Eugene Ornstein

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.

Patient state index : titration of delivery and recovery from propofol, alfentanil, and nitrous oxide anesthesia

Background The Patient State Index (PSI) uses derived quantitative electroencephalogram features in a multivariate algorithm that varies as a function of hypnotic state. Data are recorded from two anterior, one midline central, and one midline posterior scalp locations. PSI has been demonstrated to have a significant relation to level of hypnosis during intravenous propofol, inhalation, and nitrous oxide–narcotic anesthesia. This multisite study evaluated the utility of PSI monitoring as an adjunct to standard anesthetic practice for guiding the delivery of propofol and alfentanil to accelerate emergence from anesthesia. Methods Three hundred six patients were enrolled in this multicenter prospective randomized clinical study. Using continuous monitoring throughout the period of propofol–alfentanil–nitrous oxide anesthesia delivery, PSI guidance was compared with use of standard practice guidelines (both before [historic controls] and after exposure to the PSA 4000 monitor [Physiometrix, Inc., N. Billerica, MA; standard practice controls]). Anesthesia was always administered with the aim of providing hemodynamic stability, with rapid recovery. Results No significant differences were found for demographic variables or for site. The PSI group received significantly less propofol than the standard practice control group (11.9 &mgr;g · kg−1 · min−1;P < 0.01) and historic control group (18.2 &mgr;g · kg−1 · min−1;P < 0.001). Verbal response time, emergence time, extubation time, and eligibility for operating room discharge time were all significantly shorter for the PSI group compared with the historic control (3.3–3.8 min;P < 0.001) and standard practice control (1.4–1.5 min;P < 0.05 or P < 0.01) groups. No significant differences in the number of unwanted somatic events or hemodynamic instability and no incidences of reported awareness were found. Conclusions Patient State Index–directed titration of propofol delivery resulted in faster emergence and recovery from propofol–alfentanil–nitrous oxide anesthesia, with modest decrease in the amount of propofol delivered, without increasing the number of unwanted events.

Importance of the organ-independent elimination of cisatracurium.

Cisatracurium, one of 10 isomers of atracurium, undergoes pH and temperature-dependent Hofmann elimination in plasma and tissues. The clearance of cisatracurium due to Hofmann elimination and organ elimination was estimated by applying a nontraditional two-compartment pharmacokinetic model with elimination occurring from both compartments to plasma cisatracurium concentration-time data from 31 healthy adult surgical patients with normal renal and hepatic function. The elimination rate constant from the central compartment, intercompartmental rate constants, and the volume of the central compartment were obtained from the model fit. The elimination rate constant from the peripheral compartment could not be independently estimated in vivo and was therefore fixed to the rate of degradation of cisatracurium in human plasma (pH 7.4 and 37 degrees C) and held constant in the model. Total body clearance, Hofmann clearance, organ clearance, and the volume of distribution at steady-state were derived from the model parameter estimates. Renal clearance was calculated from cisatracurium urinary excretion data from 12 of the 31 patients. Clearance values (mean +/- SD) were 5.20 +/- 0.86, 4.00 +/- 1.04, 1.20 +/- 0.71, and 0.85 +/- 0.32 mL [centered dot] min-1 [centered dot] kg-1 for total body clearance, Hofmann clearance, organ clearance, and renal clearance, respectively. Hofmann clearance accounted for 77% of total body clearance. Organ clearance was 23% of total body clearance. Renal clearance, a component of organ clearance, was 16% of total body clearance. The organ-independent nature of the elimination of cisatracurium was characterized by a relationship between steady-state volume of distribution and total body clearance. The half-life is an independent variable and is not dependent on the total body clearance nor the steady-state volume of distribution. Hofmann elimination is the predominant pathway for cisatracurium elimination in humans. (Anesth Analg 1996;83:1065-71)

Desflurane and Isoflurane Have Similar Effects on Cerebral Blood Flow in Patients with Intracranial Mass Lesions

