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Update in intensive care medicine: Studies that challenged our practice in the last 5 years

Cleveland Clinic Journal of Medicine. 2011 October;78(10):665-674 | 10.3949/ccjm.78a.10188
October 1, 2011|Cleveland Clinic Journal of Medicine
Enrique Diaz-Guzman, MD;Juan Sanchez, MD;Alejandro C. Arroliga, MD, FCCP
Author and Disclosure Information

Enrique Diaz-Guzman, MD
Assistant Professor of Medicine, Chief, Pulmonary Section, Lexington Veterans Affairs Medical Center, Division of Pulmonary & Critical Care Medicine, University of Kentucky, Lexington

Juan Sanchez, MD
Assistant Professor of Medicine, Division of Pulmonary & Critical Care Medicine, Scott & White Health Center, and Texas A&M College of Medicine, Temple, TX

Alejandro C. Arroliga, MD, FCCP
Chairman and Professor, Dr. A. Ford Wolf and Brooksie Nell Boyd Wolf Centennial Chair of Medicine, Department of Internal Medicine, Scott & White Health Center, and Texas A&M Health Science Center College of Medicine, Temple, TX

Address: Enrique Diaz-Guzman, MD, University of Kentucky, L543 Kentucky Clinic, 740 S. Limestone Street, Lexington, KY 40536-0284; e-mail enriquedgz@uky.edu

ABSTRACTDuring the last 5 years, new randomized trials in critically ill patients have challenged a number of traditional treatment strategies in intensive care. The authors review eight studies that helped change their medical practices.

KEY POINTS

  • In patients with acute respiratory distress syndrome (ARDS), fluid restriction is associated with better outcomes. A pulmonary arterial catheter is not indicated in the routine management of ARDS. Corticosteroid use can result in improved oxygenation but may be associated with worse outcomes if treatment is started late, ie, more than 14 days after the onset of the disease.
  • Intensive insulin therapy is associated with hypoglycemia and may be associated with complications in medical patients.
  • In patients with septic shock, corticosteroid therapy is associated with faster shock reversal, but its effects on mortality rates remain controversial. Vasopressin improves hemodynamic variables but is not associated with a lower mortality rate.
  • Daily interruption of sedation and early awakening of mechanically ventilated patients result in better outcomes.
  • Compared with norepinephrine, dopamine is associated with more cardiac adverse events in patients with shock.

CORTICOSTEROID THERAPY IN SEPTIC SHOCK

Key points

  • Corticosteroid therapy improves hemodynamic outcomes in patients with severe septic shock.
  • Although meta-analyses suggest the mortality rate is lower with corticosteroid therapy, there is not enough evidence from randomized controlled trials to prove that the use of low-dose corticosteroids lowers the mortality rate in patients with septic shock.
  • The corticotropin (ACTH) stimulation test should not be used to determine the need for corticosteroids in patients with septic shock.

Background

A previous multicenter study,18 performed in France, found that the use of corticosteroids in patients with septic shock resulted in lower rates of death at 28 days, in the ICU, and in the hospital and a shorter time to vasopressor withdrawal. Nevertheless, the beneficial effects were not observed in patients with adequate adrenal reserve (based on an ACTH stimulation test).

This study was criticized because of a high mortality rate in the placebo group.

The CORTICUS study

SPRUNG CL, ANNANE D, KEH D, ET AL; CORTICUS STUDY GROUP. HYDROCORTISONE THERAPY FOR PATIENTS WITH SEPTIC SHOCK. N ENGL J MED 2008; 358:111–124.

The Corticosteroid Therapy of Septic Shock (CORTICUS) study was a multicenter trial that randomly assigned 499 patients with septic shock to receive hydrocortisone (50 mg intravenously every 6 hours for 5 days, followed by a 6-day taper period) or placebo.19

Patients were eligible to be enrolled within 72 hours of onset of shock. Similar to previous studies, the CORTICUS trial classified patients on the basis of an ACTH stimulation test as having inadequate adrenal reserve (a cortisol increase of ≤ 9 μg/dL) or adequate adrenal reserve (a cortisol increase of > 9 μg/dL).

Faster reversal of shock with steroids

At baseline, the mean Simplified Acute Physiologic Score II (SAPS II) was 49 (the range of possible scores is 0 to 163; the higher the score the worse the organ dysfunction).

Hydrocortisone use resulted in a shorter duration of vasopressor use and a faster reversal of shock (3.3 days vs 5.8 days, P < .001).

This association was the same when patients were divided according to response to ACTH stimulation test. Time to reversal of shock in responders:

  • 2.8 days with hydrocortisone
  • 5.8 days with placebo (P < .001).

Time to reversal of shock in nonresponders:

  • 3.9 days with hydrocortisone
  • 6.0 days with placebo (P = .06).

Nevertheless, the treatment did not reduce the mortality rate at 28 days overall (34.3% vs 31.5% P = .51), or in the subgroups based on response to ACTH, or at any other time point. A post hoc analysis suggested that patients who had a systolic blood pressure of less than 90 mm Hg within 30 minutes of enrollment had a greater benefit in terms of mortality rate, but the effect was not statistically significant: the absolute difference was −11.2% (P = 0.28). Similarly, post hoc analyses also revealed a higher rate of death at 28 days in patients who received etomidate (Amidate) before randomization in both groups (P = .03).

Importantly, patients who received corticosteroids had a higher incidence of superinfections, including new episodes of sepsis or septic shock, with a combined odds ratio of 1.37 (95% CI 1.05–1.79).

Length of stay in the hospital or in the ICU was similar in patients who received corticosteroids and in those who received placebo. The ICU length of stay was 19 ± 31 days with hydrocortisone vs 18 ± 17 days with placebo (P = .51).

Comments

The CORTICUS trial showed that low-dose corticosteroid therapy results in faster reversal of shock in patients with severe septic shock. The hemodynamic benefits are present in all patients regardless of response to the ACTH stimulation test.

Nevertheless, contrary to previous findings,18 corticosteroid use was not associated with an improvement in mortality rates. Important differences exist between these two studies:

  • The mortality rates in the placebo groups were significantly different (> 50% in the French study vs 30% in CORTICUS).
  • The SAPS II scores were different in these two trials (55 vs 49), suggesting a greater severity of illness in the French study.
  • The criteria for enrollment were different: the French study included patients who had a systolic blood pressure lower than 90 mm Hg for more than 1 hour despite fluid administration and vasopressor use, whereas the CORTICUS trial included patients who had a systolic blood pressure lower than 90 mm Hg for more than 1 hour despite fluid administration or vasopressor use.
  • The time of enrollment was different: patients were enrolled much faster in the French study (within 8 hours) than in the CORTICUS trial (within 72 hours).

A recent meta-analysis of 17 randomized trials (including the CORTICUS study), found that, compared with those who received placebo, patients who received corticosteroids had a small reduction in the 28-day mortality rate (HR 0.84, 95% CI 0.71–1.00, P < .05).20 Of note, this meta-analysis has been criticized for possible publication bias and also for a large degree of heterogeneity in its results.21

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