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Reduced midazolam clearance must be considered in
prolonged coma.
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| Article Type: | Case study |
| Subject: |
Coma
(Risk factors) Coma (Drug therapy) Coma (Case studies) Midazolam (Dosage and administration) Midazolam (Complications and side effects) Midazolam (Physiological aspects) |
| Authors: |
Meierhans, R. Stover, J.F. Bechir, M. Keel, M. Stocker, R. |
| Pub Date: | 11/01/2008 |
| Publication: | Name: Anaesthesia and Intensive Care Publisher: Australian Society of Anaesthetists Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2008 Australian Society of Anaesthetists ISSN: 0310-057X |
| Issue: | Date: Nov, 2008 Source Volume: 36 Source Issue: 6 |
| Geographic: | Geographic Scope: United States Geographic Code: 1USA United States |
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| Accession Number: | 192852809 |
| Full Text: |
Following a motorcycle accident, a 42-year-old otherwise healthy
man suffered blunt abdominal trauma with secondary intestinal injury and
fractures of the lower extremities without any severe neurologic
abnormalities. As his injuries required multiple surgical procedures he
repeatedly received benzodiazepines, hypnotics, analgesics and volatile
anaesthetics in the intensive care unit and during anaesthesia. After
stopping sedation on the second day, no reactions were observed
following trauma (Ramsay score 6). Metabolic, renal and hepatic
disorders as well as functional (EEG, SEP) and structural cerebral
lesions (CT, MRI) possibly accounting for prolonged coma were excluded.
Thereafter, an opioid antagonist (naloxone), a benzodiazepine antagonist
(flumazenil) and a central acting cholinesterase inhibitor
(physostigmine) were administered according to the manufacturer's
recommendations. Apart from physiological changes (arterial hypertension, tachycardia, tachypnoea and sweating), repetitive application of these drugs did not reverse coma. On the third day, slight occular and masticatory movements were observed but the patient remained with a Ramsay score of 5. Reduced drug metabolism was considered as a possible cause. While both fentanyl and morphine including their metabolites were below their effective blood concentrations on day 5, plasma midazolam was significantly elevated at 2.78 [micro]mol/l (therapeutic range 0.3 to 1.0 [micro]mol/l). Its metabolites, however, were very low, 1-OH-midazolam: 0.10 [micro]mol/l(therapeutic range 0.20 to 0.73 [micro]mol/l) and 1-OH-midazolam-glucuronide: 1.28 [micro]mol/l (therapeutic potency: 10% of midazolam and 1-OH-midazolam(6). Blood midazolam levels determined 40 hours later (day 7) were still increased at 0.22 [micro]mol/l. Calculated half-life for midazolam [[t.sub.1/2] = 0.693 x [delta]t/ (ln[C.sub.1] - ln[C.sub.2])] was significantly prolonged (11 vs. 1.5 to 3.5 hours (l-4)). The patient progressively awoke after the eighth day. Due to the identified slow drug clearance, anaesthesia was maintained with either propofol or isoflurane for follow-up laparotomies. Each time the patient awoke very quickly following surgery/anaesthesia. Reduced drug elimination can result from hepatic and renal insufficiency, decreased hepatic perfusion (7), altered tissue binding properties and drug-drug interactions known to inhibit the CYP3A enzyme, for instance cimetidine, azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, telithromycin and verapamil. Our patient had received fentanyl, propofol and erythromycin which might have contributed to the increased midazolam half-life. Delayed recovery from sedation can occasionally be seen in critically ill patients. Various differential diagnoses need to be considered and actively searched. After ruling out structural and functional cerebral lesions as well as hypoxic and metabolic causes, altered pharmacokinetics have to be considered justifying analysis of plasma concentrations of sedatives and their metabolites. The appropriate time-point must be considered individually. Apart from pharmacologic antagonism which can prove inefficient, patience is essential until midazolam has slowly dropped below its therapeutic threshold. In addition, drug-drug interactions must be considered and avoided. Since pharmacologic antagonism is dose-dependent, the flumazenil dose used might have been insufficient. Higher doses or continuous infusion might be required to unmask and treat this pharmacologic problem. This, however, must be balanced against systemic side-effects and induction of seizures. R. MEIERHANS J. F. STOVER M. BECHIR M. KEEL R. STOCKER Zurich, Switzerland (1.) Kassai A, Toth G, Eichelbaum M, Motz U. No evidence of a genetic polymorphism in the oxidative metabolism of midazolam. Clin Pharmacokinet 1988; 15:319-325. (2.) Wills RJ, Khoo KC, Soni PP, Patel IH. Increased volume of distribution prolongs midazolam half-life. Br J Clin Pharmacol 1990; 29:269-272. (3.) Hase I, Oda Y, Tanaka K, Mizutani K, Nakamoto T, Asada A. LV fentanyl decreases the clearance of midazolam. Br J Anaesth 1997; 79:740-743. (4.) Naritoku DK, Sinha S. Prolongation of midazolam half-life after sustained infusion for status epilepticus. Neurology 2000; 54:1366-1368. (5.) Clausen TG, Wolff J, Hansen PB, Larsen F, Rasmussen SN, Dixon JS, Crevoisier C. Pharmacokinetics of midazolam and alpha-hydroxy-midazolam following rectal and intravenous administration. Br J Clin Pharmacol 1988; 25:457-463. (6.) Bauer TM, Ritz R, Haberthbr C, Ha HR, Hunkeler W, Sleight AJ, Scollo-Lavizzari G, Haefeli WE. Prolonged sedation due to accumulation of conjugated metabolites of midazolam. Lancet 1995; 346:145-147. (7.) Thummel KE, Wilkinson GR: In vitro and in vivo drug interactions involving human CYP3A. Annu Rev Pharmacol Toxicol 1998; 38:389-430. |
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