Martha M. Abou-Donia

The Clinical Neuromuscular Pharmacology of 51W89 in Patients Receiving Nitrous Oxide/Opioid/Barbiturate Anesthesia

Background Atracurium is a mixture of ten stereoisomers. 51W89, one of these isomers, is a potent nondepolarizing intermediate‐duration neuromuscular blocking agent. Preclinical studies have shown 51W89 to be significantly more potent than atracurium but with a similar neuromuscular blocking profile. This study was undertaken to establish the neuromuscular blocking potency and pharmacodynamics of 51W89 in patients undergoing elective surgical procedures. Methods Ninety‐nine ASA physical status 1 or 2 patients undergoing elective surgical procedures under nitrous oxide/opioid/barbiturate anesthesia were studied. The neuromuscular blocking effect of 51W89 was assessed after administration of bolus doses from 0.015 to 0.4 mg/kg, as well as during and after continuous infusions from 11 to 249 min in length. Results The calculated ED95 for inhibition of adductor pollicis twitch evoked at 0.15 Hz was 0.048 mg/kg. At 0.10 mg/kg, maximum block developed within 5.2 plus/minus 0.3 min, and recovery to 95% twitch height occurred 64.4 plus/minus 3.9 min after injection. At 0.4 mg/kg, onset was 1.9 plus/minus 0.1 min, and 95% recovery developed within 121.0 plus/minus 5.9 min. Comparative recovery indexes from 5% to 95% or from 25% to 75% twitch heights did not differ significantly among all dosage groups from 0.1 to 0.4 mg/kg (means ranged from 29.6 to 32.3 min and from 12.6 to 14.3 min, respectively). The average infusion rate necessary to maintain approximately 95% twitch suppression was 1.35 micro gram/kg/min. Recovery indexes from infusions were 5–95% 33.2 plus/minus 1.8 min and 25–75% 15.0 plus/minus 0.6 min, not differing significantly from recovery indexes from single bolus doses. Twenty‐ five patients received neostigmine (0.06 mg/kg) with atropine (0.03 mg/kg) at twitch height recovery of between 6% and 21%. Antagonism to 95% control twitch height developed within 6.8 plus/minus 0.3 min, and the neostigmine‐accelerated 25–75% recovery index was 2.8 plus/minus 0.2 min. Conclusions 51W89 is a potent nondepolarizing neuromuscular blocking agent that shows noncumulative intermediate‐duration neuromuscular blocking pharmacodynamics.

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)

The Cardiovascular Effects and Histamine-releasing Properties of 51W89 in Patients Receiving Nitrous Oxide/Opioid/Barbiturate Anesthesia

Background Atracurium consists of a mixture of ten stereoisomers. One of these isomers, 51W89, is a potent intermediate‐acting nondepolarizing neuromuscular blocking agent. Its ED95 is 0.05 mg *symbol* kg1 in patients receiving nitrous oxide/opioid anesthesia. In preclinical trials, 51W89 did not show evidence of histamine release in cats at doses up to 80 times the human ED95. This study was undertaken to determine the cardiovascular effects and histamine‐ releasing properties of 51W89 in patients undergoing elective surgical procedures. Methods Sixty patients, ASA physical status 1 or 2, anesthetized with nitrous oxide/fentanyl/thiopental were studied. Patients received either 2 times the ED95 of atracurium or 51W89 or 4 or 8 times the ED95 of 51W89 as a rapid intravenous bolus under stable anesthesia, before surgical stimulation. Blood pressure and heart rate were measured by oscillometry and the electrocardiogram in patients receiving 2 times the ED95 of 51W89 or atracurium and by an intraarterial catheter and a tachograph triggered by the arterial pulse waveform in patients receiving 4 or 8 times the ED95 of 51W89. Maximal blood pressure and heart rate changes during the 5 min after administration of the muscle relaxant were recorded. Venous blood samples were obtained before the administration of relaxant and at 2 and 5 min after the administration of relaxant for determination of plasma histamine concentrations by radioenzymatic assay. Results Maximal blood pressure and heart rate changes in all groups of patients receiving 51W89 were small and similar to those observed in patients receiving 2 times the ED95 of atracurium. The mean maximum percent changes (plus/minus SE) in heart rate and mean arterial pressure were ‐0.6 plus/minus 1.5 and 0.4 plus/minus 2.5, respectively, in the group receiving 2 times the ED95 atracurium; ‐ 1.3 plus/minus 3.3 and 2.3 plus/minus 4.4, respectively, in the group receiving 2 times the ED95 51W89; ‐2.6 plus/minus 1.0 and 2.6 plus/minus 1.5, respectively, in the group receiving 4 times the ED95 51W89; and 2.4 plus/minus 1.5 and 1.0 plus/minus 1.3, respectively, in the group receiving 8 times the ED95 51W89. No patient developed a decrease in blood pressure greater or equal to 20% or an increase in heart rate greater or equal to 20% that was attributable to muscle relaxant administration. There was no dose‐related change in plasma histamine concentration associated with the administration of 51W89. One patient in the study developed transient facial flushing after the administration of atracurium. Conclusions 51W89 is a benzylisoquinolinium‐type, nondepolarizing muscle relaxant that does not affect plasma histamine concentrations. No cutaneous flushing or clinically important cardiovascular effects were noted after rapid injection of doses up to and including 8 times its ED sub 95 (0.4 mg *symbol* kg1) in healthy patients undergoing elective surgical procedures.

