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ANESTHETIC PHARMACOLOGY

Tactile Assessment for the Reversibility of Rocuronium-Induced Neuromuscular Blockade During Propofol or Sevoflurane Anesthesia

Department of Anesthesiology, Hanyang University Hospital, Seoul, Korea

Address correspondence and reprint requests to Kyo Sang Kim, MD, PhD, Department of Anesthesiology, Hanyang University Hospital, #17 Haengdang dong, Sungdong gu, Seoul 133-792, Korea. Address e-mail to kimks{at}hanyang.ac.kr

	Abstract

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We sought to determine whether tactile train-of-four (TOF) count can predict the efficacy of neostigmine administration for rocuronium-induced blockade during propofol or sevoflurane anesthesia, and to follow subsequent recovery until the TOF ratio reached 0.9. One-hundred-sixty patients, divided into eight equal groups, were randomly allocated to maintenance of anesthesia with propofol or sevoflurane. The tactile response of the adductor pollicis to TOF stimulation was evaluated on one arm, and the mechanomyographic response was recorded on the other. Neuromuscular block was induced with rocuronium 0.6 mg/kg and maintained with rocuronium to 15% of the control first twitch in TOF. Neostigmine 0.07 mg/kg was administered on reappearance of the first (Group I), second (Group II), third (Group III), or fourth (Group IV) tactile TOF response in each anesthesia. At this time, sevoflurane or the propofol dosage was reduced in each group (n = 20 in each group). The times from administration of neostigmine until the TOF ratio recovered to 0.7, 0.8, and 0.9 were recorded. The times [median (range)] to TOF ratio = 0.9 were 8.6 (4.7–18.9), 7.5 (3.4–9.8), 5.4 (1.6–8.6), and 4.7 (1.3–7.2) min in Groups I–IV during propofol anesthesia, respectively, and 28.6 (8.8–75.8), 22.6 (8.3–57.4), 15.6 (7.3–43.9), and 9.7 (5.1–26.4) min in corresponding groups during sevoflurane anesthesia, respectively (P < 0.0001). We recommend more than 2 TOF responses with propofol anesthesia and 4 TOF responses with sevoflurane anesthesia for adequate reversal within 10 and 15 min, respectively. The more tactile TOF responses present at the time of reversal achieved greater adequate recovery; however, tactile TOF responses are not a completely reliable predictor within a reasonable time period.

IMPLICATIONS: Even in the presence of train-of-four responses, the clinician should be aware that reversal may be inadequate.

	Introduction

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Despite the availability of monitoring devices with automatic quantification of the train-of-four (TOF) ratio, the intensity of neuromuscular blockade is often assessed by tactile or visual evaluation of the responses to peripheral nerve stimulation. The tactile TOF count is described in the guidelines for neostigmine-induced reversal of neuromuscular block (1–3). Volatile anesthetics, including sevoflurane, intensify the action of rocuronium-induced neuromuscular blockade (4,5), and interfere with the antagonism of neuromuscular blockade (6,7). In addition, although a TOF ratio of 0.7 was chosen as the critical value, studies in awake volunteers have demonstrated impaired ventilatory function at values <0.7 (8). Yet, there is increasing evidence of significant residual effects until the TOF ratio has reached 0.9 (9). There are no reports describing the effects of sevoflurane on the neuromuscular recovery of rocuronium-induced blockade after reversal with neostigmine at different TOF counts.

Thus, we sought to determine whether tactile TOF count at the time of neostigmine administration can predict the reversibility of rocuronium-induced blockade during sevoflurane (versus propofol) anesthesia, and to follow subsequent recovery until the TOF ratio reached 0.9.

