Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Reversal of late septic shock with supraphysiologic doses of hydrocortisone.

Bollaert PE, Charpentier C, Levy B, Debouverie M, Audibert G, Larcan A.

Crit Care Med 1998;26:645-650. [abstract]

Reviewed by Al Torres, MD, MS, University of Illinois College of Medicine at Peoria

Review posted June 27, 1999

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I. What is being studied?:

The study objective:

To examine whether "late therapy with low doses of hydrocortisone could be beneficial in patients with septic shock needing catecholamine therapy."

The study design:

A randomized, double blind controlled trial at 2 sites

The patients included:

41 adult patients with septic shock - as defined the ACCP/SCCM Consensus statement (1) - requiring catecholamines > 48 hours

The patients excluded:

Patients with a fatal underlying disease within a week of ICU admission or for whom withholding therapy was considered were excluded. Patients with a recent history of gastrointestinal bleeding or ulcer or corticosteroid treatment were also excluded. None of the patients had an absolute adrenocortical deficiency (postcorticotropin plasma concentration < 18 mcg/dl) noted after a single stimulation test and were, therefore, enrolled.

The interventions compared:

Intravenous hydrocortisone (100 mg every 8 hours for > or = to 5 days) was given to the 22 patients in the treatment group. An identical volume of placebo was given to the 19 patients in the control group.

The outcomes evaluated:

The primary outcome measure was shock reversal (a stable systolic BP of > 90 mm Hg for > or = 24 hours without volume expansion or catecholamines and a blood lactate concentration of < or = 2 mmol/L) at 7 and 28 days. Secondary endpoints included 28-day all-cause mortality, hemodynamic changes during therapy, or evidence of gastrointestinal bleeding or nosocomial infections.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. Randomization was by computer-generated list in blocks of 8 and stratified by site by the hospital pharmacists.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

Yes. All patients enrolled were accounted for through the 28-day secondary endpoint.

Were patients analyzed in the groups to which they were randomized?

Yes. 42 patients were enrolled, and 1 died before randomization. The remaining 41 were included. One hydrocortisone-treated and 4 placebo-treated patients died prior to completing the 5 days of therapy but were included in the analysis.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

Yes. There was adequate concealment of treatment vs. placebo; all the treatment units, provided daily in coded syringes, were identical in appearance.

4. Were the groups similar at the start of the trial?

Yes. Differences in age, gender ratio, surgical vs. medical admission, Simplified Applied Physiology Score, underlying disease and number of organ failures were not significantly different. The only hemodynamic variable on inclusion that was significantly different between the two groups was the placebo group had a higher mean oxygen delivery (DO2) than the treatment group (618 +/- 279 vs. 543 +/- 193 ml/min/m2, p < 0.01). One difference that was not statistically significant which may have still affected the results (although this was addressed in their analysis) was the number of "nonresponders" to the corticotropin test in the placebo group was twice as many (8 vs. 4) as in the treatment group. Some studies suggest a poor response to a corticotropin test is a predictor of mortality in adult sepsis (2,3).

5. Aside from the experimental intervention, were the groups treated equally?

Unknown. Other clinical interventions (hemodynamic goals for the first 48 hours, total amount of total fluid resuscitation, crystalloid vs. colloid administration) were not described.

III. What were the results?

1. How large was the treatment effect?

The seven-day reversal of shock (primary endpoint) was achieved in 15/22 (68%) of the treated patients vs. 4/19 (21%) of the control patients, resulting in an absolute risk difference of 47%. 28-day reversal of shock was also higher in the treatment group, regardless of site, number of failing organs, or response to the corticotropin test. Overall 28-day mortality was 32% (7/22) in the treated patients and 63% (12/19) in the control patients, with an absolute risk difference of 31%.

The authors reported reversal of shock as a strong predictor of 28-day survival regardless of group assignment, since 16/19 (84%) of such patients survived and 18/22 (84%) of those patients whose shock was not reversed within 7 days died. They also reported a significant decrease in the cumulated amount of catecholamines perfused and the median amount of colloid infused in the treatment group compared to the control group.

2. How precise was the estimate of the treatment effect?

Not very precise based on the width of the confidence intervals (CI) reported. The authors reported the 95% CI for the absolute difference in 7-day reversal of shock between the 2 groups as 17 to 77%.

The calculated number needed to treat (NNT) based on the authors' 7-day reversal of shock difference of 47% between groups was 2 (95% CI, 1 to 5).

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

No. The study was performed in adults only.

2. Were all clinically important outcomes considered?

Almost. Besides evaluating outcomes, the authors compared the short-term safety of administering corticosteroids in terms of infection and gastrointestinal bleeding. No difference was noted between the two groups. The authors did not address the potential cost savings of hydrocortisone administration if in fact it can reduce the total cumulative dose of vasoactive substances and colloid administered.

3. Are the likely treatment benefits worth the potential harms and costs?

If hydrocortisone does not increase gastrointestinal bleeding and infections, and the benefits are confirmed in multicenter studies, the cost of the medicine is quite low. The upregulation of beta receptors facilitating rapid weaning and discontinuation of vasoactive medications after the initial 48 hours could potentially reduce the length of ICU stay and, therefore, reduce the risk of potential complications including nosocomial infection, inadvertent extubation, drug administration error, etc.

Two meta-analyses examining the effect of steroids in patients with sepsis and septic shock showed a trend towards increased mortality. (4, 5) This is the only study since Schumer (6) to show a significant benefit of steroids. It is possible that these investigators have actually identified the right dose and the right population where steroids make a difference. The optimal dosing, timing, and administration form in septic children needs investigation prior to conducting a randomized controlled trial in this population.

References

1. American College of Chest Physicians/Society of Critical Care Medicine Consensus Committee: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992; 20:864-874. [abstract]
2. Rothwell PM, Udwala ZF, Lawler PG. Cortisol response to corticotropin and survival in septic shock. Lancet 1991;337:582-583. [abstract]
3. Moran A, Chapman MJ, O'Fathartaigh MS, et al. Hypocortisolaemia and adrenocortical responsiveness and onset of septic shock. Intensive Care Med 1994;20:489-495.
4. Cronin L, Cook DJ, Carlet J, Heyland DK, King D, Lansang MA, Fisher CJ Jr. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit Care Med 1995; 23: 1430-1439. [abstract]
5. Steroid controversy in sepsis and septic shock: A meta-analysis. Lefering R, Neugebauer E. Crit Care Med 1995; 23: 1294-1303. [abstract]
6. Schumer W. Steroids in the treatment of clinical septic shock. Ann Surg 1976; 184:333-339. [abstract]

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