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© 1999 International Anesthesia Research Society
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Abstract |
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Neuromuscular blocking drugs may have variable effects on heart rate (HR) and blood pressure. Rapacuronium is a rapid-acting, steroidal-derived neuromuscular blocking drug whose hemodynamic effects have not been characterized. We studied the effects of 1, 2, and 3 mg/kg rapacuronium on histamine release, HR, and blood pressure in 47 ASA physical status II or III adult patients after the induction of anesthesia with etomidate/fentanyl/N2O. Plasma histamine concentrations were measured before induction and immediately before and 1, 3, and 5 min after the rapid administration of rapacuronium. Mean arterial pressure (MAP) decreased after rapacuronium administration, but there were no significant differences among the groups for changes in HR or MAP, and there was no correlation between changes in MAP or HR and increases in histamine levels. There were no changes in HR or MAP among five patients who had significant (
1 ng/mL) increases in histamine from baseline. Seven patients had bronchospasm without increases in plasma histamine levels. Rapacuronium 2–3 mg/kg increased plasma histamine levels. However, clinically significant histamine-related sequelae did not occur in this population with 1- to 3-mg/kg doses of rapacuronium, and cardiovascular changes were not directly correlated with histamine release. Rapacuronium administration can produce hypotension via mechanisms that do not seem to be related to histamine release. Implications: Rapacuronium, a new steroidal-derived muscle relaxant, may release histamine and produce slight changes in blood pressure and heart rate after administration.
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Rapacuronium (Org 9487), which has a fast onset and short duration of action, is a new steroidal neuromuscular blocking drug under clinical investigation. The molecule is a 16-N-allyl, 17-ß-propionate analog of vecuronium (1–3). When administered as endotracheal intubating doses, vecuronium and rocuronium do not elicit histamine release and are devoid of any hemodynamic effects (4–6). After the administration of rapacuronium at doses of 1–1.5 mg/kg, good to excellent intubating conditions are obtained within 1 min, with a clinical duration of 6–9 min and a mean duration to 90% spontaneous recovery of the first twitch after a 1.5-mg/kg dose of approximately 17 min (1,2). However, there are few data defining the hemodynamic effects and histamine-releasing potential of rapacuronium. Furthermore, isolated cases of bronchospasm or erythema in patients receiving rapacuronium have been reported. We performed this study to determine histamine release and cardiovascular changes after three doses (1, 2, and 3 mg/kg) of rapacuronium when administered for intubation in adult patients.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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After institutional approval, 47 ASA physical status II or III patients between the ages of 18 and 75 yr, who were scheduled for elective surgery under general anesthesia, gave informed consent to participate in this randomized, open-label, parallel group, comparative, two-center study. Patients were excluded from participating in the study if they had significant renal or hepatic disease, metabolic or neuromuscular disorders, or known allergies to opioids or other medications used during anesthesia, if they were obese (>30% above the ideal body weight), or if they had received histamine H1-blockers within a day of surgery.
Patients received oral diazepam (0.1–0.2 mg/kg) 60–90 min before the induction of anesthesia. A radial artery cannula was inserted using 1% lidocaine, and midazolam (0.5-mg increments up to 2.5 mg/70 kg as needed) was administered. Patients breathed oxygen for 3 min and received IV fentanyl (2–4 µg/kg) 1 min before the administration of IV etomidate (0.2–0.3 mg/kg). After disappearance of eyelid reflexes, N2O/O2 (50:50) was administered via a face mask. Two minutes after the administration of etomidate, patients randomly received one of the three doses of rapacuronium as a rapid (5 s) bolus injection. N2O/O2 (50/50) was administered; face mask ventilation maintained an expiratory CO2 of 32–42 mm Hg. The patients’ tracheas were intubated 6 min after the administration of rapacuronium. After intubation, adequate depth of anesthesia was maintained with N2O/O2 (70:30), 1% isoflurane, and incremental bolus doses of midazolam and fentanyl as needed to treat increases in blood pressure or heart rate (HR) after intubation.
Patients were monitored continuously with a two-lead electrocardiograph (leads II and V) and a radial arterial catheter. HR, systolic blood pressure, diastolic blood pressure, and mean arterial pressure (MAP) were recorded before induction, after induction, and immediately before (baseline) and every minute for 5 min after the administration of rapacuronium.