	Methods

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After obtaining Hospital Ethics Committee approval and informed consent, we studied 160 patients, ASA physical status I or II, aged 18–61 yr, undergoing elective surgical procedures. The patients were randomly allocated into 8 groups of 20. No patient had any disease or metabolic abnormality known to alter neuromuscular transmission, or was receiving any drug known or suspected of interfering with neuromuscular function. After premedication with midazolam 2 mg IV, anesthesia was induced with fentanyl 2 µg/kg and propofol 2–2.5 mg/kg and maintained with 70% nitrous oxide in oxygen with sevoflurane or propofol, as allocated by a computer-generated randomization scheme. Initially, the patients’ lungs were ventilated using a bag and mask. Anesthesia was induced and, before muscle relaxant was administered, control first twitch (Tc) and TOF fade ratio (T4/T1) were established after a 5-min period of baseline stabilization. Neuromuscular blockade was induced with a bolus injection of rocuronium 0.6 mg/kg and maintained with rocuronium 0.1 mg/kg given every time the height of first twitch (T1) in TOF recovered to approximately 15% of Tc obtained before induction of neuromuscular blockade. Tracheal intubation was performed after full relaxation.

In sevoflurane anesthesia (n = 80), the end-tidal concentration of sevoflurane was monitored using a respiratory gas monitor and maintained to 1.5 minimum alveolar anesthetic concentration adjusted for age and concomitant use of nitrous oxide (1.5%–1.8% sevoflurane) as described previously (4). In propofol anesthesia (n = 80), anesthesia was maintained with a continuous infusion of propofol 8–10 mg · kg^–1 · h^–1 and 70% nitrous oxide in oxygen. Further doses of fentanyl (50 µg) were administered to treat clinical signs of inadequate anesthesia in both treatment groups. Ventilation was adjusted to maintain normocapnia (end-tidal carbon dioxide partial pressure 35–40 mm Hg), and palm skin temperature of both hands, where neuromuscular function was monitored, was maintained at >33°C by wrapping the arm in cotton wool. Patients were kept warm during anesthesia using warming blankets, and maintained nasopharyngeal temperature >35°C.

Two Myotest DBS peripheral nerve stimulators were used for stimulation of the ulnar nerves via cutaneous electrodes at the wrists. After identical time of stabilization of response to TOF stimulation at 2 Hz every 10 s, supramaximal stimulation was secured in both arms. In the arm used for mechanomyographical measurement, the resultant contraction of the adductor pollicis to TOF stimulation was recorded using a force displacement transducer and a neuromuscular function analyzer (Myograph 2000; Biometer Co., Odense, Denmark). Preload tension of the thumb was maintained at 300 g throughout the investigation. The T1 was then recorded as the control twitch height (T1 control = 100%).

In the other arm used for tactile evaluation, a moderate preload was applied to the thumb by the assessor’s second and third finger, and the number of felt responses after TOF stimulation was counted. A twitch response was defined as present if any response, regardless of strength, was felt during three consecutive TOF stimulations. The number of tactile responses was counted during 25-s periods every 2 min. In all patients, evaluation of tactile responses was performed by the same anesthesiologist who was blinded to the mechanomyographic measurements on the contralateral arm but not to the treatment groups. To account for possible differences in muscle strength between the dominant and nondominant arm, the dominant arm was used for tactile evaluation in half of the patients and the nondominant arm in the remaining patients, which was randomly assigned.

For the antagonism of neuromuscular blockade, the patients received 0.07 mg/kg neostigmine and 0.014 mg/kg glycopyrrolate at different levels of TOF recovery (3). Patients were randomly assigned to 1 of 4 groups for each anesthesia; 20 patients in each group received the reversal drugs at the reappearance of the first (Group I), second (Group II), third (Group III), or fourth (Group IV) tactile TOF response. For sevoflurane anesthesia, the end-tidal concentration of sevoflurane was adjusted to 0.5% at administration of reversal drug, and maintained until the TOF ratio exceeded 0.9. In propofol anesthesia, the dosage of the infusion was reduced to 2 mg · kg^–1 · h^–1, and continued until the TOF ratio exceeded 0.9 (6). Nitrous oxide 70% in oxygen was continued in all patients until completion of reversal. Reversal times were defined as time from administration of neostigmine until the TOF ratio recovered to 0.7, 0.8, and 0.9. The T1 response (%) at different tactile levels of TOF recovery in both groups was also evaluated during the operation.

