Arthur E. Schwartz

The Effect of Phenytoin on the Magnitude and Duration of Neuromuscular Block Following Atracurium or Vecuronium

Patients chronically receiving anticonvulsants have been reported to be resistant to the long-acting competitive neuromuscular blockers. This study examines the effects of atracurium and vecuronium on 100 neurosurgical patients; 50 receiving chronic phenytoin therapy (group I) and 50 controls (group II). During O2/N2O/ halothane anesthesia, five patients in each group were given a bolus of vecuronium 0.1 mg/kg, and a different five patients in each group were given atracurium 0.5 mg/kg, to produce neuromuscular blockade in excess of 95%. The time to maximum blockade and the recovery from atracurium was unaffected by phenyioin therapy. Recovery from vercuroinium was enhanced in the phenytoin group, as demonstrated by the recovery index, defined as the time required for recovery from 25–75% of the control neuromuscular response (7.9 ± 2.2 min compared with 17.8 ± 5.1 min in controls, P < 0.005). Similarly, the total duration of neuromuscular blockade, defined as recovery to 90% of control response, was significantly shorter in the phenytoin group (31.9 ± 6.0 min compared with 69.7 ± 12.9 min in controls, P < 0.001). The remaining 40 patients from each group were given a preselected dose of either vecuronium (0.02–0.06 mg/kg) or atracurium (0.10–0.25 mg/kg) during anesthesia with O2/N2O/fentanyl, to generate dose-response curves for the relaxants. Using analysis of covariance, the slopes and elevations for atracurium were found to be essentially identical in the two groups; as were the calculated ED50 and ED95. Patients receiving chronic phenytoin therapy were resistant to vecuronium-induced neuromuscular blockade. With vecuronium, the dose-response curves for the two groups were parallel; the curve for phenytoin patients was shifted to the right. A larger dose of vecuronium is required in phenytoin-treated patients to provide a given level of neuromuscular blockade. For example, the ED50 was 0.042 mg/kg in the phenytoin grup, compared to 0.028 mg/kg in the control group. This study demonstrates that, although vecuronium is affected by phenytoin in an interaction similar to that previously reported with the long-acting neuromuscular relaxants, atracurium is not similarly affected.

Pharmacokinetics and pharmacodynamics of rocuronium (Org 9426) in elderly surgical patients.

The effects of age on the pharmacokinetic and pharmacodynamic responses to rocuronium (Org 9426) were studied in 20 elderly (>70 yr) and 20 younger control patients (<60 yr) during N2O/O2, fentanyl anesthesia. The onset times were the same for both the elderly and younger control group, but the duration of action of rocuronium was significantly prolonged in the elderly patients. Elderly patients, when compared with the younger, also exhibited a significant decrease in plasma clearance (3.67 ± 1.0 vs 5.03 ± 1.5 mL·kg−1·min−1, mean ± SD) and volume of distribution (399 ± 122 vs 553 ± 279 mL/kg, mean ± SD). During the recovery phase of paralysis, no significant difference was seen in the log plasma concentration versus twitch tension response relationship between 20% and 80% paralysis in young and elderly patients receiving rocuronium. The differences in action of rocuronium between the elderly and younger groups can be fully explained by the observed differences in the distribution and elimination of rocuronium between the two groups. The decreased total body water and decreased liver mass which normally accompany aging are likely explanations for the pharmacokinetic changes found in the elderly in this study. We conclude that the action of rocuronium is prolonged in patients aged more than 70 yr because of decreased elimination of the drug.

Cerebral blood flow is determined by arterial pressure and not cardiopulmonary bypass flow rate

BACKGROUND During cardiopulmonary bypass, global hypoperfusion of the brain has been shown to result in ischemic insult and subsequent neurologic injury. Furthermore, outcome after focal cerebral ischemia depends on collateral circulation, which is determined by the parameters of global perfusion. We therefore measured cerebral blood flow during independent manipulations of arterial blood pressure and pump flow rate to determine which of these hemodynamic parameters regulates cerebral perfusion during cardiopulmonary bypass. METHODS Seven anesthesized baboons were placed on cardiopulmonary bypass and cooled to 28 degrees C. Pump flow rate and arterial blood pressure were altered in varied sequence to each of four conditions: (1) full flow (2.23 +/- 0.06 L.min-1.m-2, mean +/- standard deviation) at high pressure (61 +/- 2 mm Hg), (2) full flow (2.23 +/- 0.06 L.min-1.m-2) at low pressure (24 +/- 3 mm Hg), (3) low flow (0.75 L.min-1.m-2) at high pressure (62 +/- 2 mm Hg), and (4) low flow (0.75 L.min-1.m-2 at low pressure (23 +/- 3 mm Hg). During each of these hemodynamic conditions cerebral blood flow was measured by washout of intracarotid xenon. RESULTS Cerebral blood flow was greater at high blood pressure than at low pressure during cardiopulmonary bypass both at low flow (34 +/- 8.3 versus 14.1 +/- 3.7 mL.min-1 x 100 g-1) and full flow (27.6 +/- 9.9 versus 16.8 +/- 3.7 mL.min-1 x 100 g-1) (p < 0.01). At comparable mean arterial blood pressures alteration of pump flow rate produced no changes in cerebral blood flow. CONCLUSIONS These results indicate that cerebral blood flow during moderately hypothermic cardiopulmonary bypass is regulated by arterial blood pressure and not pump flow rate.

