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Antagonism of Cisatracurium and Rocuronium Block at a Tactile Train-of-Four Count of 2: Should Quantitative Assessment of Neuromuscular Function Be Mandatory?

Kopman, Aaron F., MD; Zank, Lee M., MD; Ng, Jennifer, MD; Neuman, George G., MD

Section Editor(s): Bovill, James G. Section Editor

doi: 10.1213/01.ANE.0000094985.19305.E9
Anesthetic Pharmacology: Research Report
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With a train-of-four (TOF) ratio >0.70 as the standard of acceptable recovery, postoperative residual paralysis is a frequent occurrence in postanesthesia care units (PACUs). However, detailed information regarding prior anesthetic management is rarely provided. We examined the incidence of postoperative weakness after the administration of cisatracurium and rocuronium when using a rigid protocol for muscle relaxant and subsequent neostigmine administration. Under desflurane, N2O, and opioid anesthesia, tracheal intubation was accomplished after either cisatracurium 0.15 mg/kg or rocuronium 0.60 mg/kg. The response of the thumb to ulnar nerve stimulation was estimated by palpation. Additional increments of muscle relaxant were given as needed to maintain the TOF count at 1 or 2. At the conclusion of surgery, at a TOF count of 2, neostigmine 0.05 mg/kg plus glycopyrrolate 10 μg/kg was administered. The mechanical TOF response was then measured with a force transducer starting 5 min postreversal. Patients were observed until a TOF ratio of 0.90 was achieved. There were no significant differences in the recovery profiles of cisatracurium versus rocuronium. TOF ratios at 10 min postreversal were 0.72 ± 0.10 and 0.76 ± 0.11, respectively. At 15 min postreversal, only one subject in each group had a TOF ratio of <0.70. No patient in either group arrived in the PACU with a TOF ratio <0.70. Our results suggest that if cisatracurium or rocuronium is administered by using the TOF count as a guide, critical episodes of postoperative weakness in the PACU should be an infrequent occurrence.

IMPLICATIONS: After the administration of cisatracurium or rocuronium, train-of-four (TOF) ratios <0.70 should rarely be observed in the postanesthesia care unit if neostigmine-assisted antagonism of residual block is delayed until the tactile TOF count at the thumb is 2 or more.

Department of Anesthesiology, New York Medical College, Valhalla, New York

Supported in part by a grant from Glaxo Wellcome Co.

Accepted for publication August 21, 2003.

Address correspondence to Aaron F. Kopman, MD, Department of Anesthesiology, Rm. 408, St. Vincent’s Hospital Manhattan, 170 W. 12th St., New York, NY 10011. Address e-mail to akopman@rcn.com. Reprints will not be available from the authors.

Almost 20 yr ago, Viby-Mogensen et al. (1) pointed out that undetected residual paralysis was a frequent occurrence in their postanesthesia care unit (PACU). They observed that train-of-four (TOF) fade ratios of <0.70 were often found on arrival in the PACU in patients recovering from traditional long-acting muscle relaxants. In fact, 6 of 50 individuals arrived in the recovery area with TOF ratios of ≤40%, despite the prior administration of neostigmine. These findings were rapidly confirmed by other investigators (2,3). Additional work suggested that when muscle relaxants of intermediate duration were substituted for drugs such as gallamine and pancuronium, the incidence of postoperative residual paralysis (PORC) was reduced significantly (4–6). Fifteen years ago, Bevan et al. (7), reporting on a large group of patients arriving in the PACU (approximately 15 min after reversal), observed that the TOF fade ratio was <0.70 in 36% of patients receiving pancuronium but was only 4% and 9% in patients receiving atracurium and vecuronium, respectively. Therefore, the problem of PORC should have diminished with time as muscle relaxants of short to intermediate duration gradually replaced long-acting muscle relaxants.

