Richard R. Bartkowski

Rocuronium Onset of Action: A Comparison with Atracurium and Vecuronium

The onset, maximal neuromuscular block, and duration of rocuronium were compared with atracurium and vecuronium during enflurane anesthesia. Sixty patients received rocuronium (80,100,120, or 160 μg/kg). Enflurane enhanced a rocuronium neuromuscular block in a dose-related manner; the ED50 was 104 ± 11 and 83 ± 7 μg/kg (SEM) during 1% and 2% enflurane anesthesia, respectively. Patients receiving atracurium (0.12 mg/kg) or vecuronium (0.02 mg/kg) were studied during 1 % enflurane anesthesia until seven in each group qualified by achieving a maximal block between 85% and 97%. These patients were matched with each other and with patients who had received rocuronium. Seven groups of three patients (rocuronium, vecuronium, and atracurium) were obtained. The average difference in maximal block was less than 2% between matched patients. The ratio of dose used to achieve a similar final block suggests potency ratios of 1,8.5, and 1.2 for rocuronium, vecuronium, and atracurium. Rocuroniums onset time (time from drug administration to 50%, 75%, and 90% of final block) was significantly faster than either of the other two muscle relaxants (P < 0.01). Time to 90% of final block was 1.35 min for rocuronium, 3.06 min for atracurium, and 3.71 min for vecuronium. Using these equipotent doses, atracurium also had a shorter time to develop neuromuscular block than vecuronium (P < 0.05). For these three intermediate duration neuromuscular blockers, speed of onset was inversely related to their potency, confirming a relationship that had been demonstrated for the long-acting drugs pancuronium, d-tubocurarine, and gallamine.

Drug Interactions of Clinical Significance with Opioid Analgesics

SummaryOpioid analgesics and other drugs interact through multiple mechanisms, resulting in pharmacological effects that depend upon the pharmacodynamic action studied, the interacting agents and the route of administration. Many interactions result from induction or inhibition of the hepatic cytochrome P450 mono-oxygenase system. The elimination of opioids is largely dependent on hepatic metabolism, and drug interactions involving this mechanism can therefore be clinically significant. Antibiotics are often used concomitantly with opioids in patients undergoing medical or surgical procedures; the best documented metabolic interactions are with erythromycin and rifampicin (rifampin). Erythromycin increases and rifampicin decreases the effects of opioids. Cimetidine may increase the effects of opioids by increasing their duration of action; there have been no documented cases of interactions with ranitidine. Carbamazepine, phenytoin and the barbiturates can enhance the metabolism of opioids that rely on hepatic metabolism. Other pharmacokinetic interactions include those with benzodiazepines, tricyclic antidepressants, phenothiazines and metoclopramide. Interactions involving pharmacodynamic mechanisms are more common than pharmacokinetic ones. Such interactions are manifested clinically as as a summation (additive or synergistic) of similar or opposing pharmacological effects on the same body system. Idiosyncratic interactions also occur, the mechanisms of which have not been proven to be solely modulated by either pharmacokinetic or pharmacodynamic means.The knowledge of particular opioid-drug interactions, and the causative pharmacokinetic, pharmacodynamic, and idiosyncratic mechanisms, allows for the safer administration of opioid analgesics.

Comparative accuracies of a finger blood pressure monitor and an oscillometric blood pressure monitor.

A noninvasive blood pressure monitor (Finapres) that uses the methodology of Peňaz to continuously display the arterial waveform from the finger has been introduced recently. The Finapres monitor overestimated systolic pressure by 5.8±11.9 mm Hg, while the Dinamap monitor underestimated systolic pressure by −6.9±9.2 mm Hg (P=0.003). Dinamap mean and diastolic pressure biases were less than 2 mm Hg, while the Finapres biases for these variables were significantly greater (7.7±10.0 and 8.2±9.8 mm Hg, respectively). There was no difference in systolic or mean pressure precision between the two devices (approximately 10 mm Hg), but the diastolic precision of the Dinamap unit was superior to that of the Finapres. While in most patients the Finapres monitor provided continuous blood pressure data equivalent to the data from the radial artery, marked bias (>15 mm Hg) was exhibited in 2 patients for all three pressure variables. Despite this bias, blood pressure changes were tracked closely in these 2 patients. We conclude that, in its current form, the Finapres monitor cannot be relied upon independently to accurately measure blood pressure in patients undergoing general anesthesia. Since the Dinamap monitor measures mean pressure reliably and accurately, we suggest that mean blood pressure values between the Finapres and Dinamap monitors be compared to guide one in interpreting Finapres data.

