Anesth Analg 2002;94:1100-1106
© 2002 International Anesthesia Research Society
CARDIOVASCULAR ANESTHESIA
The Hemodynamic Effects of Rapacuronium in Patients with Coronary Artery Disease: Succinylcholine and Vecuronium Compared
Nancy J. Delboy, MD,
Richard C. Tomichek, MD, and
John A. Shields, CRNA
Division of Cardiothoracic Anesthesia, St. Thomas Hospital, Nashville, Tennessee
Address correspondence and reprint requests to John A. Shields, CRNA, 9554 Normandy Way, Brentwood, TN 37027. Address e-mail to John5725{at}aol.com
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Abstract
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Rapacuronium is a nondepolarizing muscle relaxant similar in structure to pancuronium, rocuronium, and vecuronium. Rapacuronium has a mild to moderate effect on heart rate and arterial blood pressure in ASA physical status I and II patients. However, rapacuronium was often administered after, e.g., thiopental, an inhaled anesthetic, and fentanyl, thus modifying or masking the hemodynamic effects of rapacuronium. In this study, we investigated the hemodynamic effects of rapacuronium and compared its effects with those of vecuronium and succinylcholine. Sixty patients scheduled to undergo routine coronary artery bypass grafting were selected to receive rapacuronium 1.5 mg/kg, vecuronium 0.1 mg/kg, or succinylcholine 1 mg/kg. Heart rate, blood pressure, pulmonary artery pressures, and cardiac index were measured at 30- and 60-s intervals during the 2 min after the induction of anesthesia with diazepam and for a 3-min period after study drug administration. The Rapacuronium group exhibited significantly larger decreases in blood pressure and systemic vascular resistance than the Vecuronium or Succinylcholine groups. One patient in the Rapacuronium group experienced cutaneous flushing associated with a 33% decrease in blood pressure.
IMPLICATIONS: Rapacuronium is associated with a significantly larger decrease in blood pressure than succinylcholine or vecuronium, and this decrease should be considered when using rapacuronium in patients who cannot tolerate this decrease.
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Introduction
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Rapacuronium (R) is a nondepolarizing muscle relaxant similar in structure to pancuronium, rocuronium, and vecuronium (V). It has a rapid onset comparable to that of succinylcholine (S), providing similar intubating conditions 1 min after the standard intubating dose of 1.5 mg/kg (1–3). Previous studies with R have demonstrated hemodynamic effects, such as mild to moderate increases in heart rate and variable decreases in blood pressure, in ASA physical status I and II patients undergoing anesthesia for general surgery (2,4–7). Although there has been limited work in patients with coronary artery disease, similar changes in hemodynamics have been observed (8). In these studies, R was often administered after a full dose of cardiac anesthesia drugs (e.g., thiopental, an inhaled anesthetic, and fentanyl), thus modifying or masking the true hemodynamic effects of R.
To investigate the hemodynamic effects of R, hemodynamic data were collected before and after 0.2 mg/kg of diazepam and for a 3-min study period after muscle-relaxant administration. These hemodynamic data were compared with those from comparable groups of patients in whom S and V were used.
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Methods
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After approval from the hospital’s IRB, 60 ASA physical status IV patients from the ages of 39 to 79 yr who were scheduled to undergo elective coronary artery bypass grafting were included in the study after their written consent was obtained. The anesthesiologists and other physicians in the operating room were blinded to the groupings. Exclusion criteria included left ventricular ejection fraction <40%, left main coronary artery disease, redo operation, heart block more than first degree, atrial fibrillation, renal insufficiency (as evidenced by a creatinine of >2.0 mg/dL), or significant valvular heart disease. Patients judged under standard anesthesia criteria to have a difficult airway were also excluded from the study. All preoperative medication was continued until the morning of surgery.
