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The ARDS Network Authors for the ARDS Network. Ketoconazole for Early Treatment of Acute Lung Injury and Acute Respiratory Distress Syndrome: A Randomized Controlled Trial. JAMA. 2000;283(15):1995–2002. doi:10.1001/jama.283.15.1995
Members of The ARDS Network are listed below. A dagger identifies members who accept and fulfill authorship criteria.
Caring for the Critically Ill Patient Section Editor: Deborah J. Cook, MD, Consulting Editor, JAMA.
Context Three clinical studies have suggested that ketoconazole, a synthetic
imidazole with anti-inflammatory activity, may prevent the development of
acute respiratory distress syndrome (ARDS) in critically ill patients. However,
the use of ketoconazole as treatment for acute lung injury (ALI) and ARDS
has not been previously studied.
Objective To test the efficacy of ketoconazole in reducing mortality and morbidity
in patients with ALI or ARDS.
Design Randomized, double-blind, placebo-controlled trial conducted from March
1996 to January 1997.
Setting Twenty-four hospitals associated with 10 network centers in the United
States, constituting the ARDS Network.
Patients A total of 234 patients with ALI or ARDS.
Intervention Patients were randomly assigned to receive ketoconazole, 400 mg/d (n=117),
or placebo (n=117), initiated within 36 hours of fulfilling study entry criteria
and given enterally for up to 21 days.
Main Outcome Measures Primary outcome measures were the proportion of patients alive with
unassisted breathing at hospital discharge and the number of days of unassisted
breathing (ventilator-free days) during 28 days of follow-up. Secondary outcome
measures included the proportion of patients achieving unassisted breathing
for 48 hours or more, the number of organ failure–free days, and changes
in plasma interleukin 6 (IL-6) and urinary thromboxane A2 metabolites
(thromboxane B2 [TXB2] and 11-dehydro-TXB2).
Results In-hospital mortality (SE) was 34.1% (4.3%) for the placebo group and
35.2% (4.3%) for the ketoconazole group (P=.85).
The median number of ventilator-free days within 28 days of randomization
was 9 in the placebo group and 10 in the ketoconazole group (P=.89). There were no statistically significant differences in the
number of organ failure–free days, pulmonary physiology, or adverse
events between treatment groups. The median serum ketoconazole level was 1.25
µg/mL and serum levels greater than 0.5 µg/mL were detected in
96% of patients assayed. Plasma IL-6, urinary TXB2, and 11-dehydro-TXB2 levels were unaffected by ketoconazole.
Conclusions In these patients with ALI or ARDS, ketoconazole was safe and bioavailable
but did not reduce mortality or duration of mechanical ventilation or improve
lung function. These data do not support the use of ketoconazole for the early
treatment of ALI or ARDS.
The acute respiratory distress syndrome (ARDS) has been recognized for
more than 30 years as a severe form of acute respiratory failure. Patients
with this disorder are critically ill, require mechanical ventilation in an
intensive care unit (ICU), and have a high mortality, ranging from 35% to
50% in recent reports.1,2 Sepsis,
severe trauma, aspiration of gastric contents, and massive blood transfusion
are the most common clinical events that place patients at risk for the development
of ARDS.3 Recently, the concept of ARDS has
been expanded to include milder forms of the same pathophysiologic process.
