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ECONOMICS, EDUCATION, AND HEALTH SYSTEMS RESEARCH

Postanesthesia Care Unit Recovery Times and Neuromuscular Blocking Drugs: A Prospective Study of Orthopedic Surgical Patients Randomized to Receive Pancuronium or Rocuronium

Glenn S. Murphy, MD^*, Joseph W. Szokol, MD^*, Mark Franklin, MD^*, Jesse H. Marymont, MD^*, Michael J. Avram, PhD, and Jeffery S. Vender, MD^* Section Editor

*Department of Anesthesiology, Evanston Northwestern Healthcare, Northwestern University Feinberg School of Medicine, Evanston, Illinois; and Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois

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

	Abstract

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In this study, we examined the effect of choice of neuromuscular blocking drug (NMBD) (pancuronium versus rocuronium) on postoperative recovery times and associated adverse outcomes in patients undergoing orthopedic surgical procedures. Seventy patients were randomly allocated to a pancuronium or rocuronium group. On arrival to the postanesthesia care unit (PACU) and again 30 min later, train-of-four ratios were quantified by using acceleromyography. Immediately after acceleromyographic measurements, patients were assessed for signs and symptoms of residual paresis. During the PACU admission, episodes of hypoxemia, nausea, and vomiting were recorded. The time required for patients to meet discharge criteria and the time of actual PACU discharge were noted. Forty percent of patients in the pancuronium group had train-of-four ratios <0.7 on arrival to the PACU, compared with only 5.9% of subjects in the rocuronium group (P < 0.001). Patients in the pancuronium group were more likely to experience symptoms of muscle weakness (blurry vision and generalized weakness; P < 0.001) and hypoxemia (10 patients in the rocuronium group versus 21 patients in the pancuronium group; P = 0.015) during the PACU admission. Significant delays in meeting PACU discharge criteria (50 min [45–60 min] versus 30 min [25–40 min]) and achieving actual discharge (70 min [60–90 min] versus 57.5 min [45–61 min]) were observed when the pancuronium group was compared with the rocuronium group (P < 0.001). In conclusion, our study indicates that PACU recovery times may be prolonged when long-acting NMBDs are used in surgical patients.

IMPLICATIONS: Clinical recovery may be delayed in surgical patients administered long-acting neuromuscular blocking drugs. During the postanesthesia care unit admission, patients randomized to receive pancuronium (versus rocuronium) were more likely to exhibit symptoms of muscle weakness, develop hypoxemia, and require more time to meet discharge criteria.

	Introduction

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Neuromuscular blocking drugs (NMBDs) are frequently administered to patients undergoing orthopedic surgical procedures under general anesthesia. A long-acting or intermediate-acting NMBD can be selected when the length of the procedure is anticipated to exceed 60–90 min. Whenever pancuronium is used, the potential for delayed recovery in the postanesthesia care unit (PACU) must be considered. Residual neuromuscular block, defined as a train-of-four (TOF) ratio <0.7, is observed in up to 36%–42% of patients who receive intraoperative pancuronium (1–4). In contrast, only 5%–10% of patients administered intermediate-acting drugs demonstrate TOF ratios <0.7 in the PACU (3,4). Small degrees of residual paresis (TOF ratio 0.7–0.9) are associated with symptoms and signs of profound muscle weakness (5), an impaired hypoxic ventilatory response (6), pharyngeal dysfunction and an increased risk for aspiration (7,8), hypoxemia in the PACU (9), and delays in emergence from anesthesia (10). Any of these factors can potentially delay discharge from the PACU.

The effect of choice of NMBD on PACU recovery times has not previously been examined in a prospective, randomized clinical trial. We hypothesized that patients randomized to receive pancuronium would exhibit more profound postoperative neuromuscular block and that incomplete neuromuscular recovery would result in delays in readiness for PACU discharge and increased PACU length of stay (LOS). In addition, an association between pancuronium use in the operating room (OR) and impaired clinical recovery in the PACU has not been clearly established. We also tested the hypothesis that adverse outcomes associated with residual neuromuscular block would be observed more frequently in subjects in the pancuronium group. Patients were examined in the PACU for adverse events potentially related to the residual effects of NMBDs, including symptoms and signs of muscle weakness, hypoxemia and the need for supplemental oxygen, and nausea and vomiting.

