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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Article Reviewed:

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Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock

Annane D, Sebille V, Charpentier C, Bollaert PE, et al.

JAMA. 2002;288(7):862-71. [abstract; full-text for subscribers]

Reviewed by Pradip Kamat, MD, James Fortenberry, MD, Children's Healthcare of Atlanta at Egleston, Emory University School of Medicine, Atlanta, GA

Review posted November 6, 2002

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I. What is being studied?:

The study objective:

To assess whether low doses of corticosteroids improve 28-day survival in patients with septic shock and relative adrenal insufficiency.

The study design:

Placebo-controlled, randomized, double-blinded, parallel-group trial.

The patients included:

All patients 18 years or older and hospitalized in participating ICUs were prospectively enrolled in the study if they met the following criteria: (1) documented site (or at least strong suspicion) of infection, as evidenced by one or more of the following: presence of polymorphs in a normally sterile body fluid (except blood), positive culture or Gram stain of a normally sterile body fluid, clinical focus of infection (e.g., fecal peritonitis), wound with purulent discharge, pneumonia or other clinical evidence of systemic infection (e.g., purpura fulminans); (2) temperature higher than 38.3°C or lower than 35.6°C; (3) heart rate greater than 90 beats per minute; (4) systolic arterial pressure lower than 90 mm Hg for at least 1 hour despite adequate fluid replacement and more than 5 mcg/kg of body weight of dopamine or current treatment with epinephrine or norepinephrine; (5) urinary output of less than 0.5 ml/kg of body weight for at least 1 hour or ratio of arterial oxygen tension to the fraction of inspired oxygen (PaO2/FIO2) of less than 280 mm Hg; (6) arterial lactate levels higher than 2 mmol/L;(requirement dropped after protocol revision after one year) and (7) need for mechanical ventilation. A short corticotropin test had to be performed before randomization. Patients had to be randomized within 3 hours of the onset of shock (liberalized to 8 hours one year into the study).

The patients excluded:

Patients were excluded if they were pregnant or had evidence for acute myocardial infarction or pulmonary embolism, advanced form of cancer or acquired immunodeficiency syndrome (AIDS) infection, and contraindication or formal indication for corticosteroids. They also excluded patients who received etomidate during the 6 hours preceding randomization because it is a selective inhibitor of the 11-hydroxylase and therefore could interfere with cortisol response to corticotropin.

The interventions compared:

Patients were randomly assigned to receive either hydrocortisone (50-mg intravenous bolus every 6 hours) and fludrocortisone (50-mcg tablet once daily) or matching placebos for 7 days.

The short corticotropin test was performed using a 250-mcg intravenous bolus of tetracosactrin. Blood samples were taken immediately before the test and 30 and 60 minutes after the test. Cortisol response was defined as the difference between the highest of the concentrations taken after the test and those taken before the test. Relative adrenal insufficiency (i.e., nonresponders) was defined by a response of 9 mcg/dL or less.

The outcomes evaluated:

The main end point was the 28-day survival distribution from randomization in nonresponders to the short corticotropin test.

Secondary end points were 28-day survival distributions from randomization in responders to the short corticotropin test and in all patients; 28-day, ICU, hospital, and 1-year mortality rates; and time to vasopressor therapy withdrawal during the 28 days from randomization in the 2 subsets of patients and in all patients.

Adverse events were carefully monitored and classified as being possibly related to corticosteroids (superinfection, gastrointestinal bleeding, psychiatric disorders), possibly related to vasopressors (life-threatening arrhythmia, myocardial infarction, limb or cerebral ischemia), related to ICU invasive procedures, and not related to 1 of the 3 previous categories.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes, it was done by a computer - generated random number table, centrally performed, stratified by center in blocks of four.

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

Was followup complete?

Yes. Three hundred patients (placebo, 149; corticosteroids, 151) were included in the study. Only one patient was excluded from the final analysis in the corticosteroid group because of consent withdrawal.

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

Yes. There were no crossovers.

Secondary questions:

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

Yes. All patients, medical and nursing staff, and pharmacists remained blinded throughout the study period.

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

Yes. The 2 groups were balanced with respect to general characteristics (Table 1, page 864) and severity of illness (Table 2, page 865).

The severity of illness was assessed by vital signs, Simplified Acute Physiology Score (SAPS II) and Logistic Organ Dysfunction (LOD) score.

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

It appears that the two groups were treated equally. Appropriate antibiotic therapy, based on site of infection and available cultures, was promptly started and continued for at least 7 days in most cases (i.e. 95% in the placebo group, 91% in the corticosteroid group). From table 2, it appears that there were no major differences between the 2 groups with respect to fluid loading, vasopressor use and ventilatory support.

