Effects of Phenytoin on Rocuronium-induced Neuromuscular Blockade Using a Rat Phrenic Nerve-diaphragm Preparation / 대한마취과학회지

ABSTRACT

BACKGROUND: Chronic anticonvulsant therapy with phenytoin antagonizes the action of nondepolarizing muscle relaxants. Rocuronium is a new non depolarizing muscle relaxant of rapid onset and intermediate duration. This study was designed to investigate the effects of phenytoin on rocuronium-induced neuromuscular blockade using a rat phrenic nerve-diaphragm preparation. METHODS: Male Sprague-Dawley rats (200 g, n = 70) were randomly allocated into a control group (C, n = 10), three phenytoin-pretreated groups (PP, n = 30) and three phenytoin-non-pretreated groups (PNP, n = 30). In phenytoin-pretreated groups, phenytoin 50 mg/kg/day was administered intraperitoneally once a day for one day (PP1D), seven days (PP7D) or twenty eight days (PP28D). Animals were anesthetized with 40 mg/kg of thiopental sodium intraperitoneally and the diaphragm with the phrenic nerve were dissected, and the phrenic nerve-diaphragm preparation was suspended in 100 ml of Krebs solution in an organ bath. The bath was aerated with 95% O2-5% CO2 at 32oC, and the phrenic nerve was stimulated with supramaximal intensity using a stimulator. Twitch responses were measured using a precalibrated force displacement transducer and recorded. The cumulative dose-response relationships of rocuronium and phenytoin were determined. After one hour's stabilization, rocuronium 100 microgram was added to the bath, and when a stable 3-5 twitch was obtained, incremental 50 microgram doses of rocuronium were added to obtain more than 95% neuromuscular twitch inhibition at 0.1 Hz. In the phenytoin-non-pretreated group, phenytoin was administered simultaneously with the initial dose of rocuronium to a phenytoin concentration of 1 microgram/ml (PNP1), 10 microgram/ml (PNP10), or 100 microgram/ml (PNP100) in Krebs solution. Data were analyzed by probit and logistic models. In the PP group, the plasma concentration of phenytoin was analyzed by high performance liquid chromatography. RESULTS: The dose-response curve of rocuronium was significantly shifted to the left in the PNP100 group (P < 0.05), and significantly shifted to the right in the PP28D group (P < 0.05). The plasma phenytoin concentration was found to be directly proportional to the duration of the phenytoin pretreatment. CONCLUSIONS: The potency of rocuronium is reduced in chronic phenytoin therapy and increased after an acute high dose of phenytoin.