Hassan H. Ali

The Clinical Neuromuscular Pharmacology of Mivacurium Chloride (bw B1090u). A Short-acting Nondepolarizing Ester Neuromuscular Blocking Drug

Mivacurium chloride (BW B1090U), a bis-benzylisoquinolinium diester compound, was found to undergo hydrolysis in vitro by purified human plasma cholinesterase in a pH-stat titralorat 88% of the rate of succinylcholine at pH 7.4,37°C and 5 μM substrate concentration. In 72 consenting ASA Physical Status I-II patients receiving nitrous oxide/oxygen-narcotic-thiopental anesthesia, the neuromuscular blocking effect of mivacurium was assessed following bolus doses from 0.03 to 0.30 mg/kg, as well as during and following continuous infusions from 35 to 324 min in length. The calculated ED95 for inhibition of adductor pollicis twitch evoked at 0.15 Hz was 0.08 mg/kg. At 0.1 mg/kg, 96% block developed, onset to maximum block required 3.8 ± 0.5 min, and recovery to 95% twitch height occurred 24.5 ± 1.6 (SE) min after injection. At 0.25 mg/kg, onset was 2.3 ± 0.3 min; 95% recovery developed within 30.4 ± 2.2 min, an increase in duration of action of only 24% versus 150% higher dosage. Comparative recovery indices from 5 to 95% or from 25 to 75% twitch heights did not differ significantly among all dosage groups from 0.1 to 0.3 mg/kg (range 12.9 to 14.7 and 6.6 to 7.2 min, respectively). In 38 patients who received mivacurium by continuous infusion (duration 88.1 ± 7.1/47.1 min, SE/SD) for maintenance of 95 ± 4% twitch inhibition, the mean 5–95% and 25–75% recovery indices after discontinuation of infusion were 14.4 ± 0.6 and 6.5 ± 0.3 min (P > 0.5 vs. all single bolus doses). The train-of-four (T4) ratio, within 2.6 ± 0.5 min after 95% twitch recovery following bolus doses, averaged 79.5 ± 1.8% (n = 32). Similarly, after discontinuation of infusions, the T4 ratio reached 73.4 ± 1.9% within 3.4 ± 1.9 min after 95% twitch recovery (n = 33). Antagonism of residual block was seldom indicated, but, to test case of reverals, eight patients electively received ncostigmine (0.06 mg/kg) with atropine (0.03 mg/kg) at 67 to 93 (76.6 ± 3.5) % block. Twitch returned to 95% of control within 4.5 to 9.5 (6.3 ± 0.5) min after neostigmine. Mivacurium may offer increased versatility in providing clinical muscle relaxation in a variety of situations. Further studies seem appropriate.

The cardiovascular effects of mivacurium chloride (BW B1090U) in patients receiving nitrous oxide-opiate-barbiturate anesthesia

The dose-effect relationship of mivacurium chloride on arterial blood pressure, heart rate, and plasma histamine was determined in 97 consenting ASA physical status I-II patients receiving nitrous oxide-oxygen-opiate-barbiturate anesthesia. In the absence of surgical stimulation during steady state anesthetic conditions with controlled ventilation, average maximum change in tachograph-counted heart rate was 7% or less after 10-15-s injection of mivacurium at all doses from 0.03 to 0.30 mg/kg. Average peak change in mean arterial pressure measured via radial arterial catheter was 7% or less after all doses from 0.03 to 0.15 mg/kg. Transient (0.2-4.5 min) decreases in arterial blood pressure were noted after 10-15-s injection in some patients at 0.20, 0.25, and 0.30 mg/kg. When they occurred, these changes were usually accompanied by facial erythema lasting 2-5 min and were correlated with increases in plasma histamine level (P less than 0.001). Facial erythema, decrease in blood pressure, and elevation of histamine level were all accentuated by increasing the dose of mivacurium and by more rapid injection of the drug. For example, mean blood pressure decreased an average of 13% after injection of mivacurium 0.25 mg/kg over 10-15 s. In contrast, during administration over 30 and 60 s of this dose, arterial pressure decreased 7.6 and 1.5%, respectively (P less than 0.001, 10-15 s vs. 60-s injection). Average peak histamine level, which increased to 132% of control after administration of 0.25 mg/kg over 10-15 s, did not change after injection over 60 s.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical pharmacology of atracurium besylate (BW 33A): a new non-depolarizing muscle relaxant.

