Cisatracurium Pharmacodynamics in Patients with Oculopharyngeal Muscular Dystrophy

Oculopharyngeal muscular dystrophy (OPMD) was first described by Taylor in 1915 (1). This inherited disease is present all over the world, but the most frequent prevalence is found in the province of Quebec, Canada, where the carrier frequency of the OPMD mutation is estimated to be 1 in 1000 people (2). Physiopathologically, OPMD consists of intranuclear infiltration in the muscle fiber with nondegradable nuclear filaments. Clinically, the disease usually begins with bilateral eyelid ptosis or dysphagia during the fifth or sixth decade of life and evolves toward proximal limb weakness later on. OPMD can also appear earlier in life, depending on the genotype (2). The ptosis has to be corrected when it interferes with vision or when cervical pain appears secondary to constant dorsiflexion of the neck. A cricopharyngeal myotomy becomes necessary when there is dysphagia accompanied by marked weight loss, near-fatal choking, or recurrent pneumonia (3,4).

The literature regarding the anesthesia management of patients with OPMD is scarce. Only two case reports have documented the safe use of vecuronium (5) and mivacurium (6) for affected individuals, but information regarding the duration of action of the muscle relaxant cannot be obtained from these two cases.

We therefore conducted a prospective, open, and controlled study to assess cisatracurium pharmacodynamics in patients with OPMD. We hypothesized, on the basis of both the clinical manifestations of the disease and our clinical experience, that the duration of action of the muscle relaxant would be prolonged by 25% in OPMD patients. We also hypothesized that this prolongation of action would be proportional to the severity of the disease.

Methods

After IRB approval and signed informed consent, 20 patients with OPMD who were scheduled for cricopharyngeal myotomy under general anesthesia were enrolled in the study. They were matched for age (within 10 yr) to a control group of 20 patients undergoing surgery of similar duration and expected blood loss. The diagnosis of OPMD was genetically confirmed in all affected individuals by standard methods (2). Exclusion criteria were renal, hepatic, or cardiac insufficiency; patients taking drugs affecting neuromuscular junction (aminoglycosides, tetracyclines, clindamycin, procainamide, quinidine, calcium antagonists, magnesium sulfate, lithium, phenytoin, and carbamazepine); and morbid obesity (body mass index >35 kg/m²).

The patients were not premedicated. Standard monitoring was applied. A normal saline (0.9%) solution was infused through an IV catheter located on the arm opposite to the neurostimulator at a rate sufficient to replace fluid loss.

This study was conducted in accordance with the guidelines of “Good Clinical Research Practice (GCRP) in Pharmacodynamic Studies of Neuromuscular Blocking Agents” (7). Neuromuscular transmission was monitored with the Datex-Engstrom neuromuscular transmission module with five surface electrodes (Datex-Ohmeda, Helsinki, Finland). The area where the electrodes were to be placed was cleaned to ensure adequate contact. The electrodes were placed in the following manner: two stimulating electrodes on the ulnar nerve trajectory; two recording electrodes, one on the thenar eminence and the second on the lateral face of the index; and the last electrode, which served as a ground, between the stimulating and the recording electrodes, at the level of the wrist. The stimulated arm was then comfortably positioned on an arm board, swathed in a bandage and protected with a padded metal box. This arm was kept warm throughout the study period by wrapping the protective metal box in a cotton blanket.

Anesthetic induction was standardized and consisted of the administration of 100% oxygen, sufentanil 0.25–0.5 μg/kg, and propofol 0.5–3 mg/kg titrated to loss of consciousness. Under stable isoflurane anesthesia (end-tidal concentration 0.5%–1.0%), a baseline supramaximal train-of-four (TOF) stimulation was obtained. The neuromuscular transmission module automatically searches for the supramaximal stimulation by increments of 5 mA, starting at 10 mA, with 2-Hz, 200-μs stimuli. Once obtained, this supramaximal TOF stimulus was then administered every 12 s for 2 min to obtain a stable baseline. The OPMD patients included in this study all had severe dysphagia and were therefore considered as having a full stomach. Accordingly, the stabilization period was limited to 2 min in both groups, and OPMD patients were ventilated with a cricoid pressure applied during this period. Cisatracurium (0.1 mg/kg) was then given over 5 s. Throughout the study, we used the pharmacological weight for dosage calculation. The pharmacological weight was obtained according to the formula developed by Egan et al. (8) and discussed in detail in the accompanying editorial (9). This value is corrected for the patient’s sex, height, total body weight, lean body mass, and ideal body weight. The trachea was intubated when twitch suppression attained 95%. Anesthesia maintenance consisted of 50% oxygen in nitrous oxide and a stable end-tidal concentration of isoflurane (0.3%–0.7%). Increases of arterial blood pressure and tachycardia (20% increase from baseline) were treated with IV boluses of sufentanil 5 μg or propofol 10 mg as often as needed. During the surgery, oral temperature was monitored and maintained ≥35°C with a warming blanket. At the end of the recovery period, we waited until the T1 remained at the same value (no further spontaneous increase of the T1 value) for at least 3 min before giving neostigmine 0.04 mg/kg and glycopyrrolate 0.01 mg/kg to obtain the final T1 value. Intraoperative data were collected on a computer by using Datex-Ohmeda AS/3 PC data collection software.