Background:Before desflurane is advocated for patients undergoing neurosurgical procedures, it is necessary to determine the effect of desflurane on cerebral blood flow (CBF). In this study, CBF values are compared between desflurane and isoflurane at two doses. In addition, CBF reactivity to CO2 and the effect of prolonged exposure were compared between the two agents. Methods:Cerebral blood flow measurements with intravenous 133Xe were performed in 24 patients undergoing craniotomy for mass lesions, randomized to receive either isoflurane or desflurane in oxygen and air. Cerebral blood flow was determined at 1 and 1.5 MAC concentrations at PaCO2 of 25 mmHg in the absence of surgical stimulation. Intraoperatively, with 1.25 MAC anesthesia, CBF was determined at target PaCO2 of 25 and 35 mmHg. In 15 patients, an additional measurement at 1.25 MAC was made before closure. Results:At 1.0 MAC, mean ± SD CBF values for the desflurane and isoflurane groups were 18 ± 2 and 20 ± 3 ml · 100 g−1 · min−1, respectively. At 1.5 MAC, CBF values were the same for the two anesthetics; 17 ± 3 ml · 100 g−1 · min−1 for isoflurane and 19 ± 4 ml · 100 g−1 · min−1 for desflurane. During 1.25 MAC anesthesia, there were no differences between groups, with CO2 reactivity 1.3 ± 1.2 ml · 100 g−1 · min−1 · mmHg−1 for desflurane and 1.6 ± 0.6 ml · 100 g−1 · min− · mmHg−1 for isoflurane. There was no demonstrable decrease in CBF with prolonged exposure to either agent. Conclusions:Desflurane and isoflurane are similar in terms of absolute CBF, the response to increasing doses, and the preservation of CO2 reactivity.

Cerebral Hyperemia after Arteriovenous Malformation Resection Is Related to “Breakthrough” Complications but Not to Feeding Artery Pressure

To study the pathophysiology of idiopathic postoperative brain swelling or hemorrhage after arteriovenous malformation resection, termed normal perfusion pressure breakthrough (NPPB), we performed cerebral blood flow (CBF) studies during 152 operations in 143 patients, using the xenon-133 intravenous injection method. In the first part of the study, CBF was intraoperatively measured (isoflurane/N2O anesthesia) during relative hypocapnia in 95 patients before and after resection. The NPPB group had a greater increase (P < 0.0001) in mean +/- standard deviation global CBF (28 +/- 6 to 47 +/- 16 ml/100 g/min, n = 5) than did the non-NPPB group (25 +/- 7 to 29 +/- 10 ml/100 g/min, n = 90); both arteriovenous malformation groups showed greater increase (P < 0.05) than did controls undergoing craniotomy for tumor (23 +/- 6 to 23 +/- 6 ml/100 g/min, n = 22). Ipsilateral and contralateral CBF changes were similar. In a second cohort of patients with arteriovenous malformations, CBF was measured at relative normocapnia and it increased (P < 0.002) from pre- to postresection (40 +/- 13 to 49 +/- 15 ml/100 g/min, n = 57). There were no NPPB patients in this latter cohort. The feeding mean arterial pressure was measured intraoperatively before resection or at the last embolization before surgery (n = 64). The feeding mean arterial pressure (44 +/- 16 mm Hg) was 56% of the systemic arterial pressure (78 +/- 12 mm Hg, P < 0.0001) and was not related to changes in CBF from pre- to postresection. There was an association between increases in global CBF from pre- to postresection and NPPB-type complications, but there was no relationship of these CBF changes to preoperative regional arterial hypotension. These data do not support a uniquely hemodynamic mechanism that explains cerebral hyperemia as a consequence of repressurization in hypotensive vascular beds.

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.

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.

Comparison of Electrophysiologic Monitors With Clinical Assessment of Level of Sedation

OBJECTIVE To assess the correlation between 2 clinical sedation scales and 2 electroencephalographic (EEG)-based monitors used during surgical procedures that required mild to moderate sedation. PATIENTS AND METHODS Patients scheduled for elective surgery participated in this Institutional review board-approved study from March 2003 to February 2004. Level of sedation was determined both clinically using the Ramsay and the Observers Assessment of Alertness/Sedation scales and with 2 EEG measures (the Bispectral Index version XP [BIS XP] or the Patient State Analyzer [PSA 4000]). Correlation between these 2 measures of sedation were tested using nonparametric statistical tests. RESULTS The BIS XP monitor was used in 26 patients, and the PSA 4000 monitor was used in 24 patients. The Ramsay and Observers Assessment of Alertness/Sedation scores correlated with each other (r = -0.96; P < .001) and with both the BIS XP (r = -0.89 and r = 0.91, respectively; P < .001) and the PSA 4000 (r = -0.80 and r = 0.80, respectively; P < .001) values. However, this correlation was strongest only at the extremes. Between the BIS XP and PSA 4000 values of 61 and 80, the clinical sedation scores varied greatly. CONCLUSION On the basis of our results, these EEG-based monitors cannot reliably distinguish between light and deep sedation.

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.