Arterial blood samples (5 mL) were obtained immediately before the induction of anesthesia and immediately before (baseline) and 1, 3, and 5 min after the administration of rapacuronium. Arterial blood samples were collected in cold tubes containing disodium EDTA. After collection, blood samples were immediately placed on ice and centrifuged within 20 min (1500 rpm for 10 min) at 4–8°C. Duplicate aliquots (0.3 mL each) of plasma samples were stored at –20°C until analysis. Concentrations of histamine in plasma samples were determined by using an enzyme-linked immunoassay method using commercially available kits (Immunotech, Inc., Westbrook, ME). The assay was linear between 0.05 and 5 ng/mL, with inter- and intraday coefficients of variation of <10%. Rapacuronium concentrations up to 200 µg/mL were found not to interfere with the assay. Increases in plasma histamine concentrations were considered significant only if they were 1.0 ng/mL. Clinical signs of histamine release were defined as flushing, erythema, hypotension, or bronchospasm. A Wilcoxon’s signed rank test was used to test whether the plasma histamine levels at each time point were significantly different from baseline (i.e., whether the median change was significantly different from zero). This test was also used for HR and MAP changes. The percentages of patients with significant increases in histamine concentrations were also compared among dose groups by using the Cochran-Mantel-Hanszel test. Scatterplots and cross-tabulations were made to explore possible associations between plasma histamine levels, HR, and MAP. Data are reported as mean ± SD, and values of P < 0.05 were considered statistically significant.
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Results |
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The distribution and demographic characteristics of the patients are presented in Table 1. There were no apparent differences among the treatment groups with respect to age, weight, or height. Most patients within each treatment group were male and ASA physical status III. None of the patients had a history of atopy or multiple allergies.
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Plasma levels of histamine are reported for 45 of the 47 patients enrolled in the study. The data of one patient in the 1 mg/kg group were not used in the histamine analysis because he had received vancomycin during the study; vancomycin causes histamine release and hypotension. The plasma histamine levels were not determined in another patient from the 3 mg/kg group because of problems with obtaining blood samples from the arterial cannula.
Before the induction of anesthesia or the administration of rapacuronium, there were no significant differences in plasma histamine concentration among the three treatment groups (Table 2). The baseline mean histamine concentrations immediately before the administration of rapacuronium ranged from 0.20 to 0.29 ng/mL. There was no statistically significant change from baseline in the mean plasma histamine concentration after the 1-mg/kg dose of rapacuronium. A significant increase from baseline in the mean plasma histamine concentration, which peaked at 1 min after the administration of rapacuronium, was shown in the 2 mg/kg and 3 mg/kg groups. One patient in each of the 1 mg/kg and 2 mg/kg groups had a plasma histamine concentration >1 ng/mL after the administration of rapacuronium. Three patients in the 3 mg/kg group had plasma histamine concentrations >1 ng/mL after the administration of rapacuronium.
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In all three groups, HR increased and MAP decreased after rapacuronium administration (Tables 3 and 4). The pairwise comparisons of each treatment group showed no statistically significant differences among any of the groups for changes in HR or MAP. The cardiovascular changes among five patients with significant increases in histamine concentration (
1 ng/mL) from baseline are shown in Table 5. The peak increase in histamine release occurred 1 min after rapacuronium administration. There were no significant changes in HR, systolic blood pressure, diastolic blood pressure, or MAP among the five patients 1 min after the intubation dose of rapacuronium.
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The scatterplots for percent change in MAP and HR from baseline and changes in histamine levels indicate no relationship between these variables (Figures 1 and 2). There was no correlation between changes in MAP or HR and plasma histamine levels, as indicated by scatterplots of these data. One patient in the 3 mg/kg group had a significant increase in histamine (to 5.6 ng/mL) 1 min after rapacuronium administration and experienced an 11% increase in HR and a
30% decrease in MAP during the 1- to 5-min interval after rapacuronium administration (Table 5). However, a similar magnitude of change in HR and MAP was observed in another patient in the 3 mg/kg group accompanying a nonsignificant increase (peak level 0.68 ng/mL) in plasma histamine during the 1- to 5-min interval after rapacuronium administration. One additional patient had a significant increase in histamine concentration (from 0.72 ng/mL at baseline to >5.0 ng/mL 1 and 3 min after rapacuronium administration) that was accompanied by a <10% increase in HR and a 30% decrease in MAP.