Atracurium, a new non-depolarizing neuromuscular blocking agent, was studied in 70 patients anesthetized with fentanyl, thiopental, and nitrous oxide-oxygen. The dose found to produce 95% twitch inhibition (ED95) was 0.2 mg/ kg. The onset time from injection to maximum depression of twitch was 4.0 minutes at this dose; the duration to 95% recovery was 44.1 minutes. Twice the ED95 dose (0.4 mg/kg) had an onset time of 1.7 minutes and a duration of 63.5 minutes. No cardiovascular effects were observed in this dosage range. At higher doses (0.5 and 0.6 mg/kg) arterial pressure decreased 13% and 20% and heart rate increased 5% and 8%, respectively. Sixteen patients received at least four successive doses of atracurium. No clinically significant cumulative effect could be shown when recovery from 25% to 75% of control twitch height was compared for initial and final doses in the series. Atracurium spontaneously decomposes at physiologic pH via the Hofmann elimination reaction and may also undergo ester hydrolysis independent of plasma cholinesterase. These proposed pathways of inactivation may explain the lack of cumulative effect and the drugs intermediate duration of action. Based on the results of this study, atracurium offers several clinical advantages and should undergo more extensive clinical trials.

Spontaneous recovery from nondepolarizing neuromuscular blockade: correlation between clinical and evoked responses.

The effects of nondepolarizing muscle relaxants were allowed to wear off spontaneously in 10 ASA class III and IV patients following major surgery. Neuromuscular and respiratory function were followed by clinical testing and by evoked muscle responses using a train of 4 (TOF) supramaximal stimuli. At a TOF of 70 percent (range 62 to 78%), all patients sustained eye-opening, hand-grasp, and tongue-protrusion, while 9/10 sustained head-lift. Vital capacity (VC) averaged 17 ml/kg when the TOF reached 70 percent. The increase in VC correlated with the increase in TOF (r = 0.88). There was no correlation between inspiratory force (IF) and TOF, but all patients achieved an IF equal to or greater than—22 cm H2O at 70 percent. Thus, TOF correlates well with clinical signs of neuromuscular and respiratory recovery in this group of patients and complements earlier studies in healthy anesthetized patients and nonmedicated volunteers.

Clinical Pharmacology of Doxacurium Chloride A New Long-acting Nondepolarlzlng Muscle Relaxant

Doxacurium chloride (BW A938U) is a bis-quaternary benzyl-isoquinolinium diester nondepolarizing neuromuscular blocking compound that is minimally hydrolyzed by human plasma cholinesterase. The effect of bolus doses of doxacurium ranging from 10 to 80 Mg/kg were studied in 81 consenting ASA physical status I and II patients anesthetized with nitrous oxide-oxygenfentanyl-thiopental. The neuromuscular and cardiovascular effects of doxacurium were compared with those of eight patients receiving 100 μg/kg of pancuronium receiving identical anesthesia. The calculated ED95 for evoked twitch inhibition of the adductor pollicis at 0.15 Hz was 30 μg/kg. At 1.3 times the EDg5 dose of doxacurium, recovery times to 5% and 25% of control twitch height were 59.2 ± 4.1 (n = 23 of 26) and 75.7 ± 5.6 (n = 23 of 26) min respectively. For pancuronium comparable recovery times were 81.7 ± 10.3 (n = 8 of 8) and 83.0 ± 8.4 (n = 5 of 8) min. Residual doxacurium blockade was readily antagonized by neostigmine. No dose-related effect on heart rate or mean arterial pressure was seen with doxacurium at doses up to and including 2.7 times the ED95 (80 μg/kg). Doxacurium administration did not result in any elevation of plasma histamine at doses up to and including 2.7 times the ED05. In this study doxacurium appears to be a long-acting nondepolarizing relaxant with readily reversible neuromuscular blocking effects and devoid of cardiovascular effects. This profile offers clinical advantages over current long-acting agents and further clinical trials seem appropriate.