Pharmacokinetics of sufentanil in obese patients.

The pharmacokinetics of sufentanil were determined in eight obese (94.1 ± 14 kg, mean ± SD) and eight control patients (70.1 ± 13 kg) anesthetized for neurosurgery. After induction of anesthesia, 4 μg/kg of sufentanil was administered in a single intravenous bolus. Multiple arterial samples were obtained at timed intervals over 6 h, and plasma concentrations of sufentanil were measured by radioimmunoassay. Calculation of pharmacokinetic variables from the derived compartmental models demonstrated an increased volume of distribution of sufentanil in the obese (9098 ± 2793 mL/kg ideal body weight, mean ± SD) when compared with a control group (5073 ± 1673 mL/kg ideal body weight) (P < 0.01) and a prolonged elimination half-life (208 ± 82 min vs 135 ± 42 min, P < 0.05). The total volume of distribution correlated linearly with the degree of obesity, as expressed in percent ideal body weight (r = 0.67). In contrast, plasma clearance was similar in both obese and control groups (32.9 ± 12.5 vs 26.4 ± 5.7 mL/kg ideal body weight). The high lipid solubility of sufentanil probably explains the altered pharmacokinetics of this opioid in obese patients.

Pharmacokinetics and pharmacodynamics of vecuronium in the obese surgical patient

The effect of obesity on the disposition and action of vecuronium was studied in 14 surgical patients. After induction of anesthesia with thiopental and maintenance of anesthesia by inhalation of nitrous oxide and halothane, seven obese patients (93.4 ± 13.9 kg, 166% ± 30% of ideal body weight, mean ± SD) and seven control patients (60.9 ± 12.3 kg, 93% ± 6% of ideal body weight) received 0.1 mg/kg of vecuronium. Plasma arterial concentrations of muscle relaxant were determined at 1, 3, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300, and 360 min by a spectrofluorometric method. Simultaneously, neuromuscular blockade was assessed by stimulation of the ulnar nerve and quantification of thumb adductor response. Times to 50% recovery of twitch were longer in the obese than in the control patients (75 ± 8 versus 46 ± 8 min) as were 5%-25% recovery times (14.9 ± 4.0 versus 10.0 ± 1.7 min) and 25%-75% recovery times (38.4 ± 13.8 versus 16.7 ± 10.3 min). However, vecuronium pharmacokinetics were similar for both groups. When the data were calculated on the basis of ideal body weight (IBW) for obese and control patients, total volume of distribution (791 ± 303 versus 919 ± 360 mL/kg IBW), plasma clearance (4.65 ± 0.89 versus 5.02 ± 1.13 mL-min−1·kg IBW−1), and elimination half-life (119 ± 43 versus 133 ± 57 min) were not different between groups. Only when total volume of distribution and clearance are divided by patient weight (a larger value for the obese) and expressed per kilogram of actual body weight do these values appear smaller in the obese (473 ± 142 versus 993 ± 401 mL/kg and 2.83 ± 0.54 versus 5.36 ± 1.14 mL·min−1·kg−1, respectively). As obesity did not alter the distribution or elimination of vecuronium, the prolonged action seen at 0.1 mg/kg is due to an overdose when vecuronium is administered on the basis of total body weight. Clinically, ideal body weight should be used for dose calculation in the obese patient.

Pharmacodynamics of vecuronium and atracurium in the obese surgical patient

The effect of obesity on the duration of action of the nondepolarizing muscle relaxants atracurium and vecuronium was studied in 28 neurosurgical patients. In obese patients given vecuronium (0.1 mg/kg), the time to go from 5 to 25% of recovery of twitch response was statistically significantly longer (14.6 7 minutes, mean SD) than it was in nonobese control patients (6.9 ± 2 minutes). Similarly, with vecuronium times for recovery from 25 to 75% were longer (33 ± 15 minutes) in obese patients than in control patients (13.2 ± 2 minutes), as was time to 75% recovery, 82 ± 30 minutes in obese patients, 50 ± 9 minutes in controls. In contrast, obese patients given atracurium (0.5 mg/kg) exhibited no difference in recovery indexes or recovery times when compared to control patients of normal weight. The prolonged duration of action of vecuronium in obese patients is most likely related to impaired hepatic clearance and/or an overdose effect with recovery occurring during the distribution phase. That the duration of action of atracurium is not prolonged in the obese is believed due to this relaxants not depending on organ function for elimination.

Distribution, elimination, and action of vecuronium in the elderly.