Patients received IM morphine 0.12–0.15 mg/kg and scopolamine 0.3–0.4 mg as preoperative medication 90 min before the induction of anesthesia. Hypertension or hypotension requiring the use of vasoactive drugs (phenylephrine or nitroglycerin) ended the study period, and no further data were gathered. Monitoring of heart rate and rhythm, as well as ST segment analysis of leads I, II, III, aVR, aVL, aVF, and V5, was performed. Peripheral arterial (radial or femoral) cannulation and insertion of a multilumen pulmonary artery catheter (Baxter, McGaw Park, IL) through the right internal jugular vein were performed under local anesthesia. Sedation for catheter insertion was accomplished with 2.5- to 5-mg boluses of IV diazepam. Baseline hemodynamic values were obtained, including heart rate, cardiac output, pulmonary capillary wedge pressure (PCWP), mean arterial pressure (MAP), mean pulmonary artery pressure, and central venous pressure. Cardiac output determinations were made in triplicate by the thermodilution technique by using 5 mL of iced normal saline with a cardiac output computer (Model 9520A; Edwards Laboratories, Irvine, CA). Hemodynamic measurements were ascertained by using a Marquette Solar 7000 monitor (Marquette Electronics, Jupiter, FL). Cardiac index (CI), stroke volume index, and systemic vascular resistance (SVR) index were derived from the measured hemodynamic variables by use of standard formulae.
After baseline hemodynamic measurements were obtained, IV diazepam 0.2 mg/kg was administered. After the loss of the eyelash reflex, 100% oxygen was administered by mask, and the airway was managed by an attending anesthesiologist to achieve an end-tidal CO2 concentration of 25–35 mm Hg and an oxygen saturation >98%. Hemodynamic data were collected for 2 min at 60-s intervals to allow for recovery from the hemodynamic effects of diazepam. At 2 min, patients were assigned by use of a table of random numbers to receive 1 mg/kg of S, 0.1 mg/kg V, or 1.5 mg/kg R. To blind anesthesiologists, certified registered nurse anesthetists, and other physicians as to which muscle relaxant was administered, a pharmacist prepared the muscle relaxant and labeled the syringe in a blinded fashion. Heart rate and MAP were measured every 30 s after injection, and all other hemodynamic measurements were repeated every minute after injection for 3 min. Airway management proceeded as before. The patients were not instrumented or stimulated in any way during the study period (e.g., bladder catheter, central line, skin preparation, and so on). No patient exhibited signs of lightness, such as tearing, during the study period, and no patient had any recall of the study period. No inhaled drugs or other medications were given during this time period. Myocardial ischemia (as evidenced by an ST segment change >2 mm, an increase in PCWP to >20 mm Hg, hypertension, or hypotension requiring the use of vasoactive infusions [phenylephrine or nitroglycerin]) ended the study period, and no further data were gathered. Of the 60 patients enrolled, 58 completed the 3-min study period. One patient in the V group and one patient in the S group required nitroglycerin infusions for significantly increased MAP and PCWP 2 min after each muscle relaxant was given.
The study period ended after 3 min. At this time, fentanyl 6 µg/kg was administered, and phenylephrine infusion was titrated to maintain a MAP of >70 mm Hg. After the fentanyl was administered, instrumentation of the patient was allowed, and intubation was performed by an attending anesthesiologist.
Statistical analysis of the results for each variable within each group was made by repeated-measures analysis of variance followed by Bonferroni tests for pairwise comparisons. Between-group analysis was performed by analysis of variance followed by the Bonferroni posttest, where appropriate. Statistical significance was assumed at P < 0.05.
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Results
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The demographic data of the three groups are illustrated in Table 1. Although a larger number of patients in the R group were taking ß-adrenergic blockers than in the V or S groups, it was not of statistical significance. Otherwise, the three groups were comparable. Preinduction hemodynamics were similar in all three groups. The induction of anesthesia with diazepam elicited similar changes in heart rate and blood pressure in all three groups. These hemodynamic changes returned to baseline by 2 min after induction. Measured and derived hemodynamic values at the eight time periods before and after muscle relaxant administration are shown in Table 2.
Patients receiving S and R exhibited increases in heart rate during the study period (Fig. 1). For S, the increase (11%) was largest initially and decreased (1.5%) by the end of the study period. R showed an increase in heart rate initially, and it remained increased (6%) throughout the study period. One patient developed a nodal rhythm 1 min after R was administered and required transesophageal atrial pacing after the study period. Heart rates in patients receiving V decreased initially (2.5%) and remained decreased throughout the study. In individual patients, heart rate changes ranged from 0% to 58%, -3% to 33%, and -11% to 19% in the S, R, and V groups, respectively. Heart rate decreased to <50 bpm in eight patients in the V group, five patients in the R group, and three patients in the S group.