Twitch, tetanus and train-of-four as indices of recovery from nondepolarizing neuromuscular blockade

This study was undertaken to compare the sensitivities of the train-of-four response (2 Hz for 2 s), the single twitch (0.15 Hz), and the tetanic response (50 Hz for 5 s) as indices of residual nondepolarizing block. Spontaneous or induced recovery of evoked thumb adduction in response to ulnar nerve stimulation was studied. One hundred and seven adult surgical patients were divided according to the relaxant used, into six groups. We found that when the single twitch recovered to control height, the train-of-four ratio was well below 1.0. This ratio was significantly lower during spontaneous recovery than following neostigmine antagonism of the block (P < 0.01). The tetanic response was fully sustained when the train-of-four ratio was above 0.7. When the ratio was less than 0.7, variable degrees of fade of tetanus were evident. Analysis of variance indicated similar train-of-four ratios among the six groups at complete recovery of the single twitch irrespective of the relaxant technique used (P < 0.1). It is concluded that a train-of-four ratio of 0.7 or higher reliably indicates the recovery of the single twitch to control height and a sustained response to tetanic stimulation at 50 Hz for 5 s. The clinical significance of this study is as follows: the train-of-four response provides the same indication of clinical recovery from nondepolarizing block as obtained from tetanic stimulation at a physiological frequency; and reliance on the recovery of the single twitch to control height as a criterion of spontaneous return to normal clinical neuromuscular function may be misleading.

Potentiation of neuromuscular blockade in man produced by combinations of pancuronium and metocurine or pancuronium and d-tubocurarine

Simultaneous administration of combinations of pancuronium, metocurine, and d-tubocurarine (dTc) were given to A.S.A. class l-ll surgical patients during N2O-narcotic-thiopental anesthesia to determine the degree of neuromuscular blockade produced. The pancuronium-metocu-rine and the pancuronium-dTc combinations were each significantly more potent (p < 0.05) than the additive effects of each of the individual drugs given alone. This greater than additive neuromuscular blocking effect was not seen with the metocurine-dTc combination. Despite the potentiation of neuromuscular blocking intensity by the pancuronium-metocurine and the pancuronium-dTc combination, the duration of blockade was not prolonged. Possibly, such potentiation of neuromuscular blockade might be attributed to simultaneous pre- and postjunctional receptor inhibition. Additional mechanisms might involve augmented conformational attachment to pre- and postjunctional cholinergic receptors or altered protein binding such that a greater than expected proportion of unbound drug reaches its neuromuscular site of activity. Regardless of mechanism, combining pancuronium with dTc or with metocurine can provide surgical relaxation or ideal conditions for endotracheal intubation with smaller amounts of each drug than would be anticipated if their effects were simply additive.

Stimulus Frequency and Dose—Response Curve to d-Tubocurarine in Man

The relationship of the frequency of motor-nerve stimulation to the dose-response to d-tubocurarine was studied in 45 adult patients during nitrous oxide–oxygen–morphine-thiopental anesthesia. One of five stimulus frequencies, 0.1, 0.15, 0.25, 0.5, and 1.0 Hz, was employed in each of five groups of nine patients. Cumulative dose–response curves for inhibition of evoked thumb adduction were constructed at each frequency on log probit scales and the ED50 and ED95 values were determined. The apparent potencies of d-tubocurarine at 0.5 and 1.0 Hz were significantly different from that at 0.1 Hz; for example, at 0.1 Hz the ED50 and ED95 were 0.25 and 0.52 mg/kg, respectively. The corresponding values at 1.0 Hz were 0.07 and 0.15 mg/kg, respectively, or approximately 3.5 times less. The durations of recoveries of the twitch from 5–25 per cent of control at 1.0 and 0.5 Hz were 13 ± 2 min (mean ± SE) and 20 ± 2 min, respectively. These durations were significantly different from that at 0.1 Hz (30 ± 2 min). These results emphasize the importance of defining the stimulus frequency for meaningful interpretation of the dose-response relationships for nondepolarizing relaxants in man. Slow stimulus rates (0.1–0.15 Hz) are most useful clinically, since all levels of clinical relaxation can be achieved at these rates without abolishing the evoked twitch response.