The entire pathophysiologic spectrum is now called acute lung injury (ALI),
whereas ARDS refers to the more severe end of that spectrum.4
The degree of impairment of oxygenation of arterial blood is used to distinguish
patients with ARDS from those with ALI. Despite this distinction, available
data suggest the outcomes for patients with ALI are similar to outcomes of
the subset of patients with ARDS.5 Supportive
care is the current state-of-the-art therapy for ALI and ARDS; no specific
pharmacologic therapies have yet proved efficacious.1
ALI, including ARDS, is generally considered to be a consequence of
an overaggressive inflammatory response that includes inflammatory cell migration
into interstitial and alveolar spaces, with subsequent activation and release
of injurious proteases and reactive oxygen species.6,7
Pulmonary hypertension is thought to be due to activation and release of vasoactive
mediators, including arachidonic acid metabolites, accompanied by diffuse
pulmonary microvascular thrombosis.8,9
While the neutrophil is a major effector cell for lung injury, the alveolar
macrophage probably plays a central role in the host inflammatory response
that underlies ALI as a major producer of vasoactive substances, neutrophil
chemoattractants, and procoagulant substances.7,10
Ketoconazole is a synthetic antifungal imidazole that also has anti-inflammatory
activities.11 Ketoconazole inhibits thromboxane
synthase, an enzyme in the synthetic pathway of thromboxane A2
(TXA2) that acts as a potent pulmonary vasoconstrictor and aggregator
of platelets and neutrophils.12 Ketoconazole
also inhibits 5-lipoxygenase, the enzyme necessary to generate leukotrienes,
and decreases leukotriene B4 (LTB4) production, 1 of
the primary neutrophil chemoattractants implicated in ARDS.4
Cyclooxygenase is unaffected by ketoconazole. Ketoconazole also inhibits endotoxin-stimulated
alveolar macrophage production of procoagulant activity.11
Thus ketoconazole can modulate inflammatory pathways known to be involved
in ALI and ARDS.
Three clinical studies have suggested that ketoconazole may be effective
in preventing the development of ARDS in high-risk critically ill patients.13-15 One of those studies
even found ketoconazole to be significantly associated with a reduction in
mortality.14 However, the use of ketoconazole
as treatment for early ALI or ARDS has not been previously studied.
Therefore, the primary objective of this randomized trial was to assess
the effect of ketoconazole on mortality and morbidity in patients with early
ALI or ARDS. There were 2 primary efficacy variables: the proportion of patients
alive with unassisted breathing at hospital discharge and the number of days
of unassisted breathing (ventilator-free days) at day 28 after randomization.
This efficacy measure is thought to influence cost and morbidity attributable
to differences in recovery time from respiratory failure.
The National Heart, Lung, and Blood Institute organized and funded the
ARDS Network, a consortium of 10 clinical centers and a clinical coordinating
center in the United States, to design and conduct multicenter clinical trials
of novel therapies for ALI and ARDS. Each clinical center is composed of 1
or more university medical centers and affiliated hospitals. This report describes
data from the Ketoconazole and Respiratory Management in ALI and ARDS (KARMA)
Trial, the first study conducted by this network. This study had a 2 ×
2 factorial design comparing 400 mg/d of ketoconazole with placebo and a ventilatory
strategy comparing a tidal volume of 6 mL/kg with 12 mL/kg. This report describes
the results from the ketoconazole vs placebo arm of the study. The ventilator
management arm of the study will be reported separately.16
Patients were enrolled from 24 hospitals at the 10 centers constituting
the ARDS Network. Patients were eligible for the study if they were in an
ICU, required positive pressure ventilation via endotracheal or tracheostomy
tube, and had acute onset of significantly impaired oxygenation with a PaO2-to-fraction of inspired oxygen (FIO2) ratio less than or
equal to 300 (adjusted for barometric pressure), bilateral infiltrates consistent
with pulmonary edema on a frontal chest radiograph, and no clinical evidence
of left atrial hypertension or, if a pulmonary artery catheter was in place,
a pulmonary artery occlusion pressure less than or equal to 18 mm Hg.4 Patients had to be enrolled within 36 hours of developing
these criteria. The study was approved by the institutional review board at
each hospital. Consent was obtained from all patients or their surrogates
Exclusion criteria were age younger than 18 years, participation in
other interventional trials within the previous 30 days, pregnancy, increased
intracranial pressure, neurologic conditions that could impair weaning from
ventilatory support, sickle cell disease, severe chronic respiratory disease,
morbid obesity, burns covering at least 30% of total body surface area, malignancy
or other irreversible condition for which 6-month mortality was estimated
to be at least 50%, or a history of bone marrow or lung transplantation. Patients
were also excluded if the clinicians caring for them were not agreeable to
using volume-cycled assist/control ventilation for at least 12 hours or were
not committed to providing aggressive life support at the time of enrollment.
Finally, patients were excluded if they received any imidazole within 7 days
or terfenadine, astemizole, or cisapride within the preceding 3 days; had
an allergy to imidazoles or their derivatives; had severe chronic liver disease
(defined as a Child-Pugh score of ≥10)17;
or had evidence of acute viral, ischemic, or toxic hepatitis with moderate
or severe acute hepatocellular or cholestatic injury, defined as an aspartate
aminotransferase or alanine aminotransferase level of 500 U/L or more or an
alkaline phosphatase level of at least 240 U/L.