Clinical pharmacology of pipecuronium bromide.

The neuromuscular blocking and cardiovascular effects of pipecuronium, in doses ranging 2--3 times its ED95, were evaluated in 46 patients during thiopental, fentanyl, N2O/O2 anesthesia. The neuromuscular blocking effect of pipecuronium was evaluated by recording of the mechanical twitch of the adductor pollicis muscle in response to stimulation of the ulnar nerve at the wrist. Heart rate, systolic and diastolic blood pressures, and cardiac output were noninvasively measured during the onset of the neuromuscular blockade and compared to a saline control group to separate the effect of anesthesia from those of pipecuronium.The mean ± SD time from administration of pipecuronium to 90% suppression of the first twitch (T1) of the tram-of-four was 2.6 ± 0.8, 2.0 ± 0.6, and 2.1 ± 0.6 min following the 70 μg/kg, 85 μg/kg, and 100 μg/kg dose, respectively. There was no significant difference between the different doses of pipecuronium in the time to 90% suppression of T1. In general, all three doses of pipecuronium provided good to excellent intubating conditions within 3 minutes after its administration. The time from the administration of pipecuronium to 5% recovery of T1 was 52.3 ± 18.2 min in the group given 70 μg/kg. This was significantly longer in patients given 85 μg/kg (71.9 ± 15.7 min) or 100 μg/kg (71.8 ± 22.1 min). Times to the start of recovery of T1 and to 25% recovery of T1 showed a similar significant pattern. In 2/3 of the patients, administration of neostigmine (2.5 mg) resulted in adequate recovery of muscle function within 10 minutes. Only patients with T1 recovery to less than 15% of control or a T4/T1 ratio of zero tended to take longer than 10 minutes for full recovery. Heart rate and systolic and diastolic blood pressures decreased significantly after the induction of anesthesia and during the onset of neuromuscular blockade. The hernody-namic variables, however, were similar between the three pipecuronium groups and a control group (N=16) that received only saline. Therefore, no cardiovascular changes could be attributed to pipecuronium when compared to the control group. Cardiac output did not change significantly over the time course of the study.Pipecuronium bromide produces a long-acting, nondepolarizing neuromuscular blockade. A dose of 70 μg/kg can be expected to provide good intubating conditions in 3 minutes with a clinical duration of approximately one hour. Larger doses (85 μg/kg and 100 μg/kg) may shorten the onset time and increase duration on average by 20 minutes. Higher doses are thus best reserved for procedures of long duration. Because no cardiovascular effects were observed with doses ranging from 2--3 times its ED95, pipecuronium can be recommended for patients in whom cardiovascular stability is desired.

Evaluation of Neuromuscular and Cardiovascular Effects of Two Doses of Rapacuronium (ORG 9487) versus Mivacurium and Succinylcholine