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None of the five patients with histamine levels >1 ng/mL developed localized or systemic erythema or bronchospasm. Bronchospasm occurred in seven patients (two patients each in the 1 and 2 mg/kg groups and three patients in the 3 mg/kg group); one of the patients in the 3 mg/kg group also experienced hypotension. In six of the seven patients, bronchospasm occurred after intubation, and all of the episodes of bronchospasm were treated with deepening the anesthesia and ß2-adrenergic drugs. The times of bronchospasm relative to the administration of rapacuronium included one patient at 4 min, two patients at 6 min, two patients at 7 min, and two patients
120 min. There was never any difficulty in ventilating patients after rapacuronium. |
Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We noted that the rapid administration of rapacuronium produced a decrease in MAP. However, there was no correlation between histamine release and decreases in blood pressure or increases in HR. To assess histamine release caused by rapacuronium, we chose an induction technique with fentanyl and etomidate because neither drug is usually associated with histamine release (7–10). Although increases in plasma histamine levels (
1 ng/mL) occurred in five patients, including one in the 1 mg/kg group, one in the 2 mg/kg group, and three in the 3 mg/kg group, none of the increased histamine levels in these patients was associated with hypotension, erythema, or bronchospasm. In previous reports, steroidal analogs (e.g., vecuronium or rocuronium) infrequently produced significant increases in plasma histamine concentrations and caused hemodynamic changes (11–15). Current steroidal-derived neuromuscular blocking drugs (e.g., rocuronium, vecuronium) are more potent than rapacuronium; therefore, less of the drug is administered for neuromuscular blockade (3,5,6). Rapacuronium 2 and 3 mg/kg produced histamine release. Although histamine levels >2 ng/mL are required to cause significant physiologic changes (7), increased plasma histamine levels might not be associated with significant cardiovascular changes. For example, two patients in this study had >10-fold increases in histamine levels (>5.0 ng/mL) from baseline levels (<0.5 ng/mL) at one minute after a 3-mg/kg dose of rapacuronium. Both patients developed a small increase in HR (<5% and 11%) and a decrease in MAP (14% and 22%). The decrease in MAP and increase in HR occurred in the 2 mg/kg and 3 mg/kg groups. There was no correlation between changes in MAP or HR and plasma histamine levels. The mechanism of the decrease in MAP seems to be a direct vasodilating effect of rapacuronium. We noted that rapacuronium produces vasodilation via mechanisms that may represent direct arterial vasodilation (16). We previously reported that vasodilation may, in part, be due to a direct relaxant effect of rapacuronium on vascular smooth muscle, possibly mediated through the inhibition of voltage-gated, L-type calcium channels (16).
Seven patients developed bronchospasm during the study at times ranging from four minutes to more than two hours after rapacuronium administration; however, none of the patients had significant increases in plasma histamine levels (0.23–0.33 ng/mL). Six of the patients had bronchospasm that occurred after intubation that may not have been related to the administration of rapacuronium. Our patient population included patients with a smoking history and those undergoing thoracic surgery. A potential causative factor for bronchospasm in these patients is tracheal intubation during "light" anesthesia because there was an eight-minute lag between the induction of anesthesia and intubation of the trachea. Two minutes after etomidate administration, patients received rapacuronium, and six minutes later, the patients were tracheally intubated. Further, the presence of preexisting respiratory diseases (e.g., bronchitis) or history of tobacco use, especially in a Veterans Affairs Hospital population, may also have contributed to the bronchospasm. All seven patients with bronchospasm were from a Veterans Affairs Hospital, and four of the seven patients had a history of tobacco use. Additional mechanisms for bronchospasm may also include antagonizing interactions at M2-selective muscarinic receptors because bronchospasm and tachycardia are side effects that occur after rapacuronium administration (17). However, antagonizing M3-selective muscarinic activity produces bronchial relaxation and decreases salivary secretions (17). The relative affinity of rapacuronium, as well as the dose required for the activation of different subtypes of muscarinic receptors, remains undetermined (17).
In summary, rapacuronium seems to cause an increase in plasma histamine levels at doses of 2–3 mg/kg. However, significant histamine-related sequelae did not occur in this population, and hemodynamic changes were not directly correlated with histamine release.
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Acknowledgments |
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This study was supported by a grant from Organon Inc, West Orange, NJ.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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- Wierda JMKH, Broek LVD, Proost JH, et al. Time course of action and endotracheal intubating conditions of Org 9487, a new short-acting steroidal muscle relaxant: a comparison with succinylcholine. Anesth Analg 1993;7:579–84.
- Wierda JMKH, Beaufort AM, Kleef UW, et al. Preliminary investigations of clinical pharmacology of three short acting non-depolarizing neuromuscular blocking agents Org 9453, Org 9489 and Org 9487. Anaesth 1994;41:213–20.
- Kahwaji R, Bevan DR, Bikhazi G, et al. Dose-ranging study in younger adult and elderly patients of Org 9487, a new, rapid-onset, short duration muscle relaxant. Anesth Analg 1977;84:1011–8.[Abstract]
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- Yamaguchi K, Huraux C, Szlam F, Levy JH. Vascular effects of ORG 9487 in human mammary arteries, a new short acting muscle relaxant [abstract]. Anesth Analg 1998;86:SCA109.
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