Ketoconazole prevents acute respiratory failure in critically ill surgical patients.

Effective prophylaxis against acute respiratory failure (ARDS) has not been established. This study investigated whether or not ketoconazole could prevent ARDS in critically ill surgical patients. Seventy-one Surgical Intensive Care Unit (SICU) patients without liver dysfunction received either ketoconazole (n = 35), 200 mg daily via the gastrointestinal tract, or placebo (n = 36), for 21 days or until discharge from the SICU, in a prospective, randomized, double-blind study. Patients were monitored clinically for signs of ARDS, defined as all the following: intrapulmonary shunt greater than 15%, a PaO2/FIO2 ratio less than 150, normal central venous, pulmonary capillary wedge, or left atrial pressure, no other cause of hypoxemia, and a consistent chest X-ray. Thirteen patients (18%) developed ARDS with significantly increased mortality versus non-ARDS patients (69% vs. 29%). The incidence of ARDS was decreased among ketoconazole patients compared to placebo (6% vs. 31%; p less than 0.01), as was median SICU stay (7.0 days vs. 15.5 days; p less than 0.05), and median SICU cost (+5,600. vs. +12,400.; p less than 0.05). Mortality is increased with ARDS after trauma and surgery. We conclude that ketoconazole prevents ARDS, shortens SICU stay, and lowers hospital costs.

Interaction of prostaglandins, activated complement, and granulocytes in clinical sepsis and hypotension.

Activated complement, thromboxane A2, prostacyclin, and activated granulocytes have been implicated in hemodynamic dysfunction after trauma, in sepsis, and in hypovolemic and septic shock. This study evaluated the interaction of plasma concentrations of complement components C3a and C5a, thromboxane B2 (TxB), prostaglandin 6-keto-F1 alpha (PGI), and granulocyte aggregation in clinical sepsis and hypotension. Forty-eight critically ill patients were followed clinically for as long as 10 days. Plasma C3a, C5a, TxB, and PGI were measured daily by the radioimmunoassay method. Granulocyte aggregation, the percentage of maximum aggregation of zymosan-activated plasma standard curves, was performed with patient plasma and normal human leukocytes. Patients were studied in four groups: group I, nonseptic, normotensive; group II, hypovolemic shock, group III, normotensive severe sepsis; and group IV, septic shock. Plasma from 12 normal adults was the control value. PGI, TxB, C3a, C5a, and granulocyte aggregation in patients were greater than that in the control subjects. Granulocyte aggregation was increased in groups III and IV versus groups I and II. C3a was increased in group IV versus groups II and III. C5a and TxB did not vary between groups. PGI was greatly increased in group IV compared with groups I through III. C3a and C5a decreased in nonsurvivors. PaO2/FiO2 ratios correlated directly with PGI and inversely with C3a and TxB/PGI. Plasma PGI and C3a are increased in septic shock. C3a and TxB/PGI imbalances are involved in hypovolemic and septic shock.