	Methods

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After obtaining IRB approval (Evanston Northwestern Healthcare) and written, informed consent, we studied 70 patients presenting for elective orthopedic surgical procedures under general anesthesia. Because clinical and neuromuscular recovery can be influenced by age and health status, only healthy patients (ASA physical status I–II) between the ages of 18 and 59 yr were enrolled in the study. In addition, patients undergoing major orthopedic procedures (i.e., total joint replacement or major spine surgery) associated with significant postoperative pain and prolonged PACU LOS were not recruited for the study. Patients were excluded from participation in this clinical trial if any of the following criteria were met: 1) weight >30% above ideal body weight, 2) presence of an underlying neuromuscular disease, 3) use of drugs known to interfere with neuromuscular transmission, 4) renal insufficiency (serum creatinine >1.6 mg/dL), and 5) requirement for an awake tracheal intubation or a rapid-sequence intubation with succinylcholine.

Patients were randomly allocated to receive either rocuronium or pancuronium according to a computer-generated randomization code. The individual randomization assignments were concealed in opaque envelopes until the patient to whom the randomization was assigned entered the OR.

Intraoperative monitoring consisted of electrocardiography, pulse oximetry (SpO₂), capnography, and core temperature via an esophageal probe. Anesthetic management was standardized in all subjects. Propofol 2 mg/kg, fentanyl 100 µg, and lidocaine 50 mg were administered to induce anesthesia. Patients received either pancuronium 0.08–0.1 mg/kg or rocuronium 0.6–0.8 mg/kg (standard doses used at our institution) according to random allocation.

Anesthesia was maintained with sevoflurane (0.5%–3.0%) and 50% N₂O. Sevoflurane was titrated to maintain arterial blood pressure within 20% of baseline values. In addition, patients received approximately 1 µg · kg^-1 · h^-1 of fentanyl throughout the surgical procedure. Additional dosing of NMBDs was determined on the basis of neuromuscular monitoring. Boluses of either pancuronium (0.5–1.0 mg) or rocuronium (5–10 mg) were administered to maintain a moderate level of neuromuscular block (two or three visual responses at the adductor pollicis to TOF stimulation of the ulnar nerve). No NMBDs were administered during the last 20 min in the OR. All patients received ondansetron (4 mg) within 30 min of the end of the procedure. Neuromuscular blockade was reversed at the completion of surgical wound closure. Intense block (one or two responses to TOF stimulation) was reversed with neostigmine 70 µg/kg, and less intense block was antagonized with neostigmine 50 µg/kg. Glycopyrrolate was administered with the neostigmine. Extubation of the trachea was performed when clinical criteria were met (including a 5-s head lift) and four responses to TOF stimulation were observed.

The administration of pain medication was standardized in the PACU. Patients who complained of pain received 50 µg of fentanyl. Additional 50-µg boluses of fentanyl were provided by PACU nurses until verbal pain scores <3 out of 10 (0 = no pain; 10 = worst pain imaginable) were achieved.

Immediately on arrival in the PACU, TOF fade ratios were measured by using acceleromyography (TOF-Watch; Organon, Inc., Dublin, Ireland). All neuromuscular monitoring was conducted according to guidelines established in Good Clinical Research Practice in pharmacodynamic studies of NMBDs (11). The study arm was immobilized with a splint. An acceleration transducer was taped to the distal interphalangeal joint of the thumb. The study arm was positioned so that free movement of the thumb occurred during nerve stimulation. Supramaximal (50-mA) square-wave TOF stimulation was delivered to the ulnar nerve via surface electrodes. Two consecutive responses to TOF stimulation (separated by >15 s) were obtained, and the average of the 2 values was recorded. If the measurements differed by more than 10%, additional TOF ratios were obtained (up to four TOF values), and the closest 2 ratios were averaged. A second set of TOF fade ratios were measured 30 minutes after PACU admission. To maintain core temperature >35°C and arm temperature >32°C, upper body forced-air warming blankets were applied to the patient in the OR, and warmed blankets were used in the PACU.