This prediction has not come to pass. Since the year 2000, at least eight articles have come to our attention suggesting that PORC continues to be a common occurrence even after muscle relaxants of intermediate duration (8–15). This series of reports prompted a recent editorial in Anesthesiology, in which Lars Eriksson (16) suggested that “…it is time to move from discussion to action and introduce objective neuromuscular monitoring [measurements of the TOF ratio in real time] in all operating rooms, not just those occupied by researchers and aficionados of mus- cle relaxants. Objective neuromuscular monitoring…should…be used whenever a nondepolarizing neuromuscular blocking agent is administered.” Although Eriksson’s proposal represents a desirable goal, we believe that it still possible to markedly decrease the incidence of PORC with instrumentation that should be available today in any modern operating room (OR) (a simple battery-operated nerve stimulator capable of delivering supramaximal TOF stimuli). This study was designed to confirm our hypothesis that with proper intraoperative interpretation of the tactile TOF count (TOFC), significant postoperative neuromuscular weakness should be an infrequent event.

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Methods

Sixty ASA status I or II adult patients (aged 18 to 69 yr) undergoing elective surgical procedures for which the administration of a muscle relaxant was appropriate were included in the study. The expected total anesthesia time in all patients was anticipated to exceed 90 min. All patients were free from neuromuscular disease and within 25% of ideal body weight. Patients in whom difficulty with orotracheal anesthesia was anticipated were excluded from the protocol. Other exclusion criteria included a history of allergies to any study medication and current use of any drugs known to influence neuromuscular transmission. IRB approval was obtained before this project began, and all subjects gave informed consent. Patients were randomly assigned to one of two treatment groups.

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Group 1 (Cisatracurium; n = 30)

Anesthesia was induced with propofol 1.5–2.5 mg/kg IV plus fentanyl 2–4 μg/kg or alfentanil 10–20 μg/kg and was maintained with inhaled nitrous oxide (60%–65% inspired) plus desflurane (end-tidal concentration <5%) and opioid supplementation if needed. Ventilation was controlled, and end-tidal Pco2 was maintained between 32 and 38 mm Hg. All anesthetics were administered by one of the authors. The indirectly evoked response of the adductor pollicis muscle was estimated by palpation of the slightly abducted thumb. Ulnar nerve stimulation was effected by using a Fisher-Paykell (Auckland, New Zealand) constant-current nerve stimulator at a milliamperage deemed appropriate by the clinician (30–50 mA). Cisatracurium 0.15 mg/kg was administered for tracheal intubation. Additional increments (0.5–2.0 mg) were administered in a manner designed to keep the tactile TOFC at one to two detectable responses, and an attempt was made to time such increments so that the TOFC was 2 at the time of reversal. Muscle relaxant administration was guided solely by the TOFC at the thumb.

When the surgical procedure was over, reversal was accomplished with neostigmine 0.05 mg/kg plus glycopyrrolate 0.01 mg/kg administered IV. Five minutes later, the actual TOF ratio was measured for the first time. The indirectly evoked mechanical response of the adductor pollicis muscle was measured with a Life-Tech (Stafford, TX) Myotrace® APM linear force transducer and a Gould (Cleveland, OH) WindoGraf® electrophysiology monitor. A least one additional TOF recording at 10 min postreversal was obtained in the OR. Additional intraoperative TOF measurements were recorded if conditions permitted. Patients were tracheally extubated and discharged from the OR when they could respond to verbal commands and no fade was palpable on TOF stimulation.

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Group 2 (Rocuronium; n = 30)

The protocol was identical to that of Group 1 except that rocuronium 0.60 mg/kg was administered for tracheal intubation and additional increments ranged from 2.5 to 10 mg. In both groups, each patient was followed up until a TOF ratio ≥0.90 was achieved. If this value was not attained in the OR, subsequent measurements were made in the PACU until this level of recovery was reached. Only patients who demonstrated a TOFC in the range of 1–3 at the time of reversal were included in the study.

Data were analyzed by using appropriate tests; P < 0.05 was considered statistically significant. Continuous objective variables (such as mean TOF ratios at 10 min postreversal) were analyzed by a two-tailed two-sample Student’s t-test. Differences in frequency distribution between various groups (e.g., the incidence of TOF ratios <0.90 at 30 min postreversal for rocuronium versus cisatracurium) were subjected to χ2 analysis.

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Results

There were no significant differences in the demographics of the two groups, nor were there differences in the times from the initial bolus of muscle relaxant to neostigmine administration (Table 1).

