Gerald McCarthy

Temperature-dependent pharmacokinetics and pharmacodynamics of vecuronium.

Background The authors evaluated the influence of temperature on the pharmacokinetics and pharmacodynamics of vecuronium because mild core hypothermia doubles its duration of action. Methods Anesthesia was induced with alfentanil and propofol and maintained with nitrous oxide and isoflurane in 12 healthy volunteers. Train-of-four stimuli were applied to the ulnar nerve, and the mechanical response of the adductor pollicis was measured. Volunteers were actively cooled or warmed until their distal esophageal temperatures were in one of four ranges: < 35.0°C, 35.0–35.9°C, 36.0–36.9°C, and ≥ 37.0°C. With temperature stabilized, vecuronium was infused at 5 &mgr;g · kg−1 · min−1 until the first response of each train-of-four had decreased by 70%. Arterial blood (for vecuronium analysis) was sampled at intervals until the first response recovered to at least 90% of its prevecuronium level. Vecuronium, 20 &mgr;g · kg−1 · min−1, was then infused for 10 min, and arterial blood was sampled at intervals for up to 7 h. Population-based nonlinear mixed-effects modeling was used to examine the effect of physical characteristics and core temperature on vecuronium pharmacokinetics and pharmacodynamics. Results Decreasing core temperature over 38.0–34.0°C decreases the plasma clearance of vecuronium (11.3% per °C), decreases the rate constant for drug equilibration between plasma and effect site (0.023 min−1 per °C), and increases the slope of the concentration–response relationship (0.43 per °C). Conclusions Our results show that reduced clearance and rate of effect site equilibration explain the increased duration of action of vecuronium with reducing core temperature. Tissue sensitivity to vecuronium is not influenced by core temperature.

Estimation of the potency of ORG 9426 using two different modes of nerve stimulation.

The potency of ORG 9426, a new nondepolarising muscle relaxant, has been estimated using two different modes of nerve stimulation in patients anaesthetised with thiopentone, nitrous oxide-oxygen and intravenous fentanyl. The force of contraction of adductor pollicis was measured following a single twitch (ST) at 0.1 Hz or a train-of-four (TOF) mode of stimulation at 2 Hz every ten seconds. Dose-response curves were constructed using a single-dose method. The ED50, ED90 and ED95 were 147, 272 and 305 μg · kg−1 respectively using the ST mode and 125, 230 and 257 μg · kg−1 using the TOF mode of stimulation. The ED50s were not significantly different but the differences between ED90s and ED95s were significant (P <0.05) indicating greater sensitivity of the neuromuscular junction using TOF stimulation. The results of this study suggest that the information obtained by single-twitch stimulation is not the same as that obtained from the first response of the TOF stimulation, suggesting apparently increased sensitivity (and apparently greater potency) with the TOF mode of stimulation. Org 9426 appears to be a drug with relatively low potency.RésuméLa puissance de l’ORG 9426, un nouveau relaxant musculaire non-dépolarisant, a été estimée utilisant deux différents modes de stimulation nerveuse chez les patients anesthésiés au pentothal, protoxyde d’azote-oxygène et fentanyl intraveineux. La force de contraction de l’adducteur de pouce fut mesurée après un « twitch » unique (ST) à 0,1 Hz ou une ondée-de-quatre (train-of-four) (TOF) à 2 Hz chaque dix secondes. Les courbes de dose-réponse furent construites utilisant la méthode de dose unique. Les ED50, ED90 et ED95 furent 147, 272 et 305 μg · kg−1 respectivement utilisant le mode ST et 125, 230 et 257 μg · kg−1 respectivement utilisant le mode TOF. Les ED50s ne furent pas significativement différents mais les différences entre les ED90s et les ED95s furent significatifs (P < 0,05) indiquant une plus grande sensibilité de la jonction neuromusculaire utilisant la stimulation TOF. Les résultats de cette étude suggèrent que l’information obtenue par un « twitch » unique n ’est pas la même que celle obtenue par la stimulation TOF, suggérant apparemment une plus grande sensibilité (et apparemment une plus grande puissance) avec la stimulation TOF. Org 9426 apparaît comme étant une drogue ayant relativement une puissance faible.

A comparison of different pre-oxygenation techniques in the elderly.

