Accumulation of midazolam after repeated dosage in patients receiving mechanical ventilation in an intensive care unit.

Abstract

BRITISH MEDICAL JOURNAL VOLUME 289 29 SEPTEMBER 1984 799 few days later he noticed an area of numbness and paraesthesia below the right rib cage. These symptoms were more pronounced at night. A random blood glucose concentration was 12-3 mmol/l (221 mg/100 ml) and glycosylated haemoglobin 8°% (range in non-diabetics 5-7°%). Urea and electrolytes, serum Bl,, and results of liver function tests and urine analysis were normal. A Venereal Disease Research Laboratory test gave a negative result. Nerve conduction studies in the peroneal nerve were normal, though the sural nerve showed evidence of peripheral sensory neuropathy. Electromyography showed fibrillations and positive waves, an increase in the proportion of polyphasic motor unit potentials, and decreased interference patterns in the rectus abdominis innervated by T6-T12 on the right. Similar changes were seen in the right external oblique and thoracic paraspinal muscles. All studies on the left side gave normal results.Thoracic polyradiculopathy was diagnosed, and the sensory symptoms resolved over two months. No change was seen in the abdominal swelling. CommentThis patient presented with asymmetrical motor abnormalities in the abdominal muscles and mild and transient sensory symptoms affecting the right T6 and T7 dermatomes. He had electrophysiological evidence of only a mild sensory peripheral neuropathy, and, furthermore, there was no postural hypotension or clinical evidence of decreased sweating in the feet to suggest autonomic neuropathy. We could not perform standard heart rate dependent tests of autonomic function as the patient was in atrial fibrillation. Kikta et al reported on one patient with thoracic polyradiculopathy who was found to have abdominal swelling, though the patient was not diabetic and had an eight month history of abdominal pain. The diagnosis was confirmed by electromyography, and although a glucose tolerance test did not confirm diabetes it was suggestive of impaired glucose tolerance, which may have contributed to the aetiology of the polyradiculopathy.5Truncal polyradiculopathy should be considered in diabetic patients with unexplained abdominal pain or areas of muscle weakness. This case shows that such patients may present with no other neuropathic manifestations. If the diagnosis is considered early many unnecessary investigations might be avoided. Electromyography is the most helpful investigation in diagnosing this condition.3 5We thank Dr Jay Skyler for his encouragement. AJMB was supported in part by the Wellcome Foundation and Ayerst Laboratories. Accumulation of midazolam after repeated dosage in patients receiving mechanical ventilation in an intensive care unit Midazolam hydrochloride (Hypnovel) is a recently introduced imidazobenzodiazepine. Its potency and rapid onset and short duration of action after a single intravenous bolus make it an ideal agent for premedication or induction in anaesthesia for short surgical, endoscopic, and dental procedures. These same pharmacokinetic features would seem to make the dr...

Extra‐hepatic metabolism of midazolam.

“…Following this, glucuronidation occurs making the compound more water-soluble and allowing renal elimination. In the postoperative period prolonged sedation has been observed (Byatt et al, 1984;Byrne et al, 1984). A reversible failure of metabolism has been demonstrated in patients with sepsis (Shelly et al, 1987) and in a child with acute derangement of liver function following cardiac surgery (Lloyd-Thomas & Booker, 1986).…”

A pharmacokinetic interaction between roxithromycin and midazolam

“…Midazolam has an extensive first-pass metabolism with oral bioavailability less than 50% (Allonen et al 1981). The macrolide antibiotic erythromycin inhibits the metabolism of midazolam in vitro and also in humans (Byatt et al 1984;Gascon and Dayer 1991;Hiller et al 1990). In a previous study erythromycin treatment increased the area under the midazolam concentration-time curve more than four-fold and peak midazolam concentration almost three-fold after a 15-mg oral dose of midazolam, which caused more proPresented in part at the 18 th International Congress of Chemotherapy, Stockholm, Sweden, June 27-July 2, 1993 Correspondence to: J. T. Backman, Department of Clinical Pharmacology, University of Helsinki, Paasikivenkatu 4, SF-00250 Helsinki, Finland found and prolonged psychomotor effects (Olkkola et al 1993).…”

The pharmacokinetics of midazolam following orthotopic liver transplantation.

“…Intravenous midazolam has been used (Lloyd- Time to reach maximum drug concentration Thomas & Booker, 1986;O'Dea & Hopkinson, 1987;Park et al, 1986) but concern has been expressed regarding the occasional delayed recovery of critically ill patients following its administration (Byatt et al, 1984;Byrne et al, 1984;Dundee et al, 1984). This has been attributed to impaired metabolism resulting in slow clearance of the parent drug.…”

“…Following its use in critically ill patients, however, there have been reports of a prolonged duration of action (Byatt et al, 1984;Byrne et al, 1984;Dundee et al, 1984). Since midazolam is believed to be metabolised in the liver (Allonen et al, 1981), its deranged pharmacodynamics and pharmacokinetics in critically ill patients may be due to a failure of hepatic metabolism of the drug (Dundee et al, 1986).…”