A primary risk factor for ALI or ARDS was assigned by the investigators
at the time of randomization. Study subjects were later classified by primary
risk factor as having direct lung injury (eg, pneumonia, aspiration of gastric
contents) or indirect lung injury (eg, sepsis, multiple trauma, pancreatitis).4
The groups were treated equally with regard to mechanical ventilation
based on simultaneous enrollment in the ventilator strategy arm of the study.
Mechanical ventilation was performed in strict accordance with the study protocol.
Weaning from ventilatory support was also done according to the protocol and
commenced when patients met all of the following criteria: at least 12 hours
since initial protocol ventilator change; FIO2 of 0.40 or less;
positive end-expiratory pressure and FIO2 values less than or equal
to those from the previous day; not receiving neuromuscular blockade; inspiratory
efforts exhibited by the patient; and systolic blood pressure of at least
90 mm Hg without vasopressor support. Once qualified, patients were weaned
from ventilatory support with a pressure support protocol.
After informed consent was obtained, the data coordinating center provided
assignment using a computer-generated randomization, stratified by tidal volume
assignment, to either 400 mg/d of ketoconazole or placebo. The local research
pharmacist was unblinded to the treatment assignment and prepared the study
drug for administration while the patients, investigators, study coordinators,
and all clinical personnel remained blinded to the randomization.
Ketoconazole and placebo were dissolved in 60 mL of Coke Classic (The
Coca-Cola Company, Atlanta, Ga) at room temperature.18
The liquid was gently stirred for 5 minutes or until the tablet was completely
dissolved. Dissolved placebo and ketoconazole had identical appearances. The
study drug was administered enterally via gastric, duodenal, or jejunal tubes
within 4 hours of randomization. Each dose was flushed through the enteral
tube with 20 mL of normal saline; the tube was clamped for 1 hour following
drug administration. Subsequent doses were administered once daily for 21
days or until the patient achieved 48 hours of unassisted breathing. Unassisted
breathing was defined as either extubation with or without supplemental oxygen,
T-tube breathing, tracheostomy mask breathing, or continuous positive airway
pressure less than or equal to 5 cm H2O without pressure support
or intermittent mechanical ventilation assistance. Study drug was discontinued
if possible drug-induced hepatic injury developed as defined by an aspartate
aminotransferase or alanine aminotransferase level of at least 500 U/L, or
a rise in aspartate aminotransferase or alanine aminotransferase level greater
than 8 times baseline, or an alkaline phosphatase level of at least 240 U/L
that was 3 times greater than the baseline value.
Serum samples were obtained on study day 3 for the measurement of ketoconazole
levels. Ketoconazole was assayed by a modification of the bioassay method
of Bodet et al.19 Blood and urine specimens
were collected at baseline (study day 0, prior to initial study drug dose)
and on study day 3. Blood was drawn into EDTA-anticoagulated tubes, centrifuged,
and frozen at −70°C. Urine was similarly centrifuged and frozen.
Interleukin 6 (IL-6) was measured in 2 laboratories by immunoassay. Thromboxane
B2 (TXB2), a metabolite of TXA2, was measured
in the urine using an enzyme immunoassay kit. For the measurement of 11-dehydro-TXB2, 1 mL of urine was spiked with 1.0 ng of a tetradeuterated analog
of 11-dehydro-TXB2 and extracted on a liquid chromatography column.
The sample was then exposed to a 1% solution of hydrogen chloride for 2 hours,
purified by thin-layer chromatography with a mobile phase of ethyl acetate
and acetic acid (48:1). The purified compounds were then converted to their
pentafluorobenzyl esters and purified by thin-layer chromatography, with a
mobile phase consisting of ethyl acetate and heptane (3:1). The trimethylsilyl
ether was formed and quantification was achieved. Mass over charge (m/z) 511
and m/z 515 were monitored for endogenous 11-dehydro-TXB2 and the
tetradeuterated internal standard, respectively. Urinary TXB2 and
11-dehydro-TXB2 values were divided by urinary creatinine to account
for differences in renal function.