All subjects were examined for symptoms and signs of muscle weakness by one of two research assistants. A standardized examination was conducted on arrival to the PACU and again 30 min later. Questions relating to residual paresis were presented to subjects in an identical order and manner. Patients were directly asked by the research assistant about the presence or absence of visual symptoms (blurry vision), symptoms of facial weakness (difficulty smiling or facial numbness), symptoms of oral and pharyngeal muscle weakness (difficulty swallowing), and symptoms of generalized muscle weakness (weakness in all muscles). Immediately after these questions, a physical examination was performed to detect signs of residual neuromuscular block. Subjects were asked to perform a 5-s leg lift and then a 5-s head lift. These tests were not performed against resistance. Subjects were then instructed to hold a wooden tongue depressor between the incisor teeth and resist removal as gentle pressure was applied. Patients were allowed one opportunity to pass or fail each test. Research assistants collecting acceleromyography data and evaluating patients for symptoms and signs of muscle weakness were blinded to group assignment.

Patients were transferred from the OR to the PACU breathing room air. Arterial oxygen saturation in the PACU was monitored continuously by using SpO₂. Patients were encouraged by PACU nurses to breathe deeply whenever an oxygen saturation <93% was observed. Nurses caring for the patients recorded the number of mild (SpO₂ of 93%–90%) and severe (SpO₂ <90%) episodes of hypoxemia in the PACU (duration of at least 10 s). The average oxygen saturation during every 15-min interval in the PACU was noted on the data collection sheet. Supplemental oxygen was provided only if oxygen saturation remained <90% for longer than 15 s. The number of patients requiring supplemental oxygen was also recorded.

Patients were asked directly about symptoms of nausea by PACU nurses. Episodes of nausea were recorded on the data collection sheet. Any vomiting that occurred during the PACU admission was also noted. Nurses caring for patients also noted whether the episodes of nausea or vomiting required treatment and described which drugs were used.

A modified Aldrete scoring system was used to evaluate patients for readiness for PACU discharge (Appendix 1). A score of 8 of 10 points was required for discharge criteria to be fulfilled. Patients were assessed by the PACU nurse, who used this system at least once every 10 min to determine when criteria were met. The times until the patient was judged ready for discharge and was actually discharged from the PACU were recorded. Nurses collecting data in the PACU and evaluating patients for readiness for discharge were blinded to group assignment.

Sample size was calculated by using data from our institution. We examined data from the previous 100 patients who underwent orthopedic procedures lasting >90 min. The mean ± SD PACU LOS was 79 ± 41 min in patients who received rocuronium. On the basis of these data, a sample size calculation indicated that to detect a 20-min difference in PACU LOS between rocuronium and pancuronium subjects, assuming a within-group SD of 41 min, with 80% power and an of 0.05, would require 34 patients in each group, or a total of 68 subjects. Seventy subjects were therefore enrolled to ensure complete collection of data.

Data are reported as the number of patients or median and 25th–75th percentiles. Nominal data were compared between treatment groups by using Fisher’s exact probability test. Ordinal data were compared by using the Mann-Whitney ranked sum 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 ranked sum test. The criterion for rejection of the null hypothesis was P < 0.05. When a test was applied multiple times to the same set of data, the criterion for rejection of the null hypothesis was adjusted by using the Bonferroni correction.

	Results

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Seventy patients were randomized, of whom 69 completed the study. One patient in the rocuronium group was excluded from data analysis because of a protocol violation.

The two groups were comparable with respect to age, sex, ASA physical status, height, weight, history of tobacco and alcohol use, and preexisting medical conditions (Table 1). The two groups were similar in the types of surgical procedures performed. The total dose of fentanyl and neostigmine administered in the OR did not differ between groups (Table 2). The length of the surgical procedure, the time from the end of surgery until tracheal extubation, and total blood loss were similar between the groups. Patients in the rocuronium group were more likely to receive additional maintenance doses of NMBDs (29 of 34 patients) than subjects in the pancuronium group (10 of 35 patients; P < 0.001). The central temperature was >36°C at the conclusion of the surgical procedure in all patients (Table 2).

View larger version (17K): [in this window] [in a new window]   Figure 1. Train-of-four (TOF) fade ratios measured on arrival to the postanesthesia care unit (PACU) and again 30 min after PACU admission.

The incidence of postoperative nausea and vomiting did not differ between the two groups in the PACU (Table 3). The requirement for rescue antiemetics was small in the study and did not differ between groups. Similar doses of fentanyl were used for postoperative pain control in both groups (Table 3).