A comparison of the intubation conditions between mivacurium and rocuronium during balanced anesthesia.

Background Comparisons of the intubation conditions with mivacurium and rocuronium from previous reports are confounded by the use of varied induction regimens. The authors compared intubation conditions of mivacurium, rocuronium, and a placebo at 90 s and their recovery profiles during anesthesia with nitrous oxide, oxygen, and propofol. Methods After induction with midazolam, fentanyl, and propofol in a randomized blinded study, 100 patients received one of the following treatments: 0.25 mg/kg mivacurium in divided doses (0.15 mg/kg followed by 0.1 mg/kg 30 s later); 0.45, 0.6, 0.9, or 1.2 mg/kg rocuronium; or placebo. Evoked thumb adduction was measured throughout. Intubation was attempted 90 s after the initial dose of mivacurium and other treatment doses by a “blinded” physician. Intubating conditions were graded as excellent, good, poor, or not possible. Spontaneous recovery was studied until a 25% initial twitch height was reached. Mean arterial blood pressure and heart rate changes between groups were determined before induction through 6 min after administration of the study drugs. Results There were no important changes or intergroup differences in mean arterial blood pressure and heart rate. Intubation conditions were good or excellent for both mivacurium and rocuronium at the 0.9 mg/kg dose (93%) and at the 1.2 mg/kg dose (100%). Rocuronium at the 0.6 mg/kg dose was excellent in 27% of patients, whereas rocuronium at the 0.45 mg/kg dose had the least number of excellent conditions and the most poor or not possible assessments. Patients given placebo could not be intubated. Times to maximum blockade for 0.9 and 1.2 mg/kg rocuronium were the shortest. The times to 25% recovery for 0.6 mg/kg rocuronium (mean +/‐ SD = 27 +/‐ 8.6 min), 0.9 mg/kg (43.1 +/‐ 10.8), and 1.2 mg/kg (62.3 +/‐ 17.4 min) were significantly longer than were those for mivacurium (17.4 +/‐ 6.2 min). Conclusions Mivacurium in a 0.25 mg/kg divided dose and rocuronium at 0.9 mg/kg and 1.2 mg/kg provide good or excellent intubation conditions at 90 s in most patients. Rocuronium was faster in onset at the higher doses (0.9 and 1.2 mg/kg) but had more prolonged recovery times to 25% single twitch height.

The Clinical Pharmacology of Metocurine: Dimethyltubocurarine Revisited

The clinical pharmacology of metocurine (formerly dimethyltubocurarine) was studied in 55 ASA class I–II patients. Evoked force of thumb adduction was measured at 0.15 Hz during nitrous oxide–morphine–thiopental anesthesia. The ED50 and ED95 for twitch inhibition were 0.13 and 0.28 mg/kg. The dose–response curve did not differ significantly from parallelism with curves for pancuronium and d-tubocurarine. Potency ratios were 0.25 and 1.8 versus pancuronium and d-tubocurarine. The speed of onset and the duration of metocurine-induced block at high dosage employed for tracheal intubation did not differ significantly from the corresponding values obtained for approximately equipotent doses of pancuronium and d-tubocurarine. Metocurine, 0.3 mg/kg, produced 96.1 per cent mean twitch depression within 4.8 ± 0.6 (SEM) minutes. Recovery to 25 per cent of the control twitch height took 82.4 ± 12.0 (SEM) minutes at this dose. Doses in the range 0.2–0.3 mg/kg are recommended for the production of abdominal relaxation during nitrous oxide–narcotic–thiopental anesthesia. Jaw relaxation was sufficient at 0.3 mg/kg for smooth tracheal intubation in 13 of 15 patients. Neostigmine antagonism of metocurine-induced block required dosage and timing similar to those found by Katz in previous studies of d-tubocurarine and pancuronium.29329,30 Metocurine produced no significant change in heart rate or mean arterial pressure in doses as high as 0.3 mg/kg. At 0.4 mg/kg, heart rate increased 18 per cent and arterial pressure decreased 6.3 per cent. These changes were statistically significant, but generally not clinically important, and reflect a short-lasting (5–10 min) response suggestive of histamine release, which occurred in six of 18 subjects who received this dose.