The efficacy of five different techniques of pre‐oxygenation before a modified rapid intubation sequence was assessed, using oxygen saturation measurement, in patients aged over 65 years. Twenty patients in each group were pre‐oxygenated using four deep breaths or normal tidal breathing for 1, 2, 3, or 4 minutes. The acceptable period of apnoea was defined as the time taken to desaturate to 93%. The mean times (SD) taken to reach this end‐point were 3.7 (1.6), 4.1 (1.2), 5.4 (1.7), 5.4 (1.4) and 5.2 (1.7) minutes respectively. The apnoea times with 2, 3 and 4 minutes pre‐oxygenation were not significantly different from each other but were significantly longer than after four deep breaths and 1 minute. It is concluded that a pre‐oxygenation period of at least 2 minutes should be employed in the elderly before a rapid sequence induction.

Influence of Chronic Phenytoin Administration on the Pharmacokinetics and Pharmacodynamics of Vecuronium

BackgroundThe duration of action of vecuronium is reduced in patients receiving phenytoin. In this study, the authors examined, simultaneously, the influence of phenytoin on both the pharmacokinetics and the pharmacodynamics of vecuronium. MethodsThis study was approved by the institutional review board of the University of California, San Francisco, and patients gave written informed consent. Twenty-two patients, 11 taking phenytoin and all scheduled to undergo prolonged neurosurgical procedures with general anesthesia, participated in the study. In 12 patients (6 phenytoin, 6 control), vecuronium was infused at 7.5 &mgr;g · kg−1 · min−1 until the first response (T1) of each train-of-four decreased by 50%; in the remaining 10 patients (5 phenytoin, 5 control), 200 &mgr;g/kg vecuronium was infused over 10 min. Arterial blood samples were drawn at intervals over the next 5–7 h. Plasma concentrations of vecuronium and 3-desacetylvecuronium were measured by capillary gas chromatography. Pharmacokinetic and pharmacodynamic modeling was used to characterize the disposition of vecuronium and patient responses to it in the two groups. ResultsClearance was typically increased by 138% (95% confidence interval, 93–183%) in patients taking phenytoin. The effect of vecuronium was well described using a sigmoid Emax model. The concentration of vecuronium giving 50% twitch depression was increased 124% (45–202%) in patients taking phenytoin. ConclusionsChronic phenytoin therapy reduces the effect of vecuronium by mechanisms that include both increased vecuronium metabolism and reduced sensitivity of the patient to circulating concentrations of vecuronium.

Postoperative oxygenation in the elderly following general or local anaesthesia for ophthalmic surgery

Peripheral oxygen saturation was recorded on the pre‐operative night (between 2400 and 0600 h), the immediate postoperative period (first 60 min) and the first postoperative night (2400 to 0600 h) in 18 elderly patients aged 70 years or over presenting for elective ophthalmic surgery. Nine patients had surgery performed under general anaesthesia employing muscle relaxants and controlled ventilation and nine under local anaesthesia using a peribulbar block. The median (interquartile range) percentage of time during which the patients had an oxygen saturation of less than 90% was 0 (0–0.2) and 0.04 (0–0.4) on the pre‐operative night, 0.7 (0–1.4) and 0.3 (0–1.2) in the immediate postoperative period, and 0.05 (0–0.16) and 0 (0–0.3) on the postoperative night in the general and local anaesthesia patients respectively. There were no significant differences between general and local anaesthesia in respect of these data and the overall incidence of significant desaturation was low. The present study could not demonstrate any adverse effect of general anaesthesia on oxygen saturation in patients undergoing minimally invasive surgery.

Dose-responses for edrophonium during antagonism of vecuronium block in young and older adult patients

The dose‐response relationship for edrophonium during antagonism of vecuronium‐induced neuromuscular blockade was studied in two groups of adult patients of mean (SD) age 35(10.0) years (n = 42) and 77 (5.4) years (n = 42) respectively. Neuromuscular block was monitored by recording the force of contraction of the adductor pollicis muscle following train‐of‐four stimulation. Six patients in each age group received 0.1, 0.3, 0.5, 0.7, 1.0, or 1.5mg.kg‐1 of edrophonium, or normal saline at 10% recovery of T1 (first response in the train‐of‐four) after a single dose of vecuronium 0.08mg.kg‐1. The train‐of‐four ratios were recorded continuously over the next 10 min and the values at 1 min intervals from 5min onwards were used to construct the dose‐response curves. The dose‐response curves showed no significant difference between the two age groups except at 10 min. The estimated dose of edrophonium required for attaining a train‐of‐four ratio of 0. 7 at 10 min was 0.9 and 1.3 mg.kg‐1 in the younger and older groups, respectively (p < 0.05).