Profound atracurium induced neuromuscular blockade

Speed of reversal of profound atracurium induced neuromuscular blockade following edrophonium (0.5 or 1.0 mg/kg) or neostigmine (0.04 or 0.08 mg/kg) was measured using the train-of-four pattern of nerve stimulation. In all patients adequate clinical reversal was present when the ratio of the strength of the fourth to the first twitch (T4 ratio) was 0.5. Both doses of edrophonium were associated with a significantly faster speed of reversal than the smaller dose of neostigmine (p less than 0.05 in both cases). However, the larger dose of neostigmine was associated with a reversal time approaching that of edrophonium. Possible explanations for these findings are discussed in terms of contemporary theories of neuromuscular pharmacology.     

Postoperative residual block after intermediate-acting neuromuscular blocking drugs

The frequency and duration of postoperative residual neuromuscular block on arrival of 150 patients in the recovery ward following the use of vecuronium (n = 50), atracurium (n = 50) and rocuronium (n = 50) were recorded. Residual block was defined as a train-of-four ratio of <0.8. An additional group of 10 patients received no neuromuscular blocking drugs during anaesthesia. The incidence of postoperative residual neuromuscular block was 64%, 52% and 39% after the use of vecuronium, atracurium and rocuronium, respectively. Similar numbers of patients were not able to maintain a sustained head or leg lift for 5 s on arrival in the recovery ward. The mean [range] times to attaining a train-of-four ratio of > or =0.8 after arrival in the recovery ward were 9.2 [1-61], 6.9 [1-24] and 14.7 [1.5-83] min for vecuronium, atracurium and rocuronium, respectively. None of the 10 patients who did not receive neuromuscular blocking drugs had train-of-four ratios <0.8 on arrival in the recovery ward. It is concluded that a large proportion of patients arrive in the recovery ward with a train-of-four ratio <0.8, even with the use of intermediate-acting neuromuscular blocking drugs. Although the residual block is relatively short lasting, it may occasionally be prolonged, requiring close observation and monitoring of such patients in the recovery ward.     

The effect of changes in arm temperature on neuromuscular monitoring in the presence of atracurium blockade

This study was designed to investigate the relationship between arm temperature and the degree of blockade as monitored by peripheral nerve stimulation by a comparison of both arms of each patient; one exposed to the environment and the other wrapped to maintain its temperature. The decrease in the temperatures of the exposed arms were significantly more than the wrapped arms. A discrepancy was noted proportional to the temperature difference between the two arms, when the train-of-four counts were compared. A recommendation is made to maintain the temperature of the monitored arm above 32 degrees C.     

Influence of plasma cholinesterase activity on recovery from mivacurium-induced neuromuscular blockade in phenotypically normal patients

The significance of plasma cholinesterase (pChe) activity for the duration of action of mivacurium in phenotypically normal patients was evaluated in 35 patients during neurolept anaesthesia. The response to train-of-four nerve stimulation was recorded using a Myograph 2000. Ten patients with normal pChe (Group I) and five patients with decreased pChe activity (Group 2) were given a small test dose of mivacurium 0.03 mg kg-1. Mivacurium 0.1 mg kg-1 was administered following spontaneous recovery from the first dose. The mean suppression of the height of the first (T1) of the train-of-four responses following mivacurium 0.03 mg kg-1 patients with normal and decreased enzyme activity was 40% and 56%, respectively, and the mean T1 suppression after mivacurium 0.1 mg kg-1 was 100% in both groups. The times to different levels of twitch height recovery following the 0.1 mg kg-1 dose did not differ between the two groups of patients. Another 20 patients with normal or decreased pChe activity (Group 3) were given mivacurium 0.2 mg kg-1. In this group the time to maximum block was 1.4 min (1.0-4.0) mean (range) and the time to reappearance of the T1 response was 15.0 min (7.4-22.7) (range). An inverse relationship was found between the patients' pChe activity and the time to first response. It is concluded that mivacurium is short-acting in patients with normal pChe phenotype and normal to low-normal pChe activity. No patient with very low pChe activity was included in the study. A prolonged response to mivacurium may, however, be expected in these patients.     