The variables were obtained with supramaximal TOF stimulations administered every 12 s and were defined as follows:

1. Lag time: time from the beginning of cisatracurium administration until the first measurable effect of neuromuscular block.

2. Onset time: time from the beginning of cisatracurium administration until 95% T1 suppression.

3. Duration 10%: time from the beginning of cisatracurium administration until 10% T1 recovery.

4. Interval 10%–25%: time from 10% to 25% T1 recovery.

5. Interval 25%–75%: time from 25% to 75% T1 recovery.

The data recorded during the recovery period were normalized to the final T1 value.

The severity of OPMD was assessed by using a scale that was previously developed by Duranceau (10). This scale is based on an evaluation of the severity of the oropharyngeal dysphagia: it gives a score according to the frequency, duration, and severity of the dysphagia (Appendix 1).

Data were stored in an Excel database (Microsoft Corp., Redmond, WA). Demographic and ordinal data were compared by using Fisher’s exact test. Continuous data were compared by using Student’s t-test or Wilcoxon’s ranked sum test in case of a nonnormal distribution. Results are expressed as means ± sd except when stated otherwise. P < 0.05 was considered significant.

Results

Demographic and intraoperative data are summarized in Table 1. The two groups were comparable regarding age, pharmacologic weight, height, and ASA physical status. There was a difference in the sex distribution that resulted in significantly more women in the control group. Thyroid-stimulating hormone was normal for all patients. The average body temperature during surgery was also identical between groups and was within the normal range. Blood loss was minimal, and creatinine serum level was comparable and within a normal range in both groups.

Table 2 presents the neuromuscular transmission data for both groups. All patients in both groups developed 100% neuromuscular block. Onset time was significantly prolonged in OPMD patients. However, recovery variables were similar between groups. The final T1/T4 ratio and T1% values before neostigmine administration were 81.1% and 95.6% for the OPMD group and 77.5% and 95.1% for the control group, respectively.

Table 3 shows the neuromuscular transmission data for the subgroup of patients with a clinically severe form of OPMD (score ≥24 on the Duranceau scale) compared with the control group. Demographic data of both groups were similar with the exception of sex; there were more women in the control group. The onset time was, again, longer in the severely dystrophic group. The recovery variables were also identical between groups.

Discussion

This study shows that patients with OPMD have a similar recovery profile from a cisatracurium-induced neuromuscular blockade compared with an age-matched control group, regardless of the severity of the disease. Only two case reports have detailed the anesthetic management of OPMD patients. Landrum and Eggers (5) gave vecuronium 0.1 mg/kg during an IV anesthesia induction (fentanyl, lidocaine, and thiopental) to a 72-year-old patient with OPMD of unknown severity. The anesthetic was maintained with N₂O/oxygen and isoflurane. One hour after the induction, the patient had four detectable responses to TOF stimulation. An additional 1 mg of vecuronium was given. At the end of the 150-minute procedure, the patient had 4 twitches on TOF stimulation. Neostigmine 3 mg and glycopyrrolate 0.5 mg were administered, and the trachea was extubated without any complications. The postoperative course was uncomplicated. Chun (6) reported the case of a 55-year-old OPMD patient. The severity of the disease was not reported. Anesthesia induction was performed with midazolam, fentanyl, and propofol, and tracheal intubation was facilitated with mivacurium 0.12 mg/kg. Anesthesia was maintained with N₂O/oxygen and a propofol infusion. An additional 2 mg of mivacurium was given 20 minutes after induction. The neuromuscular blockade was successfully reversed with edrophonium and atropine after an undefined time period. The same patient came back 2 months later and received a larger dose of mivacurium (0.2 mg/kg) with an effective duration of action of 25 minutes. Even though these two reports show a recovery pattern that appears to be close to normal, the absence of data regarding the severity of the disease and the absence of a control group preclude a valid assessment of the duration of action of muscle relaxants in OPMD patients.