The study was analyzed on an intention-to-treat basis. The primary efficacy
variables were the proportion of patients alive with unassisted breathing
at hospital discharge and the number of days alive with unassisted breathing
(ventilator-free days) through day 28, assuming a patient survived for at
least 48 consecutive hours after initiating unassisted breathing. Secondary
efficacy variables assessed during the 28 days from randomization included:
(1) the proportion of patients who achieved unassisted breathing for 48 hours
or more, (2) the number of organ failure–free days, (3) the number of
days meeting "commence weaning" criteria, (4) the proportion of patients withdrawn
because of possible liver toxicity, and (5) the occurrence of barotrauma.
Patients were considered to have survived if they were discharged from
the hospital alive with unassisted breathing. Patients who were still receiving
assisted ventilation or in a hospital were considered censored observations
at 180 days (the last day of follow-up). The Kaplan-Meier estimate and its
SE at the last death time before 180 days was used as the 180-day mortality
Analyses of mortality and ventilator-free days were performed for the
subgroups with ARDS at baseline, sepsis-induced ALI or ARDS, trauma-induced
ALI or ARDS, and direct vs indirect lung injury. These subgroup analyses were
prospectively defined, although the study was not specifically powered to
detect differences within subgroups.
Days without organ failure were defined separately for each form of
failure. Each patient was evaluated for cardiovascular failure (systolic blood
pressure ≤90 mm Hg or required vasopressor support); central nervous system
failure (Glasgow coma score ≤12); coagulation failure (platelet count ≤
80 × 103/µL [80 × 109/L]); hepatic
failure (bilirubin ≥2 mg/dL [34.2 µmol/L]); and renal failure (serum
creatinine ≥2 mg/dL [176.8 µmol/L]). The total number of days in
organ failure was calculated and subtracted from 28 or survival time, whichever
was less, to obtain the value for organ failure–free days.
An analysis of variance was used to compare the change of TXB2, 11-dehydro-TXB2, and IL-6 levels with ketoconazole from
baseline to day 3. The covariates were baseline level and ventilator strategy.
A Mantel-Haenszel test was used to compare the frequency of qualitative
patient characteristics and adverse events between ketoconazole and placebo,
adjusting for the respiratory management group. For quantitative characteristics,
a 2-way analysis of variance was used. A proportional hazards model was used
to test for a treatment effect in the presence of covariates that were thought
to be prognostic (APACHE III score, sepsis, and trauma were defined a priori)20 or were unbalanced between treatments. A Poisson
regression was used to test for a difference in the frequency of mild, moderate,
severe, and life-threatening adverse events for each organ system using the
World Health Organization classification. All statistical tests were performed
using statistical analysis software.
The trial design required periodic review of the data by the data and
safety monitoring board after enrollment of 200, 400, 600, and 800 patients.
The progress of the ventilator study was considered separately from that of
the ketoconazole study, and it was possible that 1 could be discontinued while
the other continued to accrue patients. As a superiority trial, the ketoconazole
study was designed to have 80% power of finding a significant difference at
a 2-sided P=.05 significance level if the true mortality
difference between the treatment groups was 10%. O'Brien-Fleming boundaries
were developed to stop the trial early if superiority of 1 treatment was found.21 The study was also designed to stop early if the
observed improvement in mortality was less than 3% in favor of ketoconazole.
The study began on March 18, 1996, and all treatment with ketoconazole
and placebo was stopped on January 13, 1997, by the data and safety monitoring
board because of lack of efficacy. The ventilator management trial was continued.
A total of 234 patients were enrolled in the study: 117 were randomized
to ketoconazole and 117 to placebo (Figure
1). The number of patients enrolled at each center ranged from 10
to 38. The ventilation strategies were evenly balanced between groups. Baseline
variables did not differ by treatment group with regard to primary cause of
lung injury, severity of lung injury, severity of illness, age, sex, arterial
blood gas values, or positive end-expiratory pressure (Table 1). ARDS (PaO2/FIO2 ≤200) was present
at the time of study entry in the majority of enrolled subjects; only 13%
(n=31) had a PaO2/FIO2 ratio greater than 200 and up
to 300 at the time of randomization. Follow-up was complete for all 234 patients.
