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CARDIOVASCULAR ANESTHESIA

Recovery of Neuromuscular Function After Cardiac Surgery: Pancuronium Versus Rocuronium

Glenn S. Murphy, MD^*, Joseph W. Szokol, MD^*, Jesse H. Marymont, MD^*, Jeffery S. Vender, MD^*, Michael J. Avram, PhD, Todd K. Rosengart, MD, and Eihab A. Alwawi

Departments of *Anesthesia and Surgery, Evanston Northwestern Healthcare, Evanston, Illinois; and Department of Anesthesia, Northwestern University Feinberg School of Medicine, Chicago, Illinois

Address correspondence and reprint requests to Glenn S. Murphy, MD, Department of Anesthesia, Evanston Northwestern Healthcare, 2650 Ridge Ave., Evanston, IL 60201. Address e-mail to dgmurphy{at}core.com

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix 1. References

 
The use of pancuronium in fast-track cardiac surgical patients may be associated with delays in clinical recovery. Our objective in this study was to evaluate the incidence and severity of residual neuromuscular blockade after cardiac surgery in patients randomized to receive either pancuronium (0.08–0.1 mg/kg) or rocuronium (0.6–0.8 mg/kg). Eighty-two patients undergoing cardiopulmonary bypass were randomized to a pancuronium (n = 41) or rocuronium (n = 41) group. Intraoperative and postoperative management was standardized. In the intensive care unit, train-of-four (TOF) ratios were measured each hour until weaning off ventilatory support was initiated. Neuromuscular blockade was not reversed. After tracheal extubation, patients were examined for signs and symptoms of residual paresis. When weaning of ventilatory support was initiated, significant neuromuscular blockade was present in the pancuronium subjects (TOF ratio: median, 0.14; range, 0.00–1.11) compared with the rocuronium subjects (TOF ratio: median, 0.99; range, 0.87–1.21) (P < 0.05). Patients in the rocuronium group were more likely to be free of signs and symptoms of residual paresis than patients in the pancuronium group. Our findings suggest that the use of longer-acting muscle relaxants in cardiac surgical patients is associated not only with impaired neuromuscular recovery, but also with signs and symptoms of residual muscle weakness in the early postoperative period.

IMPLICATIONS: The use of long-acting muscle relaxants in fast-track cardiac surgical patients is associated with significant residual neuromuscular block in the intensive care unit, including signs and symptoms of residual paresis.

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix 1. References

 
The primary aim of fast-track cardiac anesthesia is to facilitate tracheal extubation within 1–8 h of intensive care unit (ICU) admission. To reliably and safely achieve prompt recovery after cardiac surgery, full recovery from the residual effects of opioids, benzodiazepines, and neuromuscular blocking drugs (NMBDs) should be present before tracheal extubation is accomplished. Therefore, some authors advocate the use of shorter-acting NMBDs in the fast-track cardiac patient (1–3). In the United States, however, nearly two thirds of cardiac anesthesiologists continue to use the long-acting drug pancuronium (4). In patients undergoing cardiopulmonary bypass (CPB), the use of pancuronium has been associated with prolonged neuromuscular blockade and delays in tracheal extubation (1,2,5).

The objective of this clinical study was to investigate the time course of recovery of neuromuscular function after cardiac surgery in patients randomized to receive either pancuronium or rocuronium. We tested the hypothesis that the use of the shorter-acting NMBD rocuronium in the operating room (OR) would result in less clinically significant neuromuscular blockade in the ICU than would the use of the long-acting NMBD pancuronium. We also tested the hypothesis that the use of rocuronium would be associated with fewer signs and symptoms of residual paresis in the fast-track patient than would the use of pancuronium.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix 1. References

 
After obtaining IRB-approved written, informed consent, 82 consecutive cardiac surgical patients requiring CPB were included in the study. Patients presenting for elective coronary artery bypass grafting (CABG) or single valvular repair or replacement surgery were eligible for enrollment. Exclusion criteria were as noted in our previous investigation (5).

Patients were randomly allocated to receive either rocuronium or pancuronium according to a computer-generated randomization code. The randomization assignment was concealed in an envelope until the patient entered the OR.

Radial artery and pulmonary artery catheters were placed by using local anesthesia. Additional monitoring consisted of electrocardiography, pulse oximetry, capnography, and transesophageal echocardiography in selected patients. Anesthesia was induced with 5–10 µg/kg of fentanyl, with the addition of 1–4 mg/kg of thiopental or 0.2–0.4 mg/kg of etomidate if required. Neuromuscular blockade was achieved with either 0.6–0.8 mg/kg of rocuronium or 0.08–0.1 mg/kg of pancuronium. Midazolam 5 mg was administered before CPB, and an additional 5 mg was provided during rewarming from CPB. Anesthesia was maintained with 0.2%–2.0% isoflurane before, during, and after CPB. Increases in blood pressure or heart rate were treated by increasing the isoflurane concentration or with 50–150 µg of fentanyl, up to a total dose of 15 µg/kg, in the OR. Nitroglycerin or nitroprusside infusions were started if these measures were unsuccessful. Hypotension was treated with ephedrine, phenylephrine, or volume replacement, as indicated.