Before beginning the study, a power analysis indicated that was set to 0.05, and ß was set to 0.20. This power analysis required 160 patients, with 20 patients in each group. One-way analysis of variance with Bonferroni correction for multiple comparisons was used to test for differences between unpaired groups. The Wilcoxon’s signed rank test was used to compare differences of reversal time between the two anesthesia techniques. A ² test was used to test for differences among groups in proportions of patients reversed to TOF ratios of 0.7, 0.8, and 0.9, respectively, after neostigmine administration. Results were considered statistically significant when P < 0.05. Data were presented as mean ± SD, median (range), absolute numbers, or percentages.

	Results

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There were no differences among the eight groups with respect to age, weight, height, sex distribution, or intraoperative variables, such as dosage of anesthetics or duration of anesthesia. The dosage of fentanyl and rocuronium during propofol anesthesia was larger compared with that in the sevoflurane anesthesia, although there was no significant difference (Table 1).

View larger version (10K): [in this window] [in a new window]   Figure 1. Time from tactile reappearance of each of the four train-of-four (TOF) responses to TOF ratio of 0.9 during sevoflurane (•) and propofol () anesthesia. Individual points represent mean ± SD values. *P < 0.0001 compared with propofol groups.

View larger version (10K): [in this window] [in a new window]   Figure 2. The mechanomyographic variation of the first train-of-four (TOF) twitch (T1) at reappearance of each of the four tactile TOF responses during sevoflurane (•) and propofol () anesthesia. Individual points represent mean ± SD values.

	Discussion

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Several studies (9,10) have suggested that a TOF ratio of at least 0.9 is needed to consider the neuromuscular block to be adequately reversed. Our results show that all patients with reappearance of >2 tactile responses at the time of neostigmine administration had a TOF ratio >0.9 within 10 minutes during propofol anesthesia (Table 2, Fig. 1). During sevoflurane anesthesia, however, waiting until 4 tactile responses were present allowed the TOF ratio to reach 0.9 within 10 minutes in 55% of patients, and within 15 minutes in 95% of patients, respectively. Our results suggest that >2 TOF responses with propofol and 4 TOF responses with sevoflurane are recommended for adequate reversal within 10 and 15 minutes, respectively.

A TOF ratio of 0.7 has been considered a clinical minimum guideline to represent adequate recovery from a nondepolarizing neuromuscular block (8,11). Kirkegaard et al. (3) demonstrated that when neostigmine was administered at even 3 or 4 TOF responses to antagonize cisatracurium (0.15 mg/kg) during propofol anesthesia, it was possible to attain a TOF ratio of 0.7 within 10 minutes in 87% of patients. However, the current results show that reappearance of the third or fourth tactile response can be used as an indicator of the reversal drug for the antagonism (95% and 100%, respectively) of rocuronium-induced block within 5 minutes during propofol anesthesia (Table 3). The times to full recovery are clearly longer with cisatracurium. The duration of action of rocuronium using a 0.6 mg/kg dose was approximately 30–40 minutes (12,13), and cisatracurium had a duration of action of 45 minutes after a 0.1 mg/kg dose and approximately 68 minutes after 0.2 mg/kg (13,14). Differences in design of this study compared with ours include the administration of cisatracurium rather than rocuronium with differences in pharmacokinetics. Our results show the possibility that rocuronium is more easily reversible than cisatracurium.

Two-thirds of patients given pancuronium as a neuromuscular blockade failed to reach a TOF ratio of 0.9 within 30 minutes, whereas 6% of patients given mivacurium failed with 2 TOF responses at reversal after desflurane or propofol anesthesia (15). Because success of reversal is influenced by the duration of action of the relaxant, the use of shorter-acting relaxants might allow a TOF ratio of 0.9 to be achieved. In the current study, 40% of patients with 1 TOF response at reversal failed to reach a TOF ratio of 0.9 in 30 minutes after neostigmine administration during sevoflurane anesthesia. This suggests that the number of tactile TOF responses present at the time of reversal with sevoflurane cannot be a reliable guide to adequate recovery from rocuronium-induced block within a reasonable time period. The prolongation and the unpredictability of reversal of intermediate-acting relaxants should also be considered clinically if in the presence of potent volatile anesthetics.