The in-hospital mortality (SE) was not different: 34.1% (4.3%) for placebo
and 35.2% (4.3%) for ketoconazole (P=.85). A proportional
hazards regression model was created using terms for treatment, APACHE III
score, sepsis, trauma, and neuromuscular blocker use. The APACHE III score
was significantly predictive, but there was no drug effect in a model that
corrected for this measure of severity of illness. There was no significant
center effect; thus, we did not adjust the main analysis for center. Kaplan-Meier
survival plots for the treatment groups were virtually identical (Figure 2).
The median number of ventilator-free days was not different between
the ketoconazole group (10 days) and the placebo group (9 days) (P=.89). The patients without ventilator-free days died or, rarely,
were still receiving assisted ventilation at 28 days. The same proportion
of patients in each arm achieved unassisted ventilation within 28 days (59%)
(Figure 3). The time to when patients
first met "commence weaning" criteria was also the same in each group, with
a median of 3 days.
Analyses of mortality and ventilator-free days were performed for the
subgroups with ARDS at baseline, sepsis-induced ALI or ARDS, trauma-induced
ALI or ARDS, and direct vs indirect lung injury. No differences were detected
between treatment groups for these selected subgroups. In addition, there
was no significant interaction, positive or negative, with the ventilator
arm of the study.16
We examined changes in pulmonary physiology for the first 4 days after
randomization. There were no significant differences between study groups
for lung injury score, PaO2/FIO2 ratio, static total
respiratory system compliance, or positive end-expiratory pressure (Table 2).
Organ failure–free days describe the number of days that a surviving
patient is free of any organ failure during the 28-day window and are a measure
of morbidity in survivors. The median number of organ failure–free days
was not significantly different between treatment groups (Table 3). There were no significant differences between study groups
in the proportions of patients who received vasopressors (51% for placebo
vs 54% for ketoconazole), nor was there a difference in the number of days
of vasopressor use.
The lower limit of detectable ketoconazole in our bioassay was 0.5 µg/mL.
Ketoconazole levels greater than 0.5 µg/mL were detected in 96% of patients
assayed in the ketoconazole group. The median serum level was 1.25 µg/mL
with the highest level being 9.5 µg/mL. The mean was not estimable because
of the relatively high detection limit in our assay (0.5 µg/mL).
Baseline and day 3 urinary TXB2 levels were assayed in 173
subjects and 11-dehydro-TXB2 levels were assayed in 40 subjects.
Values were divided by urinary creatinine to adjust for renal function. There
were no significant differences between study groups for either of the thromboxane
metabolites. Mean (SD) baseline levels of urinary TXB2 were 6.9
(6.8) ng/mg of creatinine for placebo (n=88) and 6.2 (5.3) ng/mg of creatinine
for ketoconazole (n=85). At day 3, the levels were 7.5 (11.3) ng/mg of creatinine
for placebo and 7.4 (8.4) ng/mg of creatinine for ketoconazole. Mean (SD)
baseline levels of urinary 11-dehydro-TXB2 were 4.14 (4.23) ng/mg
of creatinine for placebo (n=20) and 7.18 (12.9) ng/mg of creatinine for ketoconazole
(n=20). At day 3, the levels were 4.84 (5.57) ng/mg of creatinine for placebo
and 12.8 (26.9) ng/mg of creatinine for ketoconazole. The change from baseline
to day 3 for ketoconazole was not statistically different than the change
for placebo (P=.09).
Ketoconazole did not alter plasma IL-6 levels measured in 2 laboratories
using distinct immunoassay methods.
Barotrauma (pneumothorax, subcutaneous emphysema, or pneumomediastinum)
and the use of chest tubes was not significantly different between the 2 groups
(19% for placebo vs 24% for ketoconazole; P=.38).
There were no significant differences in the proportions of patients with
a worsening radiographic score, receiving neuromuscular blockade, or receiving
Twenty percent of all patients developed liver enzyme level elevations
meeting the criteria for possible drug-induced hepatic injury. A cholestatic
pattern was present in 14% (placebo, 11% vs ketoconazole, 16%) and a hepatocellular
injury pattern developed in 6% of all patients (placebo, 6% vs ketoconazole,
5%). However, there was no difference between placebo and ketoconazole groups
in the incidence of liver enzyme level elevations, regardless of pattern (P=.53). Because of potential drug interactions, we examined
the frequency of patients' astemizole, terfenadine, or cisapride use. Seven
patients received cisapride during the study, while no patients received the
other 2 drugs. No cardiac arrhythmias were reported for any of these 7 patients,
nor was there a difference in the incidence of arrhythmias between the 2 groups
(placebo, 7% vs ketoconazole, 9%; P=.61).