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Figure 1. Hemodynamic effects. HR = heart rate; MAP = mean arterial pressure; CI = cardiac index; SVRI = systemic vascular resistance index; MR = muscle relaxant.
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MAP increased initially (25%) in the S group and remained increased (10%) until the end of the study period. R exhibited an average 20% decline, which remained unchanged during the remainder of the study. V decreased MAP slightly throughout the study period, although this was not statistically significant. S caused a small increase and V a small decrease in SVR. Changes caused by either drug were insignificant. R produced a significant (25%) decrease in systemic vascular resistance during the study period.
CI increased significantly in the S and R groups. Although the CI remained increased during the study period in the S group, CI had returned to near baseline values by the end of the study period in the R group. V showed no significant changes in CI.
No significant changes in PCWP or stroke volume were noted in any group when compared with baseline values. Also, no patient in any group exhibited electrocardiographic changes >0.5 mm in any lead during any part of the study.
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Discussion
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Because the induction of anesthesia using moderate doses of opioids may be associated with difficulties with mask ventilation, chest wall rigidity, and laryngospasm (9), rapid onset and optimal intubating conditions are desirable. Although S possesses a rapid onset, a myriad of adverse hemodynamic effects have been associated with its use. Because of its favorable hemodynamic profile, V is frequently used for induction and endotracheal intubation in patients requiring minimal hemodynamic perturbation. However, it possesses a much slower onset time than S (10,11), even when increased doses are used to hasten onset. A muscle relaxant with the rapid-onset properties of S and the cardiovascular profile of V would be beneficial.
R is a rapid-onset, short-duration, nondepolarizing muscle relaxant that has been demonstrated to produce intubating conditions comparable to those achieved with S (1–3). Previous studies (4–6,8,12) have demonstrated dose-dependent heart rate increases of 5%–13%, with increases in CI of 12%–14%. Blood pressure and SVR decreased in these studies, 11%–22% and 10%–18%, respectively. Bronchospasm and histamine release at larger doses have also been reported (4,12,13).
In this study, patients in the R group exhibited a mild increase in heart rate that averaged from 5% to 6% during the study period, with a minimal decrease in CI despite decreased PCWP and stroke volume. However, in contrast to other studies (5,8,12), this dose of R did not elicit heart rate increases as large as those in patients receiving S. The mechanism for this mild increase in heart rate is presumed to be vagolytic in origin and similar to that seen with other aminosteroidal neuromuscular-blocking drugs, such as pancuronium and rocuronium, and it is caused by blockade of muscarinic M2 receptors (14). Compensatory increases in heart rate secondary to decreases in blood pressure and SVR may also contribute.
Although a mild increase in heart rate was consistently observed, the most notable finding was a significant decrease in MAP (up to 33%) and a decrease in SVR. These decreases in MAP and SVR were significantly more than those associated with V and contrasted with the increases in MAP and SVR seen with S. Although this decrease has been reported in previous work, this degree of decrease occurred in noncardiac surgical patients at doses >2 mg/kg (4,12).
A possible cause for this decrease in SVR is the larger proportion of patients (12 of 20) taking ß-adrenergic blockers. However, the decrease in SVR index in the patients taking ß-adrenergic blockers was not significantly larger than the decrease in patients not taking ß-blockers. The percentage decrease was slightly larger in the group not taking ß-adrenergic blockers (31% vs 23%, respectively). ß-Adrenergic blockade also had no significant effect on heart rate or CI. Another possible mechanism for this decrease in SVR involves histamine release, as has been previously reported with other neuromuscular blockers, such as d-tubocurarine and metocurine (15). However, whereas previous studies (4,13) found significant histamine release in larger doses of R (>2.5 mg/kg), insignificant amounts of histamine release were noted at doses of 1.5 mg/kg. It is interesting to note that one patient in this study experienced flushing with a decrease in MAP from 68 to 46 mm Hg. However, although histamine release was a suspected mechanism for decreases in SVR, pulmonary artery pressures remained unchanged, and a serum assay revealed normal histamine levels (0.3 ng/mL). An additional mechanism for this decrease in SVR may involve ganglionic blockade. However, the ganglionic-blocking to neuromuscular-blocking ratio in R has been reported (14) to be 20:1, much less than nondepolarizers with significant ganglionic blockade (16), such as d-tubocurarine (9.4:1). Another possible mechanism for the decrease in SVR may involve the inhibition of voltage-activated calcium channels (14). Although no single mechanism is identifiable, the source of this decrease in SVR may be related to all of these effects and warrants further investigation.