III. What were the results?

1. How large was the treatment effect?

Primary outcomes:

a) Mortality rates
Nonresponders: At day 28, there were 73 deaths (63%) in the placebo group and 60 deaths (53%) in the corticosteroid group.

Responders: At day 28, there were 18 deaths (53%) in the placebo group and 22 deaths (61%) in the corticosteroid group.

All patients: At day 28, there were 91 deaths (61%) in the placebo group and 82 deaths (55%) in the corticosteroid group.

The adjusted odds ratios with the 95% Confidence intervals are shown in the table below.

Mortality rates

28 day mortality	Adjusted Odds ratio	95% Confidence interval
Nonresponders	0.54	0.31- 0.97
Responders	0.97	0.32- 2.97
All patients	0.65	0.39- 1.07

Based on this data, there was a statistically significant reduction in mortality in nonresponders receiving corticosteroids. The number of patients needed to treat to save one additional life at day 28 was 7 (95% CI, 4-49).

A similar significant difference was observed in nonresponders at the end of hospital stay (adjusted OR = 0.53, 95% CI = 0.29-0.96%).

b) Time-to-Vasopressor therapy withdrawal
In nonresponders, at day 28, vasopressor therapy was withdrawn in 40% of patients in the placebo group and 57% in the corticosteroid group. The Hazard ratio (HR) for risk of continuing vasopressor therapy using a Cox model was 1.91 (95% CI, 1.29-2.84), and thus was clinically significant. In all patients combined, HR was 1.54 (95% CI, 1.10-2.16), which means, that the risk of continuing vasopressors was 1.5 times higher in the placebo group when compared to the steroid group. Among responders and for all patients, time to vasopressor therapy withdrawal was not clinically significant.

c) Adverse Events due to steroids
The OR for adverse events possibly related to steroids is 0.95 (95% CI = 0.53-1.71), and thus was not significant.

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

The 95% confidence intervals around the primary treatment effect - reduction in 28 day mortality in nonresponders - are rather wide: the adjusted OR is 0.31 to 0.97. Although the upper limit is less than one, it is very close to one, suggesting the true effect might be rather small. The study showed that a 7-day treatment with low doses of hydrocortisone and fludricortisone significantly reduced the risk of death in patients with septic shock and relative adrenal insufficiency in nonresponders without increasing adverse effects, but tighter confidence intervals would lend more strength to this conclusion.

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

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

Possibly. This study excluded patients less than 18 years of age. The population studied had severe septic shock, as evidenced by hypotension unresponsive both to fluid resuscitation and to low dose dopamine. Also all patients required mechanical ventilation and had inadequate urine output, lactic acidosis, or acute lung injury at study entry, indicating significant organ dysfunction. The extent to which the attributable benefit is linked to severity of illness, and the precise dose, duration and composition of steroid (glucocorticoid to mineralocorticoid ratio) needs to be defined, before this study can be applied to pediatrics.

Recent guidelines (1) recommend that hydrocortisone (not methylprednisolone) therapy should be reserved for use in children with catecholamine resistance and suspected or proven adrenal insufficiency. Patients at risk include children with purpura fulminans and associated Waterhouse-Friedrichson syndrome, children who have previously received steroid therapies for chronic illness, and children with pituitary or adrenal abnormalities.

The use of hydrocortisone in dengue shock syndrome published by Min M et al. (2) is the only randomized controlled trial that has shown a reduction in mortality in pediatric patients with steroids. More pediatric studies are required before recommending the use of steroids in pediatric septic shock.

2. Were all clinically important outcomes considered?

Yes, the authors looked at mortality, time-to-vasopressor withdrawal, as well as adverse events related to the use of steroids.

The costs involved in the corticotropin stimulation test and sampling of cortisol levels were not mentioned in the study.

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

Difficult to say. If more studies (especially pediatric studies) show a reduction in mortality from the use of low dose steroids in septic shock, then their use could be justified. It would be useful to determine the prevalence of nonresponders among septic shock patients in our PICUs. Since presumably only nonresponders benefit from steroids, either we need a rapid way to detect these patients or if they are very prevalent, then it might make sense to treat everyone.

The adverse events related to low dose steroids are minimal and can be controlled (for eg.insulin for hyperglycemia, H2 blockers for gastric ulcers etc).

References

1. Carcillo JA, Fields AI. Clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock. Crit Care Med. 2002;30(6):1365-78. [abstract]
2. Min M, U T, Aye M, Shwe TN, Swe T. Hydrocortisone in the management of dengue shock syndrome. Southeast Asian J Trop Med Public Health. 1975;6(4):573-9. [abstract]

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