P108
HEPATIC METABOLISM OF MIDAZOLAM IS INHIBITED IN CRITICALLY ILL
PATIENTS WITH ACUTE KIDNEY INJURY
Kirwan. C1,3, Philips, B1, Lee, T2, Holt, D2, MacPhee, I3
1
Departement of Intensive Care, 2Analytical Unit, 3Department of Renal Medicine, St
George’s University of London
Chronic Kidney Disease (CKD) has been shown to cause a decrease in the hepatic metabolism
of drugs in vivo and in vitro. The impact of acute kidney injury (AKI) on hepatic drug
metabolism is untested. A single time point determination of midazolam concentration, four
hours after intravenous administration, accurately predicts total midazolam exposure and thus
metabolism in critically ill patients. Midazolam metabolism is a measure of hepatic activity of
cytochromes P450 (CYP3A) 3A4 and 3A5 that are involved in the metabolism of >50% of
widely used drugs.
METHODS: All patients admitted to the adult intensive care unit were considered unless they
had received a benzodiazepine in the previous 24 hours, had acute or chronic hepatic failure,
were pregnant or were being administered major CYP3A inhibitors i.e. macrolide antibiotics or
an imidazole anti-fungal. 1mg midazolam was given intravenously at time 0 and serum
collected at 4 hours. Serum midazolam concentration was determined by mass spectrometry: T4[mid]. Patients were categorised using the AKIN / RIFLE criteria. Glomerular filtration rate
was assessed by simultaneous 4 hour creatinine clearance (4CrCl) measurements.
120
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T4 [mid] (ng.mL-1)
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RESULTS:
72 patients (53 with AKI) were recruited.
Mean age 72 (23-90); 45 male. 19 had
normal renal function with 16, 20, 17 in
groups 1(R), 2(I) and 3(F) respectively. In
critically ill patients the median (range) T4
[midazolam] concentration N v AKI was
3.15 (1.29-10.27) and 5.57 (0.59-113.6)
ng.mL-1 respectively (p<0.005). There were
two major outliers which may skew the
results in favour of the hypothesis. If these
two results are removed (Fig. 1) the
statistical significance remains strong (N v
* p<0.008; ** p=0.003; *** p=0.009)).
Standard multiple regression analysis found
the most useful predictors of T4[mid] were
‘time with AKI’ and ‘serum urea’ (beta
coefficient 0.33 and 0.31 (p<0.05)
respectively). 4CrCl, Serum creatinine and
urine output did not add further predictive
statistical power.
CONCLUSION: This study demonstrates a reduction in the hepatic metabolism of midazolam
associated with AKI. This effect is related most strongly to the length of time the patient has
suffered with AKI.