Richard S. Matteo

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.

Dose-ranging study in younger adult and elderly patients of ORG 9487, a new, rapid-onset, short-duration muscle relaxant

The purpose of this multicenter, randomized, assessor-blind placebo-controlled study was to determine which of five doses of the new, rapid-onset neuromuscular relaxant, ORG 9487, provided both good to excellent tracheal intubating conditions 60 s after administration and a clinical duration of action <20 min in 120 younger (aged 18-64 yr) and 61 elderly (aged 65-85 yr) adult patients. Anesthesia was induced with fentanyl (2-5 micro g/kg) and thiopental (3-6 mg/kg) and maintained with N2 O/O2 and a propofol infusion (50-300 micro g [centered dot] kg-1 [centered dot] min-1). Neuromuscular train-of-four (TOF) monitoring by electromyography (Datex Relaxograph) commenced immediately after anesthetic induction and was followed, within 30 s, by one of five doses of ORG 9487 (0.5, 1.0, 1.5, 2.0, 2.5 mg/kg) or a placebo. Tracheal intubation was attempted at 60 s and again, in the case of failure, at 90 s. Conditions were assessed with a 4-point scale. Maximum block, clinical duration (time to 25% T1 recovery), and recovery (TOF >or=to 0.7) were measured. Dose-dependent changes were observed in tracheal intubating conditions and neuromuscular block. Good to excellent intubating conditions at 60 s were present in most younger adult (52 of 60) and elderly (26 of 31) patients administered doses >or=to1.5 mg/kg. Mean clinical durations <20 min were observed in adult patients at doses up to 2.0 mg/kg and in geriatric patients up to 1.5 mg/kg. Thus, doses of 1.5-2.0 mg/kg ORG 9487 enabled both rapid tracheal intubation and a short clinical duration of action in adult and elderly patients. (Anesth Analg 1997;84:1011-8)

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.

Cerebral Blood Flow Reactivity to Changes in Carbon Dioxide Calculated Using End-Tidal versus Arterial Tensions

We retrospectively examined arterial and endtidal estimations of CO2 tension used to calculate cerebrovascular reactivity in 68 anesthetized patients. CBF was measured using the intravenous 133Xe technique at mean ± SD Paco2 values of 28.2 ± 5.2 and 38.8 ± 4.8 mm Hg. The correlation between all Paco2 and end-tidal Pco2 (Petco2) values was y = 0.85x −0.49 (r = 0.93, p = 0.0001). There was a moderate correlation between age and the difference between Paco2 and Petco2 (y = 0.11x + 0.79; r = 0.73, p = 0.0001). Cerebrovascular reactivity to changes in CO2 (ml 100 g−1 min−1 mm Hg−1) was similar (p = 0.358) when calculated by using either Paco2 (1.9 ± 0.8) or Petco2 (1.8 ± 0.8) and highly correlated (y = 0.86x + 0.23; r = 0.91, p = 0.0001). The CBF response to changes in CO2 tension can be reliably estimated from noninvasive measurement of Petco2.

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.

Resistance to Metocurine-induced Neuromuscular Blockade in Patients Receiving Phenytoin

Recent reports have described resistance to pancuronium-induced neuromuscular blockade in patients chronically receiving anticon-vulsants. This study examines the pharmacokinetics and pharma-codynamics of metocurine (MTC) in 12 patients undergoing cra-niotomy—six on chronic phenytoin therapy and six comparable controls. Each patient received MTC 0.2 mg/kg during the induction of general anesthesia. Quantification of plasma MTC concentration was performed by radioimmunoassay, while the response to MTC was evaluated by evoked compound electromyography (ECEMG). Patients in the phenytoin group were resistant to this dosage of MTC, as demonstrated by their response (83 ± 16% compared with 98 ± 2% depression of ECEMG in control patients, P < 0.05) and by recovery index, defined as the time required for recovery from 25 to 75% of the control ECEMG (53 ± 22 min compared with 125 ± 54 min in control patients, P < 0.01). Similarly, the total duration of neuromuscular blockade, measured to recovery to 90% of control ECEMG, was significantly shorter in the phenytoin group (122 ± 25 min compared with 269 ± 64 min in the control group, P < 0.01). Plasma concentration-time curves were fit to biexponential equations for both groups. These were used to generate two-compartment models. Neither the model parameters nor the plasma concentrations of MTC at any time in the study were significantly different for the two groups. The pharmacody-namic analysis, however, showed that patients on phenytoin require a higher plasma concentration of MTC (0.415 ± 0.095 μg/ml compared with 0.249 ± 0.066 μg/ml in control patients at 50% ECEMG, P < 0.01) to effect a given level of neuromuscular blockade. This resistance could be demonstrated at all levels of neuromuscular blockade (20–80% depression of ECEMG). On the basis of this study, it can be concluded that resistance to metocurine in patients chronically being treated with phenytoin does exist as a result of some, yet undefined, pharmacodynamic alteration in this patient group.

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.

Pulmonary Shunting during Anesthesia with Deliberate Hypotension

Pulmonary shunling (&OV0422;t,/&OV0422;t, with FIO2 = 1) was measured in 18 anesthetized patients during deliberate hypotension. Hypotension was induced in 12 patients with sodium nitroprusside and light halothane anesthesia and in six others with deep halothane anesthesia and mechanical hyperventilation. Similar results were observed in the two groups. During the hypotensive period mean arterial pressure (MAP) was reduced to 49 ± 2 torr, a 37 per cent decrease from the control level after the onset of operation and a 40 per cent decrease compared with the recovery level during closure of the wound. &OV0422;t/&OV0422;t, however, remained unchanged throughout the study; 52 ± 0.9 per cent initially, 5.4 ± 0.8 per cent during hypotension, and 4.7 ± 0.5 per cent during recovery. It is concluded that pulmonary shunting need not develop during dliberate hypotension induced with either technique.