icu

A Look at Evidence-Based Therapies in Critical Care

R. Phillip Dellinger, MD,[1] of Cooper Health Systems, Camden, New Jersey, presented a discussion on several recent evidence-based therapies in critical care medicine.
Early Goal-Directed Therapy for Septic Shock
Early goal-directed therapy for septic shock was recently shown to significantly decrease mortality in an 850-bed academic tertiary care hospital.[2] Patients were randomized to receive either standard therapy or early goal-directed therapy before intensive care unit (ICU) transfer and admission. Standard therapy included maintaining a central venous pressure above 8 to 12 mm Hg, the administration of vasopressors for systolic blood pressure less than 90 mm Hg, urine output higher than 0.5 mL/kg/hour, and maintenance of a mean arterial pressure higher than 65 mm Hg. Goal-directed therapy included the standard approach plus the administration of blood transfusion up to a hematocrit of 30% and the addition of dobutamine when the mixed venous saturation was below 70%. Of the 263 enrolled patients, 130 were randomly assigned to early goal-directed therapy and 133 to standard therapy. At the end of the study, there were significant differences between the 2 groups. The control group received significantly fewer blood transfusions, blood, and dobutamine. The early goal-directed therapy group had significantly less inhospital, 28-day, and 60-day mortality. (Inhospital mortality was 30.5% with early goal-directed therapy, as compared with 46.5% in the standard group therapy [P = .009].) This study underlines the importance of early aggressive therapy for septic patients. Although early goal-directed therapy accounted for only a brief period in comparison with the overall hospital stay, it had significant short-term and long-term benefits.
Prone Positioning in ARDS
Prone positioning was shown to improve oxygenation in patients with acute respiratory distress syndrome (ARDS).[3] In a multicenter, randomized trial, conventional treatment was compared with prone positioning for 6 or more hours daily for 10 days. A total of 304 patients were enrolled, 152 in each group. Although placing patients with acute respiratory failure in a prone position improved their oxygenation, it did not improve their survival. Reasons for this could be that patients were not placed in the prone position for adequate time (approximately 7 hours per day) and that patients with more severe ARDS, who would most likely benefit to a higher degree, were not targeted.
The PROWESS Trial
The well-known PROWESS trial[4] has demonstrated an absolute mortality reduction of 6.1% (P = .005) in patients with severe sepsis with the use of drotrecogin alfa (activated). It was a randomized, double-blind, placebo-controlled, multicenter trial. Patients with Acute Physiology and Chronic Health Evaluation (APACHE) II scores greater than 25 benefited the most. Besides decreasing mortality, drotrecogin alfa (activated) decreased pressor requirements and improved oxygenation in high-risk patients. So far, 2786 patients have been treated with drotrecogin alfa (activated) and the overall mortality is 25.3% compared with 30.8% with placebo. The major concern is bleeding: there were 79 cases of serious bleeding and 7 cases of fatal intracranial bleeding.
The cost per life-year gained by treating all patients with drotrecogin alfa (activated) was $27,936. What is important is the number needed to treat (NNT) to save 1 life for drotrecogin alfa (activated) compared with other landmark studies. For drotrecogin alfa (activated), NNT is 16 overall and 8 for the third/fourth APACHE II quartiles as opposed to 19 for streptokinase and aspirin (ISIS-2 trial), 50 for clopidogrel (CURE trial), and 100 for tissue plasminogen activator vs streptokinase (GUSTO trial). Regarding the complications associated with the use of drotrecogin alfa (activated), namely bleeding, it is 8 times more likely for a life to be saved than for a serious bleeding event to occur.
Intensive Insulin Therapy in the ICU
Intensive insulin therapy has also emerged as a significant contributor to decreased mortality in the ICU. The study by van den Berghe and colleagues[5] showed that intensive insulin therapy reduced overall inhospital mortality by 34%, bloodstream infections by 46%, acute renal failure requiring dialysis or hemofiltration by 41%, the median number of blood transfusions by 50%, and critical-illness polyneuropathy by 44%. A simple and relatively easy to apply method may yet have a substantial impact on mortality and morbidity. Hypoglycemia and increased staff workload are the 2 major drawbacks.
Daily Hemodialysis for Acute Renal Failure
Acute renal failure is a common problem in the ICU and carries significant mortality. There are good data, derived from the study by Schiffl and coworkers,[6] that show that daily hemodialysis (as compared with traditional every other day or intermittent dialysis) significantly reduces mortality (28% for daily dialysis versus 46% for alternate-day dialysis with P = 0.01). Of note, increased morbidity secondary to hypotension was not observed.
Steroid Use in the ICU
Steroids are back in vogue. After having been extensively used for many years in the ICU as a panacea, they were subsequently banned because several trials showed no benefit and often harm. The study by Annane and associates[7] was the first placebo-controlled, randomized, double-blind, multicenter trial that demonstrated a decrease in mortality with the use of steroids. This study was preceded by a study showing that a short corticotropin stimulation test had good prognostic value and could identify septic patients at high risk for death.[8] These were the patients with a blunted cortisol response, thus considered to have relative adrenal insufficiency. Following these data, low-dose hydrocortisone (50-mg intravenous bolus every 6 hours) and fludrocortisone (50-mcg tablet once daily) were administered for 7 days to patients in septic shock. The patients were classified as responders or nonresponders depending on their ability to mount a cortisol response after a short corticotropin test. The study targeted 28-day mortality. There were significant differences between the 2 groups. In nonresponders, there were 73 deaths (63%) in the placebo group and 60 deaths (53%) in the corticosteroid group (hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.47-0.95; P = .02). Vasopressor therapy was withdrawn within 28 days in 46 patients (40%) in the placebo group and in 65 patients (57%) in the corticosteroid group (HR, 1.91; 95% CI, 1.29-2.84; P = .001). Overall, there was a 10% absolute reduction in risk in the target population. For every 7 patients treated, 1 additional life could be saved at day 28. No significant beneficial effect was seen in responders. This study raises questions regarding its applicability. It appears prudent to administer hydrocortisone and fludrocortisone in septic shock and to subsequently discontinue treatment if the short corticotropin stimulation test does not demonstrate adrenal insufficiency. As nonresponders comprised the minority of the patients (one third) and there were no significant adverse results related to therapy, it would be probably better to err toward administering replacement therapy when results are inconclusive or when the test is not available. Dr. Dellinger concluded by presenting some of the NNTs derived from the recent sepsis trials (see Figure).

Intervention	NNT
Early goal-directed therapy	6-8
Drotrecogin alfa (activated)	16 (whole trial)
	8 (APACHE II > 25)
Intensive insulin therapy	29
Low-dose steroids for nonresponders to ACTH	7
Daily hemodialysis	5.5

Figure. Number needed to treat (NNT) to save 1 life.