Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Ketoconazole prevented the adult respiratory distress syndrome and reduced mortality in patients admitted to the intensive care unit

ACP J Club. 1994 May-June;120:65. doi:10.7326/ACPJC-1994-120-3-065


Source Citation

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;21:1635-42.


Abstract

Objective

To determine if ketoconazole given ≤ 24 hours after admission to the surgical intensive care unit (ICU) decreased the frequency of the adult respiratory distress syndrome (ARDS) in patients with sepsis.

Design

Randomized, double-blind, placebo-controlled trial.

Setting

Surgical ICU.

Patients

54 consecutive patients admitted to the ICU with diagnosis of sepsis, defined as 2 or more of the following in a patient with systolic blood pressure < 80 mm Hg or systemic vascular resistance of ≤ 800 dyne s/cm5: core temperature ≥ 39 °C or ≤ 35 °C, leukocyte count ≥ 12 or ≤ 4 × 109/L or ≥ 20% immature cells, positive blood culture, or a known or strongly suspected source of infection from which an identifiable pathogen was cultured. ARDS was diagnosed when diffuse infiltrates on chest radiograph were accompanied by intrapulmonary shunt of ≥ 20%, PaO2 to FiO2 ratio of < 150 requiring ventilation for ≥ 48 hours, pulmonary artery occlusion pressure of ≤ 18 mm Hg, and lack of clinical signs of heart failure. Exclusion criteria were age ≤ 16 years, pregnancy, history of cirrhosis, and liver enzyme concentrations > 2 times normal. Patients were followed for the length of ICU stay.

Intervention

Within 24 hours of diagnosis of sepsis, patients were randomly assigned to receive ketoconazole, 400 mg (n = 26), or placebo (n = 28) orally or by nasogastric tube. The drug was administered daily for 21 days or withdrawn earlier if patients left the ICU or if liver function tests showed enzyme concentrations twice their normal levels.

Main outcome measures

Frequency of ARDS, mortality rate, ventilator days, ICU days, hospital charge, and cost to the hospital.

Main results

The frequency of ARDS was decreased in the group of patients receiving ketoconazole compared with those receiving placebo (15% vs 64%, P = 0.002). The mortality rate was lower in the ketoconazole group compared with the placebo group (15% vs 39%, P = 0.05 ). The groups did not differ for ventilator days (17 d in the ketoconazole group vs 28 d in the placebo group), ICU days (19 vs 29 d), hospital charge, hospital days (39 vs 50 d), or cost to the hospital (U.S. $184 000 vs $133 000).

Conclusion

Ketoconazole administered early after diagnosis of sepsis decreased the frequency of the adult respiratory distress syndrome and mortality rate in patients in the intensive care unit.

Sources of funding: The Queens Medical Center and the Janssen Company.

For article reprint: Dr. M. Yu, Department of Surgery, University of Hawaii, 1356 Lusitana Street, 6th Floor, Honolulu, HI 96813, USA. FAX 808-537-7825.


Table. Ketoconazole vs placebo to prevent the adult respiratory distress syndrome (ARDS) in surgical patients admitted to the intensive care unit*

Outcomes at discharge Ketoconazole Placebo RRR (95% CI) NNT (CI)
ARDS 15% 64% 76% (44 to 91) 2 (1 to 4)
Mortality 15% 39% 61% (0 to 86) 4 ( 2 to infinity)

*Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


Commentary

In 1993 Yu and Tomasa succeeded in conducting a clinical trial which showed that enterally administered ketoconazole, 400 mg once a day, reduced mortality and the incidence of the development of ARDS in patients with sepsis in the surgical ICU.

The drug was given as prophylaxis for prevention of ARDS and not for treatment. A previous clinical trial by Slotman and colleagues (1) also found that prophylactic use of ketoconazole reduced the incidence of ARDS. Regrettably, no clinical trials of ARDS prophylaxis with ketoconazole have been published since then. Only a nonrandomized comparison of ketoconazole prophylaxis has been published since 1994 which also found a reduction in ARDS (2). There are 3 other items of interest regarding ketoconazole (Personal communication with Dr. M. Yu). First, an attempt to extend the use of ketoconazole to treatment of patients with established ARDS has been dropped from an ongoing, multicenter, National Institutes of Health (NIH)-sponsored study because of negative results. Thus, ketoconazole should not be used except for ARDS prophylaxis in septic patients within 24 hours of ICU admission. Second, as advanced by Dr. R. Maier, ketoconazole dissolves well in Coca-Cola, which also provides the low pH needed for maximal absorption. Third, during ketoconazole prophylaxis, hypotension associated with reduced levels of control has developed which responds to glucocorticoid replacement therapy.

Regarding other known complications of ketoconazole, fulminant liver failure has not yet been reported in patients receiving prophylaxis but the possibility is of concern. Finally, serious and potentially fatal interactions with other drugs have occurred and constitute contraindications to ARDS prophylaxis with ketoconazole. Most relevant to critical care practice is the contraindication to the concomitant use of ketoconazole and cisapride. Also important is the need to avoid H2 blockers, proton pump inhibitors, and antacids.

It is noteworthy that ketoconazole prophylaxis has been met with dismissive skepticism despite positive results in 2 clinical trials. Additional small, tightly controlled trials could provide needed confirmation and hopefully extend the results to medical patients in the ICU.

Gilbert Carroll, MD
Kaiser PermanenteFremont, California, USA


References

1. Slotman GJ, Burchard KW, D'Arezzo A, Gann DS. Ketoconazole prevents acute respiratory failure in critically ill surgical patients. J Trauma. 1988;28:648-54.

2. Sinuf T, Cook DJ, Peterson JC, Fuller HD. Development, implementation, and evaluation of a ketoconazole practice guideline for ARDS prophylaxis. J Crit Care. 1999;14:[In press].