The Neuromuscular Blocking and Cardiovascular Effects of Doxacurium Chloride in Patients Receiving Nitrous Oxide Narcotic Anesthesia

The purpose of this study was to evaluate neuromuscular and cardiovascular effects of doxacurium chloride, a new long-acting neuromuscular blocking agent, during a stable state of nitrous oxide and narcotic anesthesia. Ninety-three ASA physical status I or II patients were studied after informed written consent had been obtained. Eighty-one patients (group A) received doxacurium. The 81 patients were divided into nine subgroups according to the dose of doxacurium administered (0.01–0.06 mg·kg-1). Patients in a control group (group B) (n=12) received pancuronium. To assess neuromuscular responses, a force displacement transducer recorded the twitch response of the adductor pollicis muscle following ulnar nerve stimulation. The ED50 and ED95 for doxacurium were estimated to be 0.013 mg·kg-1 and 0.023 mg·kg-1, respectively. The time to maximum twitch suppression following a dose of 1.0 (ED95) and 1.7 (ED95) was 10.3 ± 1.3 min and 7.6 ± 0.8 min, respectively. After an ED95 dose of doxacurium the time to spontaneous recovery to 95% of control twitch height was 73.7 ± 8.7 min. With larger doses of doxacurium, 0.04 mg·kg-1 (1.7 × ED95) and 0.05 mg·kg-1 (2.2 × ED95), the time to spontaneous recovery to 95% of control twitch height was 125.8 ± 24.8 and 204.0 ± 21.2 minutes, respectively. When 25% twitch height recovery or more was present the reversal of doxacurium induced neuromuscular blockade was prompt. After administration of 0.04 mg · kg-1 of doxacurium or 0.08 mg · kg-1 of pancuronium, the time for spontaneous recovery to 25% of control twitch height recovery was 77.4 ± 7.5 min (n = 23) and 71.4 ± 6.7 min (n = 10), respectively. When identical multiple maintenance doses of doxacurium were administered, the subsequent neuromuscular block following each maintenance dose was of similar magnitude and duration. At 1,2, and 5 min following pancuronium, heart rate and mean blood pressure increased. Following doxacurium small decreases in mean blood pressure occurred at 2 and 5 min, while heart rate decreased 5 min following drug injection. Doxacurium is a new, long-acting, nondepolarizing relaxant. Further study is warranted to assess the cardiovascular effects of this neuromuscular blocking drug in patients with cardiovascular disease.

Neuromuscular and cardiovascular effects of mivacurium chloride in surgical patients receiving nitrous oxide-narcotic or nitrous oxide-isoflurane anaesthesia