PACU recovery times (median [25th–75th percentiles]) were prolonged in the pancuronium subjects. The median time from PACU admission until discharge criteria were met was 20 min longer in the pancuronium group (50 min [45–60 min]) than in the rocuronium group (30 min [25–40 min]; P < 0.001). The actual PACU LOS was also significantly longer in patients receiving pancuronium (70 min [60–90 min]) than in those administered rocuronium (57.5 min [45–61 min]; P < 0.001). Patients with postoperative TOF ratios <0.9 were more likely to have PACU admission times >60 min (23 of 39 patients) than patients with TOF values >0.9 (7 of 30 patients; P = 0.004).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Several investigations have demonstrated a frequent incidence of residual neuromuscular block in the PACU after the use of long- acting NMBDs (1–4). The clinical significance of residual paralysis associated with the use of pancuronium during the early recovery period from general anesthesia is uncertain, however. In particular, the effect of choice of NMBD on postoperative recovery times and morbidity in the PACU has not been previously examined in a prospective, randomized trial. Our results demonstrate that when long-acting NMBDs were administered to orthopedic surgical patients, delays in meeting discharge criteria were observed (40% longer than subjects who received rocuronium). During the PACU admission, patients in the pancuronium group were more likely to exhibit significant neuromuscular block, describe symptoms of profound muscle weakness, and develop hypoxemia.

Only one previous study has specifically examined the effect of choice of NMBD on postoperative recovery times. Ballantyne and Chang (12) examined the influence of intermediate-acting and long-acting muscle relaxants on PACU LOS. Data on 270 patients undergoing a variety of surgical procedures were collected retrospectively. Taking into account age, sex, and length and type of surgery, the mean PACU LOS was 30 minutes longer in patients receiving pancuronium (versus patients administered shorter-acting relaxants). Lubarsky et al. (10) studied the effect of pharmaceutical practice guidelines promoting the use of less costly anesthetic drugs (including pancuronium) on cost savings and associated outcomes. The authors observed that the time from the end of surgery to arrival in the PACU was increased after practice guidelines were instituted. However, no increase in PACU LOS was noted in this observational study. Our findings are consistent with those of Ballantyne and Chang (12). The median time from PACU arrival until discharge criteria were met was 20 minutes longer in the pancuronium group compared with the rocuronium group. The actual PACU LOS was also prolonged (by 13 minutes) in subjects randomized to the pancuronium group.

On arrival to the PACU, TOF ratios <0.7 were measured in 40% of patients in the pancuronium group compared with 5.9% in the rocuronium group. Traditionally, TOF ratios of 0.7 are considered to reflect an adequate return of neuromuscular activity (13,14). Recent data suggest that when acceleromyography is used to measure TOF fade ratios, optimal recovery from NMBDs is present only when TOF ratios >0.9 are achieved (15). In a study of 526 patients receiving a single intubating dose of an intermediate-acting NMBD and no reversal, TOF ratios >0.9 were observed in only 55% of patients in the PACU (16). In this investigation, only 17% of patients in the pancuronium group had TOF ratios >0.9 on arrival to the PACU, compared with 71% of patients in the rocuronium group. An association between TOF ratios <0.9 and prolonged recovery stay (and hypoxemia) was also documented in this study. These findings further support the use of a TOF ratio >0.9 as a new "gold standard" for complete neuromuscular recovery.

Discharge from the PACU may be delayed in a patient who exhibits obvious muscle weakness. However, a careful assessment for signs and symptoms of muscle weakness is rarely performed on postoperative patients, and no previous clinical studies have used a standardized examination to evaluate patients for symptoms of residual paresis after general anesthesia. An Aldrete scoring system requires only that patients move all four extremities before discharge. Moderately intense neuromuscular block must be present to detect obvious signs of residual paresis, because many patients can sustain a head, leg, or arm lift at TOF ratios <0.5 (17–19). We did not observe any differences between the study groups in signs of residual paresis. These results are not surprising, because most patients with TOF ratios <0.7 were able to maintain a head and leg lift and hold a tongue depressor between the incisor teeth. In contrast, a significant increase in the incidence of symptoms of muscle weakness was noted in the pancuronium group. Patients who received pancuronium were more likely to describe symptoms of blurry vision and a generalized sensation of muscle weakness. Investigations in awake volunteers have shown that the residual effects of NMBDs can produce distressing symptoms in conscious patients (5).