Table 1

Table 1

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Group 1 (Cisatracurium; n = 30)

The time (mean ± sd) from the initial bolus to reversal was 150 ± 49 min (range, 81–229 min). The total cumulative cisatracurium dosage averaged 0.22 ± 0.06 mg/kg. The mean time between the last incremental dose and reversal was 17.1 ± 8.3 min (range, 5–33 min).

Twenty-seven of 30 subjects had a TOFC of 2 at reversal. Two had a TOFC of 1, and one had a TOFC of 3. TOF ratios at 5 and 10 min postreversal were 0.49 ± 0.11 (range, 0.21–0.72) and 0.72 ± 0.10 (range, 0.38–0.94), respectively. In 19 of 30 patients, a TOF ratio ≥0.90 was attained before transfer to the PACU. In these individuals, the average time to a TOF ratio ≥0.90 was 17.7 ± 4.7 min (range, 10–28 min). In the remaining 11 patients, the average TOF ratio on arrival in the PACU was 0.91 ± 0.06 (range, 0.78–0.97), and this averaged 27.2 ± 3.8 min (range, 22–35 min) postantagonism. Twenty-eight of 30 subjects had TOF ratios ≥0.90 within 30 min of reversal (Table 2).

Table 2

Table 2

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Group 2 (Rocuronium; n = 30)

The average time from the initial bolus to reversal was 157 ± 60 min (range, 66–319 min). The total cumulative dose of rocuronium was 1.20 ± 0.3 mg/kg. The mean time between the last incremental dose and reversal was 16.4 ± 11.6 min (range, 3–64 min).

Twenty-three of 30 subjects had a TOFC of 2 at reversal. Four had a TOFC of 1, and 2 had a TOFC of 3. TOF ratios at 5 and 10 min postreversal were 0.61 ± 0.14 (range, 0.29–0.84) and 0.76 ± 0.11 (range, 0.47–0.95), respectively. Fifteen of 30 patients had a TOF ratio ≥0.90 before transfer to the PACU. In these individuals, the average time to a TOF ratio ≥0.90 was 14.4 ± 4.1 min (range, 10–24 min). In the remaining 15 patients, the average TOF ratio on arrival in the PACU was 0.87 ± 0.07 (range, 0.73–0.97), and this averaged 29.1 ± 6.0 min (range, 23–45 min) after neostigmine antagonism. In five individuals, a TOF ≥0.90 was not attained by 30 min postrecovery (Table 3).

Table 3

Table 3

Although the TOF ratio was larger in Group 2 at 5 min postreversal than in Group 1, this was the only significant difference between these groups in any of the recovery variables that we recorded. At 30 min postantagonism, only 7% (cisatracurium) and 17% (rocuronium) of the individuals in this study had TOF ratios less than 0.90.

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Discussion

Since the original report by Viby-Mogensen et al. in 1979 (1), the incidence of residual paralysis in the PACU has been extensively studied. Despite the widespread adoption of muscle relaxants of intermediate duration, PORC continues to be a frequent occurrence in the modern PACU. One group of authors observed that 239 (42%) of 568 patients arrived in their PACU with TOF ratios less than 0.70 (8). These are truly alarming numbers. However, it is often difficult to interpret such reports because the details of intraoperative anesthetic management are not always provided. Was a peripheral nerve stimulator used? Was residual block always antagonized? Frequently we are left uninformed.

While some investigators have suggested that the incidence of PORC may be decreased with careful intraoperative monitoring (17,18), not all observers have been able to demonstrate that this is actually so (19). Although we recognize that our sample size is modest (n = 30 in each group), the results of this investigation suggest that with careful intraoperative monitoring, postoperative neuromuscular weakness should be an uncommon event. The lowest TOF ratios we encountered on patient arrival in the PACU were 0.73 (rocuronium) and 0.78 (cisatracurium), and only 2 subjects of the 60 studied had TOF ratios <0.70 15 minutes after reversal. It should be noted that several of our patients received doses of muscle relaxant that were given not because they were clinically indicated, but because the protocol required that they be administered. In the real world of daily clinical practice, we think that it is possible to improve on our observations.