We examined the frequency of spontaneously reported adverse events by
body system class. There was a trend toward more reports of cardiovascular
adverse events in the ketoconazole group (P=.07).
There were 5 reports of circulatory failure in patients taking ketoconazole
(4 lethal), 3 cases of hypotension (1 lethal), and 1 case of hypertension.
Three of these reports were from the same patient, and none were reported
by investigators to be either unexpected in the course of ARDS or associated
with the intervention. There were 2 reports of circulatory failure in patients
given placebo (1 lethal and 1 severe), neither of which was considered by
investigators to be associated with the study drug. As noted above, no significant
differences in cardiovascular organ failures (Table 3), arrhythmias, or vasopressor use were observed.
The strengths of this study are its relatively large size and its multicenter
composition, leading to a heterogeneous population of patients with ALI or
ARDS. In addition, baseline clinical characteristics were well balanced between
the 2 groups, and drug absorption in an acidic beverage led to good bioavailability
in critically ill patients. Unfortunately, ketoconazole did not improve mortality,
time free from mechanical ventilation, or lung function.
Ketoconazole can modify the inflammatory response of macrophages in
a manner that might be expected to improve the course of ALI and ARDS.11 Two small, single-center randomized trials of high-risk
patients demonstrated that ketoconazole prophylaxis leads to less frequent
development of ARDS and improved survival.13,14
After our study was under way, a third study was published supporting these
observational findings.15 If efficacy could
be established in ALI and ARDS, ketoconazole would be an attractive treatment
option because of its low cost and toxicity.
The 2 previous clinical trials studied the effects of ketoconazole in
critically ill patients at risk for ARDS.13,14
Slotman et al13 used 200 mg/d of ketoconazole,
administered enterally, in 71 high-risk surgical patients and found ARDS developed
in 31% of the placebo group, compared with 6% of the ketoconazole-treated
group (P<.01). A reduction in median ICU length
of stay was also observed but was not significantly altered. Yu and Tomasa14 began with a 200-mg/d dose of ketoconazole, also
administered enterally, but the dose was doubled after the first 5 patients
were treated because of low serum concentrations of the drug. The patients
(n=54) in that study were surgical patients with sepsis. The frequency of
ARDS development in the placebo group was 64% compared with 15% in the ketoconazole-treated
group (P=.002). A reduction in mortality from 39%
to 15% (P=.05) was also observed, although significant
reductions in ventilator and ICU days were not achieved. The third, more recent
study compared the use of a ketoconazole practice guideline for ARDS prophylaxis
in 1 hospital ICU with no guideline in another hospital's ICU.15
The guideline called for 200 mg/d of ketoconazole via nasogastric tube for
21 days or until ICU discharge in patients at risk for ARDS. Forty patients
were studied, 20 in each ICU. Implementation of the guideline was associated
with a significantly lower rate of ARDS. Serum drug concentrations were not
The study reported here was designed as an early treatment in contrast
to the studies that were reported as prevention trials.13-15
However, many patients in the Yu and Tomasa14
study already had what would now be considered ALI or ARDS by current American-European
Consensus Conference definitions.4 Many of
the patients had PaO2/FIO2 ratios less than 300 and
some had ratios less than 200, suggesting that several patients may have had
early ALI at the time of enrollment (M. Yu, MD, oral communication, February
1996). For those with ALI or ARDS at the time of enrollment, ketoconazole
still appeared efficacious in their study. The mortality in the treatment
group with a PaO2/FIO2 ratio less than 300 was 19% compared
with 63% in the comparable placebo group (M. Yu, MD, oral communication, February
1996). Therefore, the timing of the drug delivery (prior to ARDS vs early
in the course of ARDS) does not appear to explain fully the differences in
Patients enrolled in the studies by Slotman et al13
and Yu and Tomasa14 were predominantly surgical
patients with trauma and/or sepsis, and ours were a mixture of medical and
surgical patients. Therefore, we performed a subgroup analysis of patients
with ALI complicating trauma or sepsis and found that these subgroups did
not derive a survival benefit from ketoconazole. Inferences need to be made
cautiously, because our study was not powered for these subgroup analyses.