S was associated with increases in all hemodynamic variables. While the patients were heavily premedicated, muscle fasciculations may have produced considerable stimulation in patients receiving a relatively small dose of diazepam (0.2 mg/kg), eliciting autonomic activation and increases in heart rate, blood pressure, and CI. In addition, these hemodynamic changes may have been affected by the selection of scopolamine as a premedicant (17), which may have resulted in increased vagolysis from S. Another factor affecting hemodynamics may have been the lack of a defasciculating dose of a nondepolarizing drug (18), inducing unopposed autonomic activation by S. Whether the hemodynamic effects were caused by stimulation in a light patient or by another cause of autonomic activation, the results were undesirable in this patient population and did not occur in patients receiving V or R.
Implications of these findings are related to R’s effects on heart rate and blood pressure. Diazepam itself has been associated with mild changes in heart rate and blood pressure when used alone, but it may cause significant decreases in blood pressure and SVR when combined with other drugs, such as fentanyl (19). R’s effect on SVR may be additive, causing additional decreases in blood pressure. If the choice of muscle relaxants is indeed important in optimizing hemodynamics during the induction of anesthesia, then certainly, given these findings, the same con-sideration should be given R as is given pancuron-ium when choosing muscle relaxants. Its selection should be based on an understanding of the patient’s underlying pathophysiology, concurrent medications, choice of premedicant, and other anesthetics. The effect of R on SVR and MAP should be considered when these are used on hypotensive patients or patients dependent on a higher perfusion pressure, such as in left main coronary artery disease or significant carotid artery disease. In addition, any increase in heart rate may further increase the risk of myocardial ischemia. Reports of cutaneous flushing and bronchospasm (12) introduce other issues that may limit its use, especially in patients with reactive airway disease.
Limitations of this study involve the dose of diazepam used and variables affecting hemodynamics before achieving a steady state of anesthesia. The induction of anesthesia is usually performed with thiopentone 2–4 mg/kg, propofol 2 mg/kg, or another sedative/hypnotic. The induction of anesthesia for coronary artery bypass is usually performed with diazepam 0.3–0.6 mg/kg and varying doses of an opioid, such as fentanyl. By using a smaller dose of diazepam (0.2 mg/kg) and not including fentanyl, the effects of S, R, and V during the study period were not truly representative of hemodynamic response during the induction of anesthesia. In addition, although attempts were made to limit other variables by minimizing patient stimulation and allowing sufficient time for the hemodynamic variables to return to baseline after diazepam administration, achieving a steady state of anesthesia may have limited the effect of airway management, fasciculations, and extraneous stimulation. However, the use of fentanyl in combination with diazepam often requires the use of vasopressors to maintain blood pressure, and attaining a steady state of anesthesia could mask the hemodynamic effects of R. Possibly, other approaches minimizing the effects of induction and airway management may have decreased these variables affecting hemodynamics. However, the methodology used in this study may more clearly define the hemodynamic effect of these neuromuscular-blocking drugs without the influence of previously administered anesthetics, such as thiopentone, fentanyl, or inhaled anesthetics.
Future studies should evaluate any synergistic effect on heart rate and blood pressure when R is used concomitantly with diazepam and fentanyl for induction. Other studies should also compare the hemodynamic effects of R and rocuronium, especially with regard to heart rate and blood pressure changes and maintenance of CI in patients undergoing cardiac surgery. In addition, animal studies involving muscarinic receptors may further add to data regarding R’s mechanism of SVR decrease.
In summary, R is associated with changes in blood pressure, which may be detrimental in patients requiring an increased blood pressure. These findings are consistent with previous work demonstrating vasodilation and decreases in SVR. Although no adverse outcomes, including ST segment change, increase in PCWP, or increased morbidity or mortality, were observed, the hemodynamic effects of R should be considered before its use.
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Acknowledgments
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Organon Pharmaceuticals supplied 20 vials of vecuronium 10 mg and 40 vials of rapacuronium 100 mg.
The authors thank Pam Hull, Vanderbilt University, for her assistance with statistical analysis.
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Accepted for publication December 11, 2001.
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Abstract
Introduction