A comparison of the neuromuscular blocking effects and reversibility of cisatracurium and atracurium

The neuromuscular blocking effects and the reversibility of cisatracurium 0.1 or 0.15 mgkg⁻¹ were compared with those of atracurium 0.5 mgkg⁻¹ during anaesthesia with propofol, nitrous oxide and isoflurane. Neuromuscular block was monitored using train-of-four stimulation while recording the mechanomyographic response of the adductor pollicis muscle. The block was either allowed to recover spontaneously or was antagonised with neostigmine 50 μgkg⁻¹ at 10% or 25% recovery of the first twitch of the train-of-four. The median times to maximum block were 2.7, 2.2 and 1.5 min following cisatracurium 0.1 and 0.15 mgkg⁻¹ and atracurium 0.5 mgkg⁻¹, respectively. After cisatracurium 0.1 mgkg⁻¹ had been given, the median time to recovery of the train-of-four ratio to 0.8 ('adequate recovery') was 74 min during spontaneous recovery, 48 min after reversal with neostigmine when the first twitch of the train-of-four had returned to 10% of control and 50 min after reversal when the first twitch of the train-of-four had returned to 25% of control. These times for cisatracurium 0.15 mgkg⁻¹ and atracurium 0.5 mgkg⁻¹ were 90, 66 and 57 min and 75, 56 and 54 min, respectively. Administration of neostigmine significantly shortened the time to adequate recovery for both drugs but there were no significant differences in the case of either neuromuscular blocking drug between the groups of patients given neostigmine at 10 or 25% recovery of the first twitch of the train-of-four.     

Feedback control of neuromuscular blockade

A simple system for closed-loop control of neuromuscular blockade is described. It comprises a Datex Relaxograph, a small relay and a syringe pump. The equipment is commercially available and requires no complex custom-built electronics. Atracurium was infused in a semicontinuous manner to 11 patients who underwent general anaesthesia for a variety of surgical procedures. Neuromuscular blockade oscillated within a narrow range around the preset level. The mean rate of infusion of atracurium was 0.5 mg/kg/hour (SD 0.13). The mean recovery time was 25.5 minutes (SD 7.95).     

Clinical automatic control of neuromuscular blockade

A simple feedback control technique has been used to automatically deliver pancuronium to anaesthetised surgical patients. The dosage rate is automatically adjusted at 10-second intervals, according to the measured evoked, rectified, integrated electromyogram. When set to demand 80 percent blockade, in 40 patients, the controller maintained blockade at a steady mean level of 72.9 percent (consuming pancuronium at a mean rate of 0.47 microgram/kg/minute). The main clinical practical problems involved protection against electrical noise and the need to spend time setting up the equipment.     

Time to peak effect of neostigmine at antagonism of atracurium- or vecuronium-induced neuromuscular block

Study Objective: (1) To determine the time to peak effect of neostigmine (time to peak antagonism) during atracurium- or vecuronium-induced neuromuscular block; and (2) to determine the effect on time to peak effect of neostigmine during atracurium-induced neuromuscular block, when the dose of neostigmine is increased from 35 μg/kg to 70 μg/kg.

Design: Prospective, randomized clinical study.

Setting: Gynecologic operating room suite at a university hospital.

Patients: 45 ASA I and II women admitted for gynecologic laparotomy.

Interventions: Anesthesia was performed with thiopental sodium, fentanyl, halothane, nitrous oxide, and atracurium or vecuronium. Train-of-four (TOF) stimulation and mechanomyography were used to monitor neuromuscular transmission. Neostigmine was administered while a constant degree of neuromuscular block was maintained at a twitch height at a point between 4% and 11% of the control twitch height, using a continuous infusion of atracurium or vecuronium. The patients were randomized to three groups, with 15 patients in each group. Group 1 received atracurium block antagonized with neostigmine 35 μg/kg; group 2 received vecuronium block antagonized with neostigmine 35 μg/kg; and group 3 received atracurium block antagonized with neostigmine 70 μg/kg.

Measurements and Main Results: The degree of neuromuscular block at antagonism was similar in the three groups. Time to peak effect (mean ± SD) on TOF ratio was significantly longer in Group 1 (9.7 ± 3.0 minutes) versus Group 2 (6.6 ± 1.4 minutes; (p < 0.05). The time to peak effect on TOF ratio during atracurium-induced block was reduced from 9.7 ± 3.0 minutes to 6.3 ± 2.0 minutes when the dose of neostigmine was increased from 35 μg/kg to 70 μg/kg (p < 0.05). The peak effect on TOF ratio was significantly greater in Group 3 compared with Group 1 (p < 0.05), while it was similar in groups 1 and 2.