Because we have no reason to doubt the validity of the work of previous investigators and have considerable faith in our own methodology, an attempt to reconcile our results with those of other researchers is required. First, it must be emphasized that we used a very rigid protocol. Our results represent the outcome not of an entire department, but of four individuals who understood the procedure to be followed in detail and were committed to adhering to it. In addition, with few exceptions, all patients had TOFCs of 2 or 3 at the time antagonism was attempted (2 patients in Group 1 and 4 in Group 2 had TOFCs of only 1 at reversal). Reversal was never attempted in the absence of an evoked response to TOF stimulation.

The shortest interval between neostigmine administration and PACU testing that we were able to achieve was 22 minutes, and the average value was closer to 30 minutes. Hence, our PACU findings may in part reflect a longer reversal to PACU arrival time than that experienced by other investigators. In the report of Bevan et al. (7), for example, the interval from reversal to testing in the PACU was <15 minutes. It may be argued that a 25- to 30-minute interval (reversal to PACU) does not represent clinical reality in many settings. We would, however, point out that at 15 minutes postreversal, only 3% of our subjects had a TOF ratio <0.70. We would also note that we initiated antagonism of the muscle relaxant not during application of the surgical dressing, but as soon as the need for surgical relaxation was over (e.g., closure of abdominal fascia).

We think that our results are in general agreement with those reported recently by Kirkegaard et al. (20) After a single bolus of cisatracurium 0.15 mg/kg, they attempted reversal at threshold TOFCs of 1, 2, 3, and 4 with neostigmine 0.07 mg/kg (a dose somewhat larger than the one that we used). When the TOFC was 2, they reported a median TOF ratio of 0.80 at 9.8 minutes (range, 5.3–25.0 minutes) after reversal. Our average TOF value at this time (10 minutes) was 0.76 ± 0.11 (30% of subjects had TOF values <0.70). We certainly agree with Kirkegaard et al., who concluded that to achieve rapid (within 10 minutes) reversal to a TOF ratio of 0.70 in >90% of patients, 3 or 4 tactile responses should be present at the time of neostigmine administration. Nevertheless, even when reversal of cisatracurium or rocuronium was initiated at a TOFC of 2, the TOF ratio was <0.70 in only 2 of the 60 patients we studied at 15 minutes postreversal.

In the light of our results, we think that Eriksson’s (16) suggestion that quantitative monitoring of neuromuscular function should be mandatory when nondepolarizing muscle relaxants are administered is unnecessarily restrictive. It sends a message that know- ledgeable and safe management of muscle relaxants is not possible without such equipment. Put somewhat differently, it implies that the administration of an intermediate-acting muscle relaxant guided only by subjective estimation of the TOFC represents substandard care. We respectfully disagree. We do not believe that the frequent incidence of PORC reported by Debaene et al. (15), Baillard et al. (8), and many other investigators is unique to their institutions. Their results represent not so much the inadequacy of available monitors as the failure of clinicians to apply principles that are already well known. The prescription for reducing the incidence of PORC is not a secret:

  1. The tactile TOFC should be monitored during surgery. Use of a peripheral nerve stimulator is not optional.
  2. Traditional long-acting muscle relaxants should be avoided (7,21).
  3. Avoid total twitch suppression. A TOFC of 1 represents >90% twitch suppression. Neuromuscular block of this depth cannot be antagonized promptly by anticholinesterases (22).
  4. Where possible, attempt to achieve a TOFC of 3, and preferably 4, before anticholinesterase-induced reversal (20).
  5. Recognize that any detectable fade on TOF stimulation represents grossly inadequate recovery. Most clinicians cannot detect the presence of any fade once the TOF ratio exceeds 0.40 (23).
  6. With rare exceptions, failure to detect TOF tactile or visual fade does not mean that reversal is unnecessary. In the absence of objective monitoring, reduced doses of anticholinesterases should still be given (24,25).

These comments are not meant to imply that objective monitoring of the TOF ratio cannot help the clinician. On the contrary, when attempting to antagonize profound block the opposite is clearly true (26). Nevertheless, with proper intraoperative use of a simple peripheral nerve stimulator and a basic understanding of neuromuscular pharmacology, TOF ratios <0.70 should rarely be observed in the PACU. Prompt recovery to a TOF ratio of 0.90 or more is less easily achieved. It is not always possible within 30 minutes to realize a TOF ratio of 0.9 in all patients, regardless of the number of tactile responses present at neostigmine administration (20).

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