care Med 2005, 172:1440-1446.5. Rhen T, Cidlowski JA: Antiinfl ammatory action of glucocorticoids – new mechanisms for old drugs. N Engl J Med 2005, 353:1711-1723.6. Confalonieri M, Urbino R, Potena A, et al.: Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Am J Respir Crit Care Med 2005, 171:242-248.7. Sprung CL, Annane D, Keh D, et al.: Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008, 358:111-124.8. Roberts I, Yates D, Sandercock P, et al.: Eff ect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically signifi cant head injury (MRC CRASH trial): randomised placebo-controlled trial. Lancet 2004, 364:1321-1328.9. de Jong FH, Mallios C, Jansen C, Scheck PA, Lamberts SW: Etomidate suppresses adrenocortical function by inhibition of 11 beta-hydroxylation. J Clin Endocrinol Metab 1984, 59:1143-1147.10. Marik PE, Pastores SM, Annane D, et al.: Recommendations for the diagnosis and management of corticosteroid insuffi  ciency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med 2008, 36:1937-1949.doi:10.1186/cc10596Cite this article as: Aleti VS, Yende S: Glucocorticoid therapy for trauma – ready for prime time? Critical Care 2012, 16:301.Aleti and Yende Critical Care 2012, 16:301 http://ccforum.com/content/16/1/301Page 3 of 3

Glucocorticoid therapy for trauma--ready for prime time?

Venkata S Aleti

Sachin Yende

Crossref

Glucocorticoid therapy for trauma - ready for prime time?

Name not available

Cidlowski JA: Antiinfl ammatory action of glucocorticoids – new mechanisms for old drugs.

CJ: Age-associated infl ammation and toll-like receptor dysfunction prime the lungs for pneumococcal pneumonia. J Dis

Eff ect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically signifi cant head injury (MRC CRASH trial): randomised placebo-controlled trial. Lancet

Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study.

Hydrocortisone therapy for patients with septic shock.

Lamberts SW: Etomidate suppresses adrenocortical function by inhibition of 11 beta-hydroxylation. J Endocrinol Metab

Modeling the two-hit hypothesis for evaluating strategies to prevent organ injury after shock/resuscitation.

Multiple organ failure. How valid is the “two hit” model? J Emerg Med

Preinfection systemic infl ammatory markers and risk of hospitalization due to pneumonia. Am J Respir Crit Care Med

Recommendations for the diagnosis and management of corticosteroid insuffi ciency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med

Glucocorticoid therapy for trauma--ready for prime time?

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