However, we do not believe that patient selection alone can explain the contrasting
results between this trial and prior studies.
We used the same dosage of ketoconazole used by Yu and Tomasa.14 In that study, ketoconazole concentrations of 0.202
(0.341) µg/mL were achieved in patients who did not develop ARDS, compared
with levels of 0.146 (0.127) µg/mL in those patients who subsequently
developed ARDS. Therapeutic concentrations for fungal treatment are reported
to be between 0.1 and 10 µg/mL.23 We
delivered ketoconazole via the gastrointestinal tract as in both previous
studies, but we first dissolved the ketoconazole in Coke Classic, which has
a pH of 2.5.18 Dissolving the drug in acidic
beverages circumvents problems of dissolution and, thus, absorption in patients
with high gastric pH such as those treated with histamine-2 blockers or antacids.18,24,25 Once dissolved, ketoconazole
is well absorbed from the gut independent of pH.26
The use of an acidic beverage to deliver ketoconazole probably explains why
we achieved ketoconazole blood levels nearly 10 times higher (median value=1.25
µg/mL) than those reported by Yu and Tomasa.14
As an assessment of the bioactivity of ketoconazole at the drug levels
achieved in this population, we measured urinary TXB2 and 11-dehydro-TXB2, the major urinary metabolites of TXA2, to estimate the
effect of ketoconazole on thromboxane synthase activity. Plasma TXB2 levels were lower in ketoconazole-treated patients compared with placebo
in 1 study,13 and another study demonstrated
a decrease in plasma of TXB2 after treatment with ketoconazole
compared with no change with placebo.14 However,
use of plasma TXB2 to assess in vivo production of TXA2
is problematic, because variable ex vivo platelet activation during blood
drawing can radically alter results.27 Therefore,
urinary measurements of thromboxane metabolites have been used by many investigators
to estimate thromboxane biosynthesis in vivo.27
We were unable to demonstrate an effect on the generation of thromboxane metabolites
with ketoconazole. Interleukin 6 was selected as a generic marker of a systemic
inflammatory response.28,29 None
of the prophylaxis trials measured this cytokine. We reasoned that if the
arachidonic acid cascade was altered, there might be less secondary stimulation
of other inflammatory pathways. We were unable to demonstrate such an effect.
It is possible that the lack of effect of ketoconazole on clinical outcomes
relates to the lack of a clinically significant effect on pulmonary and systemic
inflammation. While the dosage chosen for this study was reasonable given
previous clinical data, the dose-response curve of ketoconazole in ALI is
unknown. It is conceivable that lower blood levels of ketoconazole, such as
those seen in Yu and Tomasa's study,14 have
more of an anti-inflammatory effect than the higher levels achieved in this
study. Biphasic dose-response effects have been observed when manipulating
arachidonic acid metabolism as well as in the treatment of severe sepsis.30,31
Although 21% of patients receiving ketoconazole developed abnormalities
in liver enzymes with a hepatocellular or cholestatic liver injury pattern
sufficient to suggest drug-induced hepatitis, this number was not significantly
different from the placebo group (17%), and no serious adverse effects related
to liver failure were reported. Thus, we believe most of these abnormalities
were due to coexistent illness rather than to ketoconazole.
This large, multicenter trial did not confirm promising initial reports
from 3 smaller studies. Given the heterogeneous population studied, we believe
our findings are generalizable to the majority of patients with ALI. The dosage
and timing of the ketoconazole administration and patient selection do not
appear to explain these disappointing results. Higher blood levels of ketoconazole
were achieved than in previous studies; thus, we cannot exclude an inverse
dose-response relationship, although we believe it is unlikely.
Ketoconazole therapy appeared to be safe and was bioavailable when administered
enterally to critically ill patients. However, we found no improvement in
survival, ventilator-free days, organ failure–free days, or any measure
of lung function. This study does not support the use of ketoconazole for
the early treatment of ALI or ARDS.