The neuromuscular and cardiovascular effects of mivacurium chloride were studied during nitrous oxide-oxygen narcotic (fentanyl) (n = 90) and nitrous oxide-oxygen isoflurane (ISO) anaesthesia (n = 45). In addition, a separate group (n = 9) received succinylcholine during fentanyl anaesthesia to compare its neuromuscular effects with mivacurium. Mivacurium was initially administered as a single bolus in doses from 0.03 mg · kg−1 to 0.25 mg · kg−1 to study the dose-response relationships, as well as the cardiovascular effects of mivacurium. Neuromuscular block (NMB) was measured by recording the twitch response of the adductor pollicis muscle following ulnar nerve stimulation (0.15 Hz, 0.2 ms supramaximal voltage). The ED95 values for mivacurium were estimated to be 0.073 mg · kg−1 and 0.053 mg · kg−1 in the fentanyl and ISO groups respectively. The duration of block (time from injection to 95 per cent recovery) for a dose of 0.05 mg · kg− 1 mivacurium was 15.3 ± 1.0 min and 21.5 ± 1.3 min for fentanyl and ISO anaesthesia, respectively. The recovery index (25–75 per cent) between initial bolus dose (6.1 ± 0.5 min), repeat bolus doses (7.6 ± 0.6 min), mivacurium infusion (6.7 ± 0.7 min) and succinylcholine infusion (6.8 ± 1.8 min) were not significantly different. There was minimal change in mean arterial pressure (MAP) or heart rate (HR) following bolus doses of mivacurium up to 0.15 mg · kg−1. Bolus administration of 0.20 mg · kg−1 or 0.25 mg · kg−1 of mivacurium decreased MAP from 78.2 ± 2.5 to 64.0 ± 3.2 mmHg (range 12–59 per cent of control) (P < 0.05). The same doses when administered slowly over 30 sec produced minimal change in MAP or HR.RésuméLes effets cardiovasculaires et neuromusculaires du chlorure de mivacurium ont été étudiés lors d’une anesthésie au narcotique (fentanyl) protoxyde d’azote-oxygène (n = 90) et isoflurane (ISO) protoxyde d’azote-oxygéne (n = 45). En plus, un groupe séparé (n = 9) a reçu du succinylcholine lors d’une anesthésie au fentanvl afin de comparer ces effets neuromusculaires avec le mivacurium. Le mivacurium a été initialement administré comme un bolus unique les doses de 0,03 mg · kg−1 et 0,25 mg · kg−1 afin d’étudier la courbe dose-réponse et les effets cardiovasculaires du mivacurium. Le bloc neuromusculaire (NMB) a été mesuré en enregistrant la réponse au twitch de l’adducteur du pouce après stimulation du nerf cubital (0.15 Hz, 0.2 ms voltage supramaximal). Les valeurs de ED95 du mivacurium ont été estimées à 0,073 mg ·kg−1 et 0,053 mg · kg−1 respectivement pour le groupe fentanyl et ISO. La durée du bloc (temps à partir de l’injection à la recouvrance à 95 pour cent) pour une dose de 0,05 mg · kg−1’ de mivacurium était de 15,3 ± 1,0 min. et 21,5 ± 1,3 min. respectivement pour le groupe fentanyl et le groupe ISO. L’index de recouvrance (25–75 pour cent) entre le bolus initial (6,1 ± 0,7 min) la dose de rajout (7,6 ± 0,6 min) et la perfusion de mivacurium (6,7 ± 0,7 min) et la perfusion de succinycholine (6,8 ± 1,8 min) n’était pas significativement différent. On a observé des changements minimes dans la pression artérielle moyenne (MAP) ou la fréquence cardiaque (HR) après le bolus de mivacurium jusqu’à 0,15 mg · kg−1. Une administration en bolus de 0,20 mg · kg−1 ou 0,25 mg · kg−1 de mivacurium a diminué la pression artérielle moyenne de 78,2 ± 2,5 à 64.0 1 3,2 mmHg (écart de 12–59 pour cent du contrôle) (P < 0.05). Les mêmes doses lorsque administrées lentement au-dessus de 30 secondes ont produit des changements minimes de la pression artérielle moyenne et de la fréquence cardiaque.

Hemodynamic effects of doxacurium chloride in patients receiving oxygen sufentanil anesthesia for coronary artery bypass grafting or valve replacement

Doxacurium chloride is an investigational long-acting neuromuscular blocking drug, which has been shown to be devoid of cardiovascular side effects when administered in modest doses to healthy patients. This is the first hemodynamic study of doxacurium in adult patients with cardiac disease. Forty-one patients scheduled to undergo cardiac surgery were studied. Anesthesia consisted of induction with midazolam 0.2–0.3 mg/kg and sufentanil 0.01–0.03 mg followed by an infusion of sufentanil at 0.03–0.06 mg ± min−1. Baseline hemodynamic data were collected during a stable state of sufentanil anesthesia. Doxacurium was then administered in doses of 1, 2, or 3 times its ED95 of 0.025 mg/kg. Hemodynamic measurements were repeated at 2, 5, and 10 min after doxacurium injection in the absence of surgical stimulation. An additional group of control patients received saline instead of doxacurium. Baseline hemodynamic measurements were similar among groups. There was a slight decrease in heart rate in all groups over time. However, there was no significant difference between the groups of patients receiving doxacurium and the control group in which the heart rate decreased progressively from 52 beats/min at baseline to 49 beats/min 10 min after doxacurium administration. At no time was there any significant change in mean arterial pressure, right atrial pressure, or cardiac output. Likewise derived hemodynamic variables including cardiac index, stroke volume, and pulmonary vascular resistance were unchanged. In addition to the decrease in heart rate, the hemodynamic changes, which reached statistical significance, were clinically insignificant and occurred predominantly in the group of patients receiving doxacurium 0.08 mg/kg. Baseline pulmonary artery occlusion pressure was 13 mmHg, and it increased to 14, 15, and 15 mmHg at 2, 5, and 10 min, respectively. Accordingly, pulmonary vascular resistance fell from 139 dyne · s · cm−5 at baseline to 114, 103, and 102 dyne · s · cm−5 at 2, 5, and 10 min, respectively. There was also a significant increase in stroke volume from 67 to 74 ml at 10 min in this group of patients receiving the largest dose. It is concluded that doxacurium has no clinically significant effect on measured or derived hemodynamic variables at doses up to 3 times its ED95. This combination of a long duration of action and absence of circulatory effects makes doxacurium a potentially useful drug for patients with limited cardiac reserve undergoing prolonged operations.