BACKGROUND This study compares the neuromuscular blocking and cardiovascular effects of rapacuronium (ORG 9487), a new aminosteroid nondepolarizing muscle relaxant, to recommended intubating doses of succinylcholine and mivacurium. METHODS Adult patients were randomized in an open-label fashion to receive 1-5 microg/kg fentanyl before 1.5 mg/kg propofol induction followed by 1.5 or 2.5 mg/kg rapacuronium, 1.0 mg/kg succinylcholine, or 0.25 mg/kg mivacurium (i.e., 0.15 mg/kg followed by 0.1 mg/kg 30 s later). RESULTS Patient neuromuscular blockade status was monitored by measuring the train-of-four response to a supramaximal stimulus at the ulnar nerve every 12 s. Percentage of the first twitch of the train-of-four (T1) at 60 s was similar in patients receiving 1.5 mg/kg rapacuronium, 2.5 mg/kg rapacuronium, and succinylcholine and was significantly less than in patients in the mivacurium group (26, 16, and 18%, respectively, vs. 48%; P < 0.01). Times to 80% T1 depression were also similar among patients in the 1.5 mg/kg rapacuronium, 2.5 mg/kg rapacuronium, and succinylcholine groups and significantly longer in the mivacurium group (62, 54, and 54 s, respectively, vs. 112 s; P < 0.01). Clinical duration was longer in all groups compared with the succinylcholine group; however, clinical duration in the 1.5 mg/kg rapacuronium group was shorter compared with the mivacurium group (15 vs. 21 min, respectively; P < 0.01). Heart rate changes were mild in the 1.5 mg/kg rapacuronium, succinylcholine, and mivacurium groups. The patients in the 2.5 mg/kg rapacuronium group had significantly higher heart rates compared with patients in the mivacurium group. No differences were found in blood pressure changes among patients in the four groups. CONCLUSIONS Rapacuronium, 1.5 and 2.5 mg/kg, produced neuromuscular blockade as rapidly as succinylcholine and significantly faster than mivacurium. Although succinylcholine continued to show the shortest duration, 1.5 mg/kg rapacuronium used a rapid onset and a relatively short duration and may be considered an alternative to succinylcholine.

Sufentanil Disposition: Is It Affected by Erythromycin Administration?

Background:Because oral erythromycin administration has been associated with reduced elimination of alfentanil, suspicion has been raised about related opioids with similar metabolic pathways. A controlled crossover study of sufentanil pharmacokinetics was undertaken to resolve this issue. Methods:Six subjects had measurements of plasma concentrations for 9 h after intravenous administration of sufentanil (3 μgAg). Each subject was studied following no erythromycin (control) and after 1− and 7-day courses of erythromycin base. Results:Plasma concentrations during the 9 h of measurement were similar before and after erythromycin. Terminal half-life and clearance and distribution volume did not change significantly among treatment groups. Values measured after 7 days of erythromycin were similar to controls. Conclusions:Prior administration of erythromycin docs not alter pharmacokinetics of sufentanil in the 9 h following sufentanil administration. Thus, there are no apparent clinical consequences of prior or concomitant erythromycin administration in patients receiving sufentanil for procedures of 9 h or less.

Efficacy and safety of divided dose administration of mivacurium for a 90-second tracheal intubation

STUDY OBJECTIVE To compare the safety and effectiveness of 0.25 mg divided doses of mivacurium chloride to succinylcholine for a 90-second tracheal intubation. DESIGN Randomized, double-blind, multicenter study in two groups. SETTING Operating rooms at four university medical centers. PATIENTS 200 healthy ASA status I and II adult patients scheduled for elective surgery with general anesthesia and endotracheal intubation. INTERVENTIONS Patients were premedicated with 1 to 2 mg midazolam and 2 micrograms/kg fentanyl. Anesthesia was induced with 2 mg/kg propofol. Group A received 0.25 mg/kg mivacurium given as a divided dose (0.15 mg/kg followed in 30 seconds with 0.1 mg/kg). Group B (control) received 1.5 mg/kg succinylcholine (SCh) preceded two minutes earlier by 50 micrograms/kg d-tubocurarine (dtc). MEASUREMENTS AND MAIN RESULTS Tracheal intubation grading, train-of-four response of the adductor pollicis, heart rate (HR), and mean arterial blood pressure (MAP) were measured and evaluated. Chi-square analysis was performed for comparison between Group A and Group B with respect to the frequency distribution of intubation using the scores excellent, good, and poor and not possible (combined). Group B had a significantly higher excellent score of intubation than Group A, 84% versus 56% (p < 0.0001). No significant difference was found between the two groups when the scores excellent and good were combined (Fishers Exact test, p = 0.28). The changes in MAP and HR were similar for the two groups. CONCLUSIONS When Sch is not desirable, mivacurium 0.25 mg/kg given as a divided dose provides good to excellent intubation conditions 90 seconds after the initial dose without significant changes in MAP or HR. It can be an appropriate alternative for short surgical procedures. It must be emphasized that this conclusion does not apply to rapid-sequence induction-intubation.

The pharmacokinetics of droperidol in anesthetized children.