The increasing variability in the reversal time was shown when the TOF ratio target was increasing from 0.7 to 0.9 (3). Interindividual variability was found to be much larger during sevoflurane anesthesia compared with propofol anesthesia (6). We found similar results and the potential of sevoflurane for long reversal time to achieve a TOF ratio of 0.9 (ranging up to 75.8 minutes for sevoflurane and 18.9 minutes for propofol). The reason for this marked prolonged reversal time after an intermediate-duration neuromuscular blockade with a predictable recovery profile is not readily apparent. All patients were healthy and had normal neuromuscular function. We suspect that some individuals may be markedly sensitive to sevoflurane enhancement of their neuromuscular blockade.

The results (TOF ratio = 0.7 = 10.9 minutes) of our study are inconsistent with those (TOF ratio = 0.6 = 6 minutes) of Sutcliffe et al. (16). Differences in the design of that study compared with ours include electromyography monitoring and the maintenance of a lesser end-tidal concentration of sevoflurane (1.0%) compared with those of 1.5%–1.8% in our study, although we reduced the end-tidal concentration of sevoflurane to 0.5% at administration of the reversal drug. This prolongation of the effect of rocuronium with sevoflurane may be caused by a direct effect of the volatile anesthetic on neuromuscular transmission, which is not influenced by reversal drugs (17).

The large variability has been shown in other studies using electromyography (18) and mechanomyography (3,19). In the present study, there was also a large variability in the level of mechanomyographic recovery at the different TOF counts, but no difference between sevoflurane and propofol anesthesia (Fig. 2). The current results for rocuronium (T1/Tc = 34% and 36% with sevoflurane and propofol, respectively) are quite similar to those of O’Hara et al. (19) despite the differences in methodology.

The tactile twitch was very weak at the threshold return of each twitch to palpation. The tactile response frequently was discernible only because it followed previous other twitches (20). In the present study, it was also difficult to constantly measure the tactile response for a long time, because accurate mechanical recordings require a constant preload for the strength and the absolute magnitude of the response. The tactile measurement was performed by a doctor with considerable experience in the use of neuromuscular monitoring equipment in order to minimize observer variability, and randomized with regard to the use of the dominant or nondominant hand.

The present study may be criticized because sevoflurane administration was not clinically continued after neostigmine administration. Although this study elicited a residual effect of sevoflurane, whose end-tidal concentration was reduced from 1.5%–1.8% to 0.5% at administration of the reversal, it may have been more similar to clinical conditions if a slow rate of propofol infusion had been maintained in the sevoflurane group, and if sevoflurane had then been discontinued completely at administration of neostigmine with propofol continued in order to maintain anesthesia.

The anesthetic duration of 40 minutes is sufficient for equilibration of the muscular compartment with volatile anesthetics that have a high blood-gas coefficient (21). In the present study, after the age-adjusted end-tidal concentration of inhaled anesthetic was reached, another minimum of 80 minutes was allowed to elapse before the reversal was given. In clinical practice, intermediate-duration neuromuscular blocking drugs are often given repeatedly and not as a single bolus. Thus, we chose rocuronium as the neuromuscular blocking drug because of its clinical use, and gave it repeatedly to adjust approximately 15% of Tc for about 2 hours of the anesthetic time.

We conclude that >2 TOF responses with propofol anesthesia and 4 TOF responses with sevoflurane anesthesia can be recommended to a TOF ratio of 0.9 within 10 and 15 minutes, respectively. The tactile TOF responses present at the time of reversal cannot be a completely reliable predictor for adequate recovery within a reasonable time period.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999