A two-center comparison of the cardiovascular effects of cisatracurium (Nimbex) and vecuronium in patients with coronary artery disease.

Cisatracurium (Nimbex Trademark) is an intermediate-acting benzylisoquinolinium neuromuscular blocker that is one of the stereoisomers of atracurium. It causes no clinically significant cardiovascular side effects or histamine release in doses up to 8 times ED95 in healthy patients. Seventy patients undergoing elective myocardial revascularization consented to participate in an Institutional Review Board approved pilot study (10 patients) and an open-label, randomized, controlled trial comparing the hemodynamic effects of cisatracurium with vecuronium (60 patients) at two centers. The patients were anesthetized using 100% oxygen, fentanyl, and midazolam, and tracheal intubation was facilitated with succinylcholine. At least 5 min after tracheal intubation, baseline hemodynamic measurements were obtained. The patients received 0.10 mg/kg of cisatracurium (2 times ED95) or 0.10 mg/kg of vecuronium (2 times ED90) as follows: cisatracurium over 60 s (Pilot Group A, n = 5); cisatracurium over 30 s (Pilot Group B, n = 5); cisatracurium over 5-10 s (Group C, n = 30); or vecuronium over 5-10 s (Group D, n = 30). The hemodynamic measurements were repeated at 2, 5, and 10 min after cisatracurium or vecuronium injection. There were no episodes of cutaneous flushing. One patient was hypotensive before and after cisatracurium administration, and was excluded from analysis. Otherwise, there were no episodes of hypotension requiring therapy in any patient after cisatracurium. Fifteen patients overall were excluded from the analysis for one or more of the following: light anesthesia, treatment for hypotension <10 min prior to baseline, or equipment difficulties. Although there were multiple statistically significant (P < 0.05) hemodynamic changes from preinjection to postinjection, in no case were Groups C and D discordant, and no patient who received cisatracurium had a >or=to20% decrease in the mean arterial pressure. The hemodynamic changes observed in the cisatracurium patients were minor (<15% change from baseline) and indistinguishable from those observed in the patients receiving vecuronium. A rapid bolus (2 times ED95) dose of cisatracurium results in small hemodynamic side effects in patients with coronary artery disease. (Anesth Analg 1995;81:1010-4)

Hemodynamic effects of mivacurium chloride administered to patients during oxygen sufentanil anesthesia for coronary artery bypass grafting or valve replacement

The hemodynamic effects of mivacurium chloride were studied in 54 adult cardiac patients anesthetized with midazolam and sufentanil. After baseline data were collected, a placebo (N = 9) or mivacurium was administered over 60 seconds, the latter in doses of 0.15 (N=18), 0.20 (N=18), or 0.25 (N=9) mg/kg. Measurements were repeated 2, 5, and 10 minutes later. Baseline measurements were similar. A slight decrease in heart rate over time reached statistical significance in several groups including the control group. Mean arterial, mean pulmonary arterial, pulmonary arterial occlusion, and right atrial pressures and cardiac output did not change, nor did systemic and pulmonary vascular resistances and cardiac index. Besides the decrease in heart rate, the only hemodynamic change to reach statistical significance was an increase in stroke volume in patients given mivacurium 0.25 mg/kg. Significant hypotension occurred in two patients; in one, a sudden decrease in mean arterial pressure of 24% occurred 1 minute after mivacurium 0.20 mglkg. Blood pressure was restored by ephedrine 10 mg. In the other patient, given mivacurium 0.25 mg/kg, mean arterial pressure decreased 50% from 73 to 37 mm Hg. Recovery was rapid without treatment. It is concluded that mivacurium administered in doses of 0.15 to 0.25 mg/kg over 60 seconds to cardiac patients is associated with few significant hemodynamic effects. However, a small number of patients may experience significant transient hypotension when given doses greater than of 0.15 mg/kg, two times the ED95.