Conclusion: The time to peak effect of neostigmine 35 μg/kg is about 6 to 10 minutes when antagonizing a constant degree of atracurium- or vecuronium-induced neuromuscular block at a twitch height at a point between 4% and 11%. Even though the time to peak effect was longer with atracurium than with vecuronium, clinically significant differences between the antagonizing effect of atracurium versus vecuronium block were not demonstrated. The time to peak effect during atracurium-induced block decreased when the dose of neostigmine was increased from 35 μg/kg to 70 μg/kg.     

Spontaneous recovery of residual neuromuscular blockade after atracurium or vecuronium during isoflurane anaesthesia

With atracurium and vecuronium, spontaneous recovery of residual neuromuscular blockade monitored electromyographically during 0.5% isoflurane anaesthesia was studied in 60 patients undergoing plastic surgery. After thiopentone, in random order, either atracurium 0.5 mg kg-1 or vecuronium 0.1 mg kg-1 was administered and isoflurane added to N2O and O2 mixture. Following spontaneous recovery of both the single twitch amplitude (T1) to 75% of the control value and the train-of-four ratio (TOF ratio) to 75%, incremental doses of the relaxant were given to maintain the T1 at less than 10%. Before the end of surgery, the blockade was again permitted to recover spontaneously. During the initial spontaneous recovery, the mean recovery time of T1 from 25% to 75% (the recovery index) with atracurium was longer (P less than 0.001) than that with vecuronium (13.2 min and 10.1 min, respectively) but, during the second recovery, the mean recovery index was shorter (P less than 0.05) with atracurium than with vecuronium (16.1 min and 19.8 min, respectively). The recovery time from T1 75% to TOF ratio 75%, indicating the recovery rate of residual neuromuscular blockade, with atracurium was about 15 min after both the initial and the second recoveries. With vecuronium, the respective recovery times were significantly (P less than 0.001) longer (25.6 min and 38.5 min, respectively). It is concluded that with vecuronium there is slower spontaneous recovery of residual neuromuscular blockade than with atracurium.     

Mivacurium-induced neuromuscular blockade in patients with atypical plasma cholinesterase

The duration of action of mivacurium was evaluated during a modified neurolept anaesthesia in 17 patients heterozygous for the usual and the atypical plasma cholinesterase (pChe) gene (E^a₁E^a₁) and in five patients homozygous for the atypical gene (E^a₁E^a₁). The response to train-of-four nerve stimulation was recorded using a Myograph 2000. Five heterozygous patients were given a small dose of mivacurium 0.03 mg kg bw^-1 intravenously (Group 1). The mean (range) suppression of the first twitch in the train-of-four response (T₁) was 91% (69–100%). The time to 90% T₁ recovery was 23.9 min (14.0–31.3 min). Twelve other heterozygous patients (Group 2) received mivacurium 0.2 mg kg bw^-1 (2.5 * ED₉₅). In these patients the time to 100% T₁ suppression was 1.4 min (1.1–2.0 min). The time to reappearance of the T₁ response, to 90% T₁ recovery, and the recovery index (25.3 min (14.5–34.5), 45.5 min (30.9–59.2), and 9.8 min (6.8–19.6), respectively) were significantly longer than reported in phenotypically normal patients. Five patients homozygous for the atypical gene (Group 3) were given 0.03 mg kg bw^-1 mivacurium. The time to reappearance of T₁ response following this low dose of mivacurium ranged from 26–128 min. In all five patients the neuromuscular block was successfully antagonized with neostigmine preceded by atropine. In conclusion, mivacurium-induced neuromuscular blockade was moderately prolonged in patients heterozygous for the usual and the atypical gene for plasma cholinesterase. Patients homozygous for the atypical plasma cholinesterase gene appear to be markedly sensitive to mivacurium.     

Antagonism of neuromuscular blockade

Glycopyrronium 5 or 10 micrograms/kg was administered either simultaneously with, or 1 minute before, edrophonium 1 mg/kg in order to antagonise competitive neuromuscular blockade in 80 children. Both doses of glycopyrronium given before the edrophonium resulted in an initial significant (p less than 0.01) increase in heart rate. Heart rate decreased significantly (p less than 0.01) in all groups after the edrophonium was given, and only glycopyrronium 10 micrograms/kg administered before edrophonium prevented a substantial decrease below baseline. Initial heart rate responses to glycopyrronium or edrophonium are rapid, and measurements at intervals of 30 seconds may be necessary to record these changes.     