The effects of age on the pharmacokinetics and pharmacodynamics of vecuronium in eight elderly patients aged 72–86 yr and eight younger adults aged 26–48 yr undergoing elective surgical procedures under nitrous oxide-fentanyl anesthesia were studied. Vecuronium (0.1 mg/kg) was given as an intravenous bolus, and the ulnar nerve was stimulated with a square-wave impulse of 0.2-ms duration. The response to stimulation at a frequency of 0.1 Hz was measured and recorded with a force displacement transducer applied to the thumb. Spontaneous recovery was significantly longer in elderly patients than in younger patients (50% recovery time, 97.1 ± 29 vs 39.8 ± 14 min, mean ± SD; recovery index [25%−75%], 49.4 ± 11 vs 15.0 ± 8 min). In addition, in elderly patients elimination half-life of vecuronium was significantly prolonged (125 ± 55 vs 78 ± 21 min, P = 0.04) and plasma clearance reduced (2.6 ± 0.6 vs 5.6 ± 3.2 mL·kg−1·min−1, P = 0.049). The prolonged duration of action of vecuronium in the elderly surgical patients thus appears to be secondary to altered pharmacokinetics consistent with an age-related decrease in renal and hepatic functions.

Electroencephalographic burst suppression in elderly and young patients anesthetized with isoflurane.

The electroencephalograms of seven elderly (70–85 years) and seven younger patients (23–31 years) anesthetized with a concentration of isoflurane sufficient to produce burst suppression were studied. Anesthesia in these unpremedicated subjects was induced by inhalation of nitrous oxide, isoflurane, and oxygen. Tracheal intubation was facilitated with succinylcholine and the lungs were next ventilated with oxygen and isoflurane to produce an end-tidal concentration of 1.7%. Isoflurane concentration was determined by infrared analysis of expired gas collected from a Teflon catheter inserted through the endotracheal tube. After 25 minutes at steady state, the EEG was recorded for 5 minutes prior to surgical stimulation. Arterial blood pressure, temperature, and ventilation were maintained at normal values. In elderly patients the EEG had both a greater proportion of total time in electrical silence (76.0 ± 10.8% vs 37.6 ± 15.4%; P < 0.01) and a greater number of isoelectric periods (19.7 ± 8.1 vs 10.7 ± 5.4; P < 0.05). This demonstrates a discrete alteration with age in the central nervous system sensitivity to isoflurane.

Pancuronium Increases the Duration of Electroencephalogram Burst Suppression in Dogs Anesthetized with Isoflurane

Earlier studies have demonstrated both a decrease as well as no effect on halothane MAC after administration of nondepolarizing neuromuscular relaxants. To clarify further the relationship between neuromuscular blocking agents and anesthetic potency, the authors studied the effect of pancuronium on steady-state electroencephalogram (EEG) burst suppression produced by isoflurane in dogs. Anesthesia was induced using isoflurane and oxygen via mask without the administration of other drugs. The trachea was intubated, and isoflurane was administered at a concentration sufficient to produce EEG burst suppression. Thereafter, end-tidal isoflurane concentration, temperature, and end-tidal PCO2 were meticulously maintained at constant values. Dogs in group 1 (n = 6) received pancuronium 0.1 mg.kg-1. The percent of the EEG that was isoelectric increased from 21 +/- 9% (mean +/- SD) to 35 +/- 11% (P less than 0.01). After the return of single-twitch response to train-of-four stimulation, neostigmine 0.05 mg.kg-1 and glycopyrrolate 0.01 mg.kg-1 were administered. This resulted in a reduction in EEG isoelectricity to 19 +/- 8% (P less than 0.01), similar to the value before pancuronium administration. In group 2 dogs (n = 6), the percent isoelectricity of the EEG prior to pancuronium was 25 +/- 10%. After administration of pancuronium 0.02, 0.04, and 0.2 mg.kg-1 sequentially, the percent isoelectricity of the EEG was 29 +/- 11, 37 +/- 15, and 43 +/- 9%, respectively. This represents a dose-related increase in isoelectricity for the 0.04- and 0.2-mg.kg-1 doses (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and pharmacodynamics of pipecuronium bromide (Arduan) in elderly surgical patients

The neuromuscular response to pipecuronium bromide (Arduan), 70 μg/kg, was studied in 20 elderly (>70 yr) and 10 younger Patients (<60 Yr) during nitrous oxide, fentanyl, and droperidol anesthesia. The adductor Pollicis response to single 0.2-ms suparamaximal pulses was recorded. Although all younger patients were completely paralyzed, 2 of 20 elderly patients did not attain paralysis. Onset time in the elderly was prolonged (6.9 ± 2.6 vs 4.3 ± 1.5 min, P < 0.02). Spontaneous recovery was similar in both groups, with 75% recovery occurring at 133 ± 52 min in the elderly and 146 ± 46 min in the younger patients. The pharmacokinetic variables were similar for the two groups, and pharmacodynamic analysis revealed a similar sensitivity at the neuromuscular junction. The pharmacologic actions of pipecuronium in otherwise healthy patients do not differ between young and elderly adults.