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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Fluconazole improves survival in septic shock: A randomized double-blind prospective study.

Jacobs S, Price Evans DA, Tariq M, Al Omar NF.

Crit Care Med. 2003 Jul;31(7):1938-46. [abstract]

Reviewed by Peter Meaney MD, Children's Hospital of Philadelphia

Review posted December 15, 2003

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I. What is being studied?:

The study objective:

To demonstrate whether fluconazole reduces multiple organ failure and 30 day mortality in early septic shock

The study design:

Prospective randomized double blind study

The patients included:

71 general adult intensive care patients: All patients admitted to the ICU and diagnosed to be in early septic shock (within 24 hrs of onset) from either intra-abdominal sepsis or nosocomial pneumonia. Criteria established by the American Society of Chest Physicians/Critical Care Society Consensus Conference were used for the diagnosis of septic shock. Nosocomial pneumonia was defined by means of a clinical pulmonary infection score of 6 or greater was indicative of pneumonia and quantification (greater or equal to 10³ CFU) of a known pathogen cultured from the lower respiratory tract. Only index (first) cases were considered for study.

The patients excluded:

Pregnant women; patients aged < 16 yrs; patients with cirrhosis of the liver, underlying malignancy, or neurologic failure (Glasgow Coma Scale score < 6); or any patient considered as having a hopeless prognosis, i.e., any patient unlikely to survive 30 days.

The interventions compared:

200 mg of fluconazole daily in 100 ml of isotonic saline over 1 hr by intravenous infusion (test group), or 100 ml of isotonic saline alone by intravenous infusion over 1 hr (placebo group) for the duration of their septic shock.

The outcomes evaluated:

1. 30 day survival
2. Number of organ failures

Note: length of stay for both ICU and total hospital were commented on but not analyzed in depth. They did not perform subgroup analysis on the LOS compared with treatment intervention.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes, the patients were randomized by a closed envelope system.

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

Was followup complete?

Yes, all 71 patients had complete follow up at 30 days. This represented only 5% of their ICU patient population and represented not a total percentage of their population with sepsis, but rather a subgroup in which a causative mechanism could objectively be measured.

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

Yes, all patients were analyzed in the groups to which they were randomized. There were no crossovers.

Secondary questions:

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

Yes, this was a double blind trial

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

In many aspects the groups were similar. The groups were balanced in incidence of chronic renal, pulmonary, cardiovascular and hepatic diseases, although severity was not discussed. There was no significant difference in creatinine, pressure adjusted heart rate, platelet number, white blood count, INR. In addition, the APACHE II and MODS 1 scores had no significant difference of mean scores. What was interesting was that the placebo groups had both a lower PaO2/FiO2 ratio (157.2 vs 203.2; the p value was reported as 0.023 with a footnote that this was not significant after Bonferoni correction for multiple comparisons) as well as an apparently higher incidence of chronic immunology conditions, especially in the intra-abdominal sepsis group (8 vs 4); however, this was not a statistically significant difference. Certainly these two factors represent a potential confounding bias. Due to the small numbers in the trial, the high degree of immune conditions in the abdominal placebo group significantly might have affected the validity of the trial.

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

They attempted to maintain uniform treatment with all receiving PA catheters, criteria for titration of norepinephrine, standardization of antibiotic regimen, monitoring for secondary infection, avoidance of both non-steroidal and steroid medications. In addition glucose was controlled equally in both groups. They did not mention standardization of mechanical ventilation.

III. What were the results?

1. How large was the treatment effect?

Overall, the Relative Risk ratio (RR) for death was 0.43 (95% CI 0.22-0.86).

The authors also performed subgroup analysis of patients with intra-abdominal sepsis and pneumonia for all of their comparisons. There was no difference in the pneumonia group in survival, RR for death 0.71 (95% CI 0.32-1.55). There was a difference in the intra-abdominal sepsis group. The RR for death 0.21 (95% CI 0.06-0.80).

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

The estimate of the treatment effect is not very precise as seen by the large CI of the RR of death (0.22-0.86). For patients treated with fluconazole, the overall risk of dying was 40% that of controls, with the range being as low as 20% to as high as 80% the rate of the control group. The width of the confidence intervals indicate the small number for patients in this trial, but as they do not cross 1 and thus are significant. The number needed to treat (NNT) to prevent one death is 1/RD (risk difference or absolute risk reduction), in this case 1/32%, or 3 patients. This study indicates that fluconazole would be a very effective strategy for adults with septic shock.

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

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

These were adult patients with nosocomial pneumonia or intra-abdominal sepsis in an ICU in Riyadh Armed Forces Hospital, Riyadh, Saudi Arabia. The individual causes of infection were for the most part similar to pediatric patient's with intra-abdominal sepsis and nosocomial pneumonia, and these two organ systems make up the predominant suspected initial entry. If this study was valid, I believe that it would be appropriate to believe that children would have a similar improvement in survival rates. As the overall mortality rate for children with sepsis is lower, the NNT would be expected to be much greater. I do not believe that this study provides the necessary evidence to begin treating pediatric patients with fluconazole.

2. Were all clinically important outcomes considered?

Based on the hypothesis that fluconazole improves survival based on mediation of the immune system, patients should have been stratified prior to randomization and/or analysis to control for bias. It was unclear what the specific definitions of organ failure were in this article. There were no clinically significant fungal infections reported.

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

I do not think that this study should make fluconazole standard therapy in pediatric septic shock. Immune modulation in treatment of both ARDS and septic shock has been disappointing to date. Previously, ketoconazole had shown promising results in the prevention and treatment of ARDS in small trials (1-4). Subsequently however, the ARDS network demonstrated in a larger, multicenter trial a lack of treatment benefit (5).

Having a small number of patients increases the chances of an unequal randomization and there appears to be what may be important differences (in immunologic conditions) between the groups. Because of the strict criteria of documenting a specific microbe as the source of sepsis, they were only able to accrue 71 patients during the 2 year study period. I believe that the results are significant enough to warrant further evaluation of fluconazole in the septic population. If this study's results can be corroborated, the moderate cost and minimal side effects of fluconazole would be far outweighed by its benefit in survival and reduction in organ failure. The benefit of fluconazole over ketoconazole in its ability to be given intravenously would be significant in a treatment group where gut ischemia is a valid concern.

References

1. Williams JG, Maier RV. Ketoconazole inhibits alveolar macrophage production of inflammatory mediators involved in acute lung injury (adult respiratory distress syndrome).Surgery 1992 Aug;112(2):270-7 [abstract]
2. Slotman GJ, Burchard KW, D'Arezzo A; Gann DS Ketoconazole prevents acute respiratory failure in critically ill surgical patients. J Trauma 1988 May;28(5):648-54. [abstract]
3. Yu M, Tomasa G. A double-blind, prospective, randomized trial of ketoconazole, a thromboxane synthetase inhibitor, in the prophylaxis of the adult respiratory distress syndrome. Crit Care Med 1993 Nov;21(11):1635-42. [abstract]
4. Sinuff T, Cook DJ; Peterson JC, Fuller HD. Development, implementation, and evaluation of a ketoconazole practice guideline for ARDS prophylaxis. J Crit Care 1999 Mar;14(1):1-6. [abstract]
5. The ARDS Network. Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2000 Apr 19;283(15):1995-2002. [abstract]

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