Additional maintenance dosing of NMBDs was determined on the basis of peripheral nerve stimulation of the facial nerve. The facial nerve was stimulated, and the response at the muscles surrounding the eye was observed. One or two responses to train-of-four (TOF) stimulation were maintained throughout the intraoperative period. Twenty percent of the initial dose of muscle relaxant was provided as a bolus to achieve this goal. No NMBDs were administered during the last 30 min in the OR.

Median sternotomy and CPB were used in all patients. Standard CABG or single valvular surgery was performed by one of three surgeons, who were blinded to group assignment. Moderate hypothermic CPB (bladder temperatures of 30°C–34°C) with a membrane oxygenator and crystalloid prime was used in all patients. Mean blood pressures of 50–70 mm Hg and blood flows of 2.4–2.8 L · min^-1 · m^-2 were maintained during CPB. The use of vasoactive drugs was at the discretion of the anesthesiologist managing the case. Patients were actively warmed to 37°C before removal of the aortic cross-clamp and weaning from CPB.

Propofol sedation was initiated at sternal closure. An infusion of 25–75 µg · kg^-1 · min^-1 was maintained until the criteria for weaning of ventilatory support were met, at which time the infusion was terminated or the rate significantly reduced. ICU care was standardized, and weaning from ventilatory support and tracheal extubation was accomplished when strictly defined criteria were met (Appendix 1). Criteria for weaning did not include any tests for recovery of neuromuscular function. ICU staff involved in the care of study patients were blinded to group assignment.

Immediately on arrival to the ICU, TOF fade ratios (ratio of the fourth twitch to the first) were recorded by using the TOF-Watch acceleromyograph (Organon, Dublin, Ireland). All monitoring was conducted according to guidelines established for good clinical research practice in pharmacodynamic studies of neuromuscular transmission (6). Core temperatures were maintained >35°C and hand temperatures at >32°C by using warmed blankets or forced-air warming in the ICU. The study arm was immobilized on an arm board, which was positioned parallel to the patients’ body. The acceleromyographic probe was placed on the distal portion of the thumb, which was allowed to move freely. The ulnar nerve at the wrist was supramaximally stimulated (50 mA), and the responses at the adductor pollicis were recorded. The mean of three consecutive TOF ratios was used for each evaluation. TOF monitoring was conducted at 60-min intervals and was terminated when weaning of ventilatory support was initiated. All TOF data were collected by an investigator blinded to group assignment. Clinicians caring for the patient in the ICU were also blinded to TOF data.

The time required to wean from ventilatory support (from the initiation of reduced mechanical ventilation until tracheal extubation) was noted. The duration of tracheal intubation was also recorded. Fifteen minutes after extubation, patients were examined for symptoms and signs of muscle weakness. Standardized examinations were conducted by a single investigator to reduce intraobserver variability. Subjects were directly asked by the investigator about the presence or absence of the following symptoms: visual symptoms (difficulty focusing eyes), symptoms of facial weakness (difficulty smiling), symptoms of oral and pharyngeal muscle weakness (difficulty in smiling or swallowing), and symptoms of generalized muscle weakness. Questions were presented to the subjects in an identical order and manner. Immediately after these questions, a brief physical examination was conducted to detect signs of residual paresis. Patients were asked to maintain a 5-s head-lift and then a 5-s leg-lift. These tests were not performed against resistance. After this, subjects were directed to hold a wooden tongue depressor between their incisor teeth. They were asked to resist removal of the tongue depressor as gentle pressure was applied by the examiner. Patients were allowed one opportunity to pass or fail each test.

Sample size was based on data from a previous study examining the use of pancuronium in cardiac surgical patients, in which significant neuromuscular blockade was identified in 13 of 20 patients when criteria for weaning ventilatory support were met (2). A sample-size calculation estimated that 41 patients would be required in each group to detect a 50% reduction in the incidence of impaired neuromuscular recovery in subjects receiving rocuronium, with = 0.05 and 80% power.

Nominal data were compared between treatment groups by using Fisher’s exact probability test. Ordinal data were compared by using the Mann-Whitney U-test. Because nearly all of the interval data failed the Kolmogorov-Smirnov test for normality of the underlying population, these data were also compared by using the Mann-Whitney U-test. The Bonferroni correction was used to adjust the criterion for rejection of the null hypothesis (P < 0.05) for multiple applications of these tests.