Despite the wide use of droperidol to reduce nausea and vomiting in children, its pharmacokinetics have not been described in pediatric patients. Twelve ASA Class I-II children, undergoing tonsillectomy and adenoidectomy, received standardized anesthesia; none of the children received premedication. After induction of general anesthesia, droperidol (0.05 mg/kg) was injected intravenously as a bolus. Droperidol plasma concentrations were determined by radioimmunoassay. Pharmacokinetic data were analyzed by model-independent methods. The pharmacokinetic parameters (mean +/- SD) for the studied population were elimination half-life: 101.5 +/- 26.4 min, mean residence time: 127.2 +/- 28.6 min, volume of distribution at steady state: 0.58 +/- 0.29 L/kg and clearance: 4.66 +/- 2.28 mL.kg-1 x min-1. The clearance and volume of distribution at steady state values are lower than those reported for the adult population, and they apparently decreased in a parallel fashion. The smaller volume of distribution at steady state is consistent with the lipophilic distribution of droperidol and the reduced content of adipose tissue in children. The elimination half-time and mean residence time values are similar to those reported previously for adults. The relatively short half-life of droperidol for our pediatric population does not explain its extended antiemetic action. It does, however, reaffirm that the pharmacokinetic duration of a drugs action is only one of the determinants of its clinical duration.

Time-course of respiratory depression after an alfentanil infusion-based anesthetic

Postoperative respiratory depression after alfentanil administration has been described in several case reports. The effects of a prolonged alfentanil infusion on the CO2 response curve or cognitive function have not been studied. Twenty-one ASA physical status I or II patients were studied after a prolonged alfentanil infusion (>90 min) to determine the incidence of postoperative respiratory depression, arterial O2 desaturation, and impairment of cognitive function. Each patients recovery was observed at 30-min intervals for evidence of respiratory depression (utilizing the Read CO2 rebreathing method), desaturation by pulse oximetry (severe desaturation defined as arterial O2 saturation <90%), and cognitive function (utilizing Trieger dot and digit substitution tests). Plasma samples were also examined for secondary elevations in alfentanil plasma concentrations. Significant depression of the CO2 response curve and cognitive function was found up to 1 h postoperatively. Arterial O2 desaturation was seen in 11 of 21 patients (52%). No correlation was found between arterial O2 desaturation and cognitive function scores or CO2 rebreathing results. Increased depression of the CO2 response curve was not necessarily associated with severe desaturation episodes. A secondary increase in plasma alfentanil concentration was detected in 5 of the 21 patients (24%), but these patients did not experience further depression of the CO2response curve. We conclude that prolonged alfentanil administration may result in severe arterial O2desaturation with significant depression of the hyper-capnic respiratory drive during the first hour in the postanesthesia care unit, even though the majority of our patients were easily aroused in response to verbal stimuli.

Intraoperative hemodynamic, renin, and catecholamine responses after prophylactic and intraoperative administration of intravenous enalaprilat.

This study was designed to evaluate effects of enalaprilat, an angiotensin-converting enzyme inhibitor, on hemodynamic and hormonal responses during surgery at endotracheal intubation, incision, and limb-tourniquet inflation. Thirty patients undergoing limb procedures with general anesthesia (N2 O/narcotic technique) and a pneumatic tourniquet were randomized to receive either preoperative enalaprilat (1.25 mg intravenously [IV] 20 min prior to induction) or intraoperative enalaprilat (0.625 mg IV at the onset of tourniquet-associated hypertension), with appropriate placebo controls. Arterial blood pressure and heart rate increased significantly in response to intubation in the placebo group. Although there were no significant differences in catecholamine levels, plasma renin activity was significantly increased at postincision in the preoperative-enalaprilat group versus the placebo group. This suggests that activation of the renin-angiotensin system may play a key role in mediation of intraoperative hemodynamic responses to endotracheal intubation. With respect to tourniquet hypertension, preoperative or intraoperative treatment with enalaprilat reduced neither the pressor response to tourniquet inflation nor the amount of enflurane subsequently required to control arterial blood pressure. These findings suggest that this response is mediated by pain pathways, and may be treated more effectively with anesthesia/analgesia. (Anesth Analg 1995;80:583-90)