VECURONIUM is commonly used in the critical care setting. One reason is its relatively short duration of action, which allows clinical assessment of patients within a few hours after discontinuing administration of the drug. We recently encountered a case in which extremely prolonged vecuronium action was observed.
An otherwise healthy 61-yr-old woman weighing 42 kg lost consciousness in her bathroom in June 2000. At the time of arrival in the emergency room, she had a Glasgow Coma Scale score of 4, a blood pressure of 178/72 mmHg, a heart rate of 78 beats/min, and a respiratory rate of 22 breaths/min. She underwent tracheal intubation, and computerized tomography of the head was performed. The scan showed subarachnoid and intraventricular hemorrhage. Because of her poor neurologic condition, conservative therapy with controlled ventilation was chosen. Propofol and vecuronium were intravenously administered at 70 and 4 mg/h, respectively, for 15 h 40 min to ensure immobility and to control blood pressure. Neuromuscular function was not monitored. Rectal temperature was maintained between 34 and 35°C. Phenytoin, 250 mg/day, was administered, and in addition, she received hydrocortisone, cefotiam, aztreonam, and mannitol. The family reported no history of renal disturbance. Blood urea nitrogen and serum creatinine concentrations were 15 and 0.7 mg/dl, respectively, at the time of admission.
On the second hospital day, her pupils were fully dilated, and her electroencephalogram was isoelectric. Her family voluntarily presented an organ donor card in the patient’s own writing. To allow a diagnosis of brain death, the propofol and vecuronium infusions were stopped. At the time of their discontinuation, blood urea nitrogen and serum creatinine concentrations were 27 and 1.6 mg/dl, respectively. Serum concentrations of alanine aminotransferase, aspartate aminotransferase, and bilirubin were within normal limits.
Twenty-three hours after discontinuation of propofol and vecuronium, we attempted to confirm the return of normal neuromuscular function, using ulnar nerve stimulation. Marked fade to tetanic stimulation was noted. Therefore, we assessed neuromuscular transmission by accelerometer (TOF-Guard; Biometer, Odense, Denmark). A train-of-four stimulus was applied over the ulnar nerve, and the evoked responses were measured at the adductor pollicis muscle. The T4/T1 ratio was only 25%. Subsequent administration of neostigmine increased this to 50%. Results of a subsequent nerve conduction study and electromyography were normal. At this time, blood concentrations of vecuronium and its active metabolite 3-desacetylvecuronium measured by liquid chromatography–tandem mass spectrometry were 33.3 and 81.0 ng/ml, respectively (table 1).
Fifty-seven hours after discontinuation of vecuronium, the train-of-four ratio reached a value greater than 75%. Sixty-four hours after discontinuation, urinary output progressively increased to 10,270 ml/day. Aggressive fluid replacement and 3–5 μg · kg−1· min−1intravenous dopamine were used. Systolic blood pressure, central venous pressure, and heart rate were maintained at approximately 90–100 mmHg, 8–10 mmHg, and 80–85 beats/min, respectively. Serum sodium, potassium, calcium, and magnesium concentrations were maintained within normal limits.
Sixty four hours after discontinuation of vecuronium, the patient’s train-of-four ratio was consistently greater than 80%. Blood concentrations of vecuronium and 3-desacetylvecuronium were 15.6 and 65.2 ng/ml, respectively (table 1). Although she was now deemed as meeting the legal requirements for a diagnosis of brain death, ultrasound examination showed polycystic lesions on the kidneys, which were considered to be unsuitable for transplantation.
The prolonged neuromuscular blockade observed in this case is potentially explained by slow clearance of vecuronium and its metabolite, 3-desacetylvecuronium. 1The normal elimination half-life of vecuronium in healthy volunteers is 25–61 min, whereas that of 3-desacetylvecuronium is approximately threefold longer. 23-Desacetylvecuronium is 70% as potent as vecuronium. 3A median concentration of 123 ng/ml 3-desacetylvecuronium produces 50% depression of twitch tensions. 2This is generally consistent with our own observed train-of-four ratios and blood concentrations of vecuronium and 3-desacetylvecuronium (table 1).
Although animal data suggest that the liver is the main organ of elimination of 3-desacetylvecuronium as well as vecuronium, 4many reports show that renal failure is associated with high plasma concentrations of 3-desacetylvecuronium and prolonged paralysis. 1,2,5In general, uremia decreases the hepatic clearance of many drugs that are eliminated principally by the liver. Caldwell et al. 2predicted that the ratio of the steady-state concentrations of 3-desacetylvecuronium and vecuronium would be approximately 0.2, using the values obtained in their study. However, plasma concentrations of 3-desacetylvecuronium exceeded those of vecuronium in our patient (table 1). There could be either disproportionally decreased clearance of 3-desacetylvecuronium relative to vecuronium or increased metabolic conversion of vecuronium to 3-desacetylvecuronium, associated with renal disturbance in this patient. 2
Prolonged neuromuscular blockade in this patient may be related to her preexisting polycystic kidney. This disease is characteristic by the progressive enlargement of a portion of renal tubule segments, typically causing renal insufficiency by the fifth or sixth decade of life. 6It is often accompanied by cerebral aneurysms. 6Potential renal parenchymal ischemia may be caused by cyst expansion, which might worsen along with progression of diabetes insipidus in this case.
Other possible coexistent factors might influence clearance of vecuronium and 3-desacetylvecuronium in this patient. Metabolic acidosis and electrolyte abnormalities, including hypermagnesemia, are reportedly variables associated with prolonged neuromuscular blockade. 1However, these values were meticulously corrected. Phenytoin might alter the neuromuscular response to vecuronium. 7Administration of corticosteroids to patients with long-term use of nondepolarizing neuromuscular agents has been implicated as a cause of prolonged muscle weakness. 8,9Mannitol might also influence the clearance of vecuronium. 10However, insufficient data are available regarding these issues to permit further speculation.
In Japan, the diagnosis of brain death requires confirmation of no residual effect of muscle relaxants because these are believed to potentially influence the decision-making process, e.g. , interfering with examination of the swallowing reflex. 11The measurement of blood concentrations of vecuronium and 3-desacetylvecuronium were not mandated as part of legal decision making in this case, but their measurement fortuitously revealed the extremely prolonged clearance of vecuronium and its primary metabolite.
The authors thank Naosuke Sugai, M.D., Ph.D. (Department of Anesthesiology, Chigasaki Tokushukai Medical Center, Kanagawken, Japan), for valuable comments in preparing the manuscript.