TOF data were compared within and between groups by using two-factor analysis of variance, with repeated measures on one factor. Post hoc analysis was conducted with the Tukey-Kramer multiple comparison test. Data are presented as mean ± SD or median (range). The criterion for rejection of the null hypothesis was P < 0.05.

	Results

Top Abstract Introduction Methods Results Discussion Appendix 1. References

 
Of the 82 patients enrolled, data from 3 were excluded from analysis. Two patients were excluded when surgical reexploration was required because of excessive bleeding, and one was excluded because of protocol violation. Forty patients in the rocuronium group and 39 patients in the pancuronium group completed the study.

Patients’ clinical characteristics are shown in Table 1. There were no significant differences between the groups with respect to age, sex distribution, weight, height, preexisting medical conditions, or type of surgical procedure. Intraoperative data are presented in Table 2. There were no differences between the groups in anesthetic or surgical management during the intraoperative period. The time of ICU admission (early versus late afternoon) was similar in the two groups.

View larger version (18K): [in this window] [in a new window]   Figure 1. Train-of-four (TOF) fade ratios measured on arrival to the intensive care unit (Hour 0) and then each hour for the next 4 h. Significant differences (P < 0.05) were noted between the rocuronium and pancuronium groups at all measurement times, between measurements at all times and those at Hour 0 within the rocuronium group, and between measurements at Hours 3 and 4 and those at Hour 0 within the pancuronium group.

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1. References

The aim of this clinical study was to determine the time required to achieve spontaneous recovery of neuromuscular function in fast-track cardiac surgical patients randomized to receive either pancuronium or rocuronium. Our results are consistent with the findings of McEwin et al. (1) and Van Oldenbeek et al. (2). A mean TOF ratio of 0.99 was measured in the rocuronium group 4 hours after admission to the ICU. This represents nearly complete recovery from the effects of muscle relaxants administered in the OR. In the pancuronium group, a mean TOF ratio of only 0.26 was observed 4 hours after ICU arrival. When ventilatory weaning was initiated, median TOF ratios of only 0.14 were recorded in the pancuronium subjects. Significant residual paresis (TOF ratios <0.7) was present in some of the patients in the pancuronium group for more than 8–10 hours in the ICU.

Patients were examined for signs and symptoms of residual paresis 15 minutes after tracheal extubation. A significantly larger number of patients in the pancuronium group (32 of 39) noted at least one symptom of muscle weakness when compared with the rocuronium group (7 of 40). The most prominent symptoms were a sensation of generalized weakness, difficulties in speaking, and visual disturbances. Many patients in the pancuronium group also noted weakness in the muscles of facial expression. Our results are in accordance with the findings of a previous study that examined the relationship of the TOF fade ratio to clinical symptoms of residual paralysis (7). At TOF ratios of 0.85–0.90, awake volunteers noted a generalized fatigue and visual problems. Severe weakness of the muscles of facial expression was present when TOF ratios of 0.70–0.80 were recorded. The number of patients who were able to maintain a 5-second leg-lift or oppose the removal of a tongue depressor from between the incisor teeth was significantly reduced in the pancuronium group. Although the ability to sustain a 5-second head- or leg-lift may occur when TOF ratios of 0.50 are attained (8), some subjects will be unable to perform these tasks until TOF ratios more than 0.80 are reached (7,9). The most sensitive test on physical examination for residual paresis may be the ability to maintain incisor teeth apposition; TOF ratios must exceed 0.85 before subjects can resist a vigorous effort to remove a tongue depressor (7). In this investigation, we did not measure TOF ratios when patients were examined for signs and symptoms of residual paralysis, because supramaximal nerve stimulation is painful in awake subjects. However, the presence of these signs and symptoms after extubation suggests that clinically significant residual neuromuscular blockade occurred frequently in patients who received pancuronium.

There are several possible explanations for the prolonged neuromuscular blockade observed in the pancuronium group. First, excessive doses of pancuronium may have been used. Initially, patients were administered 2–3 times the 95% effective dose of rocuronium and 1.2–1.8 times the 95% effective dose of pancuronium. We maintained a moderate level of neuromuscular blockade (one or two twitches) during the intraoperative period. Although muscle relaxation is not absolutely required during cardiac surgery, the use of NMBDs may reduce the risk of body or diaphragmatic movement during light levels of anesthesia and prevent shivering associated with hypothermia. Because TOF monitoring can assist titration of muscle relaxants to specific end-points and prevent the occurrence of postoperative residual paralysis (10), we monitored intraoperative neuromuscular blockade carefully to reduce the risk of NMBD overdosage. Second, the use of facial nerve monitoring in the OR may have resulted in relative overdoses of relaxants, because the muscles surrounding the eye are relatively resistant to nondepolarizing drugs (11). Although both groups would have received similar relative overdoses, the effect may have been more pronounced when the longer-acting drug was used. Direct muscle stimulation of the orbicularis oculi muscle may have occurred, which would also result in a relative overdose. Third, alterations in the pharmacokinetic and pharmacodynamic properties of pancuronium, which are induced by CPB, can contribute to postoperative residual muscle weakness (12–16). Increased sensitivity of muscles to pancuronium has been shown to persist into the post-CPB period (17).