In this study, a significant increase in the incidence of hypoxemia in the PACU was noted in patients in the pancuronium group. An association between residual neuromuscular block (TOF <0.9) and postoperative hypoxemia was also observed. Previous observational studies have suggested that impaired recovery of neuromuscular transmission after the use of long-acting NMBDs can contribute to low SpO₂ values in the early postoperative period. Bissinger et al. (9) observed that residual paralysis after pancuronium was a significant risk factor for oxygen desaturations in the PACU. The need for supplemental oxygen in the PACU was doubled in patients who received pancuronium when compared with those administered atracurium (4). Several theories may explain how the residual effects of NMBDs can influence postoperative gas exchange. At a TOF ratio of 0.7, the hypoxic ventilatory response is reduced by 30% in awake volunteers (6). Partial paralysis can also reduce pharyngeal muscle tone and disturb swallowing patterns (7,8). In a recent volunteer study (20), upper airway obstruction was observed in 4 of 12 subjects, and an inability to swallow normally was noted in 7 of 12 subjects at a TOF ratio of 0.83. In susceptible postoperative patients, this degree of residual paresis may result in upper airway obstruction and tracheal aspiration. Data from Berg et al. (4) suggest that residual neuromuscular blockade after the use of pancuronium is a risk factor for postoperative respiratory complications.

Postoperative nausea and vomiting, which can increase PACU LOS, is a common complication after general anesthesia. The administration of neostigmine to reverse the effects of NMBDs can contribute to nausea and vomiting, particularly when larger doses are used (21,22). We expected that more episodes of nausea and vomiting would be observed in the pancuronium group, because larger doses of neostigmine are needed to antagonize more intense neuromuscular block. However, the overall incidence of nausea (13%) and vomiting (8.7%) in the PACU was infrequent in this study and did not differ between groups. The use of anticholinesterases in the OR was similar in the pancuronium and rocuronium groups. This suggests that the TOF count was not different at the time when neuromuscular block was reversed. In addition, discharge from the PACU was not delayed in any patient in this study because of postoperative nausea and vomiting. Our findings are in agreement with those of a previous observational study in which no increase in the incidence of nausea or vomiting was observed when clinicians routinely used pancuronium instead of shorter-acting NMBDs (10).

There are several limitations to this investigation. First, muscle relaxation is not an absolute requirement for orthopedic surgery. However, many clinicians maintain neuromuscular blockade during orthopedic surgery to reduce the risk of patient movement and facilitate surgical exposure. At our institution, maintenance doses of NMBDs are typically administered to patients undergoing the surgical procedures we studied. Second, clinicians in the OR were not blinded to the assignment of NMBDs. Blinding during the intraoperative period was not possible, because anesthesia care providers could easily determine which drug was administered, on the basis of hemodynamic changes during induction and neuromuscular monitoring. Research assistants and PACU nurses assessing patients during the postoperative period were blinded to group assignment, however. Third, differences in the incidence of postoperative hypoxemia may not have been observed if supplemental oxygen had been administered to all subjects. We do not routinely provide oxygen therapy to young, healthy patients undergoing orthopedic procedures. However, data from this study and other clinical studies suggest that supplemental oxygen should be routinely used in the PACU if NMBDs are administered in the OR.

In conclusion, we observed delays in readiness for and in actual PACU discharge when long-acting NMBDs were used. In this small, carefully controlled study, patients who received rocuronium met discharge criteria 40% earlier than those administered pancuronium. Symptoms of muscle weakness and episodes of hypoxemia were more frequent in patients administered pancuronium.

Table 1

	Acknowledgments

The authors wish to thank the following Certified Registered Nurse Anesthetists in the Department of Anesthesiology at Evanston Northwestern Healthcare, Chicago, IL: Maryann Teister, Karen Hamlett-Kleinhenz, Jeffery Scharfe, Ruth Bilharz-Holst, and Audrey Baldauf.

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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 (1) Citing Articles via Google Scholar Google Scholar Articles by Murphy, G. S. Articles by Vender, J. S. Search for Related Content PubMed PubMed Citation Articles by Murphy, G. S. Articles by Vender, J. S.