Although this remains poorly studied, variable responses to muscle relaxants are reported for various types of muscular dystrophy. In a prospective and controlled study, Ririe et al. (11) showed that patients with Duchenne’s muscular dystrophy had a significantly prolonged recovery time after a bolus of vecuronium when compared with healthy controls (28 versus 20 minutes, respectively; P = 0.03). Only one case report (12) has described the anesthetic management of a patient with facioscapulohumeral muscular dystrophy. The authors found that the sensitivity to atracurium was similar to that of the healthy population, but a more rapid recovery was observed: 16.5 and 6.5 minutes compared with 28.8 and 12.3 minutes for the 5%–95% and 25%–75% recovery indices, respectively, in the affected individuals and the controls. Two case reports have presented the response to nondepolarizing muscle relaxants in patients with nemaline rod muscular dystrophy, a form of dystrophy characterized by nonprogressive symmetric skeletal muscle weakness that principally affects the proximal skeletal muscles. In both cases, the authors documented a normal response (13,14).

In this study, we obtained a significant prolongation of the onset of action of cisatracurium in the OPMD group. The onset of action of muscle relaxants is highly dependent on the blood flow irrigating the neuromuscular junction: a more rapid blood flow is associated with a decrease in onset time (15). Because OPMD does not affect the myocardium, the cardiac output of affected individuals should not be decreased. A hypothesis to explain the delayed onset could be that the blood flow is impaired at the muscular level in OPMD patients. However, this is pure speculation, because no evidence of this can be found in the literature.

Nondepolarizing muscle relaxants are competitive antagonists of acetylcholine that bind to pre- and postsynaptic cholinergic receptors and induce muscular relaxation. The neuromuscular junction is not involved in the pathophysiologic process of OPMD (3,16,17). This supports our finding that no differences in recovery times were observed between groups. In addition, patients with OPMD will typically present proximal limb weakness at some time, with a sparing of distal muscles. In this study, neuromuscular stimulation was performed on the trajectory of the ulnar nerve, and evoked potentials were recorded at the level of the adductor pollici muscle, a muscle probably not affected by the dystrophia. This could be another explanation for the absence of a difference in recovery times for OPMD patients compared with the control group. Because OPMD predominantly affects oculopharyngeal muscles, assessment of the neuromuscular blockade at the laryngeal level could have yielded different results.

This study has some limitations. The control group contained more women than the OPMD group. In our center, the surgery that most closely resembles cricopharyngeal myotomy is thyroidectomy for a thyroid nodule. As a group, thyroid diseases are more prevalent in female patients, and the opposite is true for OPMD. Some data in the literature show that sex affects the time-course and dose-response relationship of muscle relaxants, with a right shift for men, meaning that a larger dose is necessary for men to obtain the same neuromuscular response as women (18–20). In these studies, however, steroidal muscle relaxants were used. For cisatracurium, one group has found no pharmacodynamic difference imputable to sex (21). In addition, the pharmacological weight we used for dosage calculation in this study already considers sex.

The score of severity we used to stratify the OPMD patients is a clinical score (Appendix 1). OPMD is an inherited disease, and its severity also depends on the kind of mutation the patient has (2,17). This implies that with a more severe mutation form, clinical symptoms will appear earlier in life. Our group of OPMD patients shared the same (GCG)₉ size of PABPN1 mutation. However, we believe that the neuromuscular symptoms presented by the patient are the most significant factor affecting the recovery of neuromuscular blockade. In addition, genetic testing is not a very practical tool for the clinician to evaluate the severity of a disease in the perioperative period.

In conclusion, this study shows no difference in recovery times from a cisatracurium-induced neuromuscular blockade between OPMD patients and a control group undergoing surgery of similar duration and expected blood loss. In a subgroup analysis, we also showed that theduration of action of cisatracurium was not affected by the severity of the neuromuscular disease.

Appendix 1.