There are some limitations to this investigation. Residual neuromuscular block was not reversed at the conclusion of the cardiac procedure. The administration of anticholinesterase drugs in the ICU may have eliminated the differences between the groups. In the United States, however, NMBDs are seldom reversed after cardiac surgery. A recent survey of cardiac anesthesiologists revealed that only 9% of the respondents routinely reversed neuromuscular blockade after CPB (4). We did not use recovery of TOF fade ratios as a criterion for initiating weaning of ventilation or extubation, because peripheral nerve stimulators are rarely used in the care of postoperative cardiac patients (4). Only one test of residual muscle weakness, a negative inspiratory force of -20 cm H₂O, was performed before extubation. A negative inspiratory force of -20 cm H₂O can be generated in the presence of a TOF fade ratio as small as 0.5, however (8). An additional limitation was that TOF monitoring was terminated at the start of ventilatory weaning. At this time point, propofol infusions were turned off or the rate of the infusions was significantly reduced to allow the patient to awaken. Because supramaximal nerve stimulation is painful in the awake patient, we ended TOF data collection when weaning was initiated. Therefore, the time required to achieve complete neuromuscular recovery in the pancuronium group was not determined. The frequent incidence of symptoms of muscle weakness in the ICU suggests that significant residual paresis may persist beyond the weaning and extubation period in this group. Finally, we limited our study to patients requiring CPB. These findings should not be applied to patients undergoing off-pump coronary artery bypass procedures.

In this investigation, acceleromyography was used to quantify TOF fade ratios in the ICU. Several studies have shown a good correlation between TOF ratios measured with this method and TOF ratios obtained with mechanomyography (18–20). Some questions have been raised about the accuracy of acceleromyography in determining TOF ratios, however. In particular, the control TOF ratio is consistently larger when measured with acceleromyography (1.10–1.20) than with mechanomyography (1.00) (20,21). Therefore, results obtained with acceleromyography may not be directly comparable to data obtained with mechanomyography or electromyography. When recovery of neuromuscular function is monitored with acceleromyography, TOF ratios >0.9 are required before single twitch height returns to more than 90% (21). These results suggest that TOF ratios <0.9 measured with the TOF-Watch represent incomplete neuromuscular recovery. With this criterion, all but 1 of the 40 patients in the rocuronium group achieved adequate clinical recovery (TOF >0.9) from the effects of NMBDs by the time ventilatory weaning started. In contrast, only 6 of the 39 patients in the pancuronium group demonstrated TOF ratios >0.9 when weaning was initiated.

Our results suggest that the use of shorter-acting muscle relaxants may be associated with improvements in neuromuscular recovery and fewer signs and symptoms of muscle weakness in the fast-track cardiac surgical patient. Clinicians should be aware of the potential for prolonged neuromuscular blockade when pancuronium is administered during surgery. Methods to reduce the risk of residual neuromuscular blockade should be considered in the fast-track patient population, including the use of intermediate-acting NMBDs, intraoperative and postoperative neuromuscular monitoring, routine examinations for clinical signs of muscle weakness before extubation, and pharmacological reversal of residual neuromuscular block whenever pancuronium is used.

	Appendix 1.

Top Abstract Introduction Methods Results Discussion Appendix 1. References

 
Criteria for weaning mechanical ventilatory support

 Hemodynamic stability

 Absence of uncontrolled arrhythmias

 Central temperature >36.0°C

 Chest tube drainage <100 mL in the past 2 h

 Arterial oxygen tension >60 mm Hg with an oxygen fraction <0.5

 pH >7.3

Criteria for tracheal extubation

 All of the criteria for weaning ventilatory support met

 Negative inspiratory force more than -20 cm H₂O

 Patient responsive to simple commands

Criteria adapted from Cheng et al. (22).

	Acknowledgments

 
Supported by an educational grant provided by Organon, Inc. (West Orange, NJ). Organon, Inc. had no role in the design of this project or in the preparation of this article.

	References

Top Abstract Introduction Methods Results Discussion Appendix 1. References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Murphy, G. S. Articles by Alwawi, E. A. Search for Related Content PubMed PubMed Citation Articles by Murphy, G. S. Articles by Alwawi, E. A. Related Collections Cardiovascular Heart Pharmacology