Respiratory function in children during recovery from neuromuscular blockade

Residual neuromuscular blockade is a major risk factor for respiratory insufficiency. We examined the relationship between neuromuscular and respiratory function in 18 ASA I or II children aged 2–4 years. Lung function was measured by pneumotachography and transpulmonary pressure, neuromuscular transmission by first twitch response ratio (T1:T1) and train-of-four ratio (TOFR), before and at specific points in recovery from vecuronium paralysis. The tidal volume was directly related to maximal inspiratory pressure at occlusion ( P _Iocc), P <0.001, whereas the minute ventilation (V_E) was related to the respiratory drive (P0.1), P <0.001. The best predictors of minute ventilation were the P0.1 ( r =0.57), and the TOFR ( r =0.62). P _Iocc and P0.1 correlated closely ( r =0.889, P =0.002) but TOFR and T1:T1 did not correlate with either. Our results show that the occlusion pressure measurements, P0.1 and P _Iocc, were good predictors of both V_E·kg⁻¹ and respiratory work.     

Cardiovascular changes at antagonism of atracurium

The cardiovascular changes in the 10 minutes following antagonism of an atracurium-induced block were studied in 32 patients. A 5:1 ratio combination of either 15, 35, 55 or 75 micrograms/kg neostigmine, with a corresponding dose of 3, 7, 11, or 15 micrograms/kg of glycopyrronium was used for antagonism. The least change in heart rate was with neostigmine 15 micrograms/kg with an increase of more than 15 beats/minute found in only one patient. Antagonism with 35, 55 and 75 micrograms/kg neostigmine mixture produced the greatest increase in heart rate at one minute and this was significantly different from the effect of the 15 micrograms/kg dose. Twenty out of 24 patients given the larger doses had heart rate increases in excess of 15 beats/minute and in nine patients this ranged from 30 to 52 beats/minute, representing increases of 46-80% above baseline values. Arterial pressure increases after antagonism were statistically significant in all four groups, with no between-group difference; these were clinically unimportant. When antagonising an atracurium-induced block with clinically useful doses of neostigmine, the standard 5 : 1 ratio combination with glycopyrronium will result in an initial tachycardia.     

Neostigmine and edrophonium as antagonists of atracurium and pancuronium

Edrophonium 0.5 mg/kg or neostigmine 0.04 mg/kg were administered to two groups of 30 patients each for antagonism of atracurium- or pancuronium-induced neuromuscular block at 25% single twitch recovery. Neuromuscular block was studied using both single twitch and train-of-four (TOF) nerve stimulation. The times to 100% single twitch recovery were significantly more rapid for patients receiving edrophonium (P less than 0.01) in both groups (atracurium and pancuronium); the TOF ratios were similar for atracurium, but for pancuronium they were greater after neostigmine than after edrophonium, and only at 25 min were these ratios similar. It is concluded that edrophonium in a dose of 0.5 mg/kg antagonizes neuromuscular blockade induced by atracurium, as does neostigmine in a dose of 0.04 mg/kg, but the former does not consistently antagonize neuromuscular blockade induced by pancuronium even at 25% of single twitch recovery.     

Effect of epidurally administered bupivacaine on atracurium-induced neuromuscular blockade

The effect of epidurally administered bupivacaine on duration, intensity and reversal characteristics of atracurium-induced neuromuscular blockade was studied in 30 healthy patients anaesthetized with thiopentone, fentanyl, midazolam and nitrous oxide. Fifteen patients received, in addition, epidural anaesthesia with bupivacaine. The remaining patients served as controls. The ulnar nerve was stimulated at the wrist and the evoked twitch response from the adductor pollicis was measured with a force displacement transducer. Neuromuscular blockade was induced with atracurium 0.5 mg i.v. and maintained with repeated doses of atracurium 0.15 mg/kg whenever the twitch height had recovered to 15% of the initial twitch height. After operation, the neuromuscular blockade was reversed with neostigmine when the twitch height had recovered to 15%. In the epidural group the clinical duration of neuromuscular blockade, time until first response to train-of-four (TOF) and reversal time were all significantly prolonged (P less than 0.05). Post-tetanic count (PTC) after 20 min was also significantly lower in the epidural group (P less than 0.05). It is therefore concluded that epidurally administered bupivacaine prolongs atracurium-induced neuromuscular blockade. The clinical implication of the modest prolongation is, however, limited.     

Neuromuscular transmission and its blockade

The role of two recently introduced muscle relaxants--atracurium and vecuronium--in contemporary anaesthetic practice is assessed. Recent advances in the physiology of neuromuscular transmission, particularly the roles of calcium and calmodulin, are reviewed, and new ideas concerning the reversal and monitoring of neuromuscular blockade are discussed.