Cardiopulmonary Effects of the Novel Neuromuscular Blocking Drug GW280430A (AV430A) in Dogs

Background: This investigation determined the cardiopulmonary side effects of a novel nondepolarizing neuromuscular blocking drug with an ultrashort duration of action in anesthetized male beagles.

Methods: The ED95 for GW280430A was first determined in four animals. These data were then used to guide bolus dosing in multiples of ED95 in six dogs instrumented for hemodynamic measurements as well as inspiratory pressure and pulmonary compliance. Cardiopulmonary data were compared before and after the conclusion of a 60- to 90-min GW280430A infusion and in response to subsequent incremental bolus dosing starting with 3.125 x ED95. An adverse response was regarded as an alteration of 10% or greater in any variable. Arterial blood was obtained for histamine analysis before and 1 min after each dose.

Results: The ED95 of GW280430A was 0.064 +/- 0.01 mg/kg, and stable neuromuscular blockade was maintained with infusion of 0.012 +/- 0.002 mg [middle dot] kg-1 [middle dot] min-1. With the exception of a late 14% increase in heart rate, there were no cardiopulmonary changes during infusion. Bolus dosing produced no cardiopulmonary change until a decrease in mean arterial pressure was elicited in four of six dogs at 25 x ED95. This response was modest, transient, and associated with a concomitant increase in plasma histamine concentration. There were no accompanying changes indicative of direct myocardial depression, pulmonary vasoconstriction, or bronchospasm.     

Preclinical Pharmacology of GW280430A (AV430A) in the Rhesus Monkey and in the Cat: A Comparison with Mivacurium

Background: No replacement for succinylcholine is yet available. GW280430A (AV430A) is a representative of a new class of nondepolarizing neuromuscular blocking drugs called asymmetric mixed-onium chlorofumarates. It undergoes rapid degradation in plasma by chemical hydrolysis and inactivation by cysteine adduction, resulting in a very short duration of effect. The neuromuscular, cardiovascular, and autonomic pharmacology of GW280430A is compared herein with that of mivacurium.

Methods: Adult male rhesus monkeys and adult male cats were anesthetized with nitrous oxide-oxygen-halothane and chloralose-pentobarbital, respectively. The neuromuscular blocking properties of GW280430A and mivacurium were compared at a stimulation rate of 0.15 Hz in the extensor digitorum of the foot (monkey) and the tibialis anterior (cat). Sympathetic responses were assayed in the cat in the nictitating membrane preparation, and vagal effects were evaluated in the cat via observation of bradycardic responses after stimulation of the cervical right vagus nerve.

Results: GW280430A and mivacurium were equipotent in the monkey (ED95 was 0.06 mg/kg in each case). GW280430A was half as potent as mivacurium in the cat. The total duration of action of GW280430A was less than half that of mivacurium in the monkey; recovery slopes were more than twice as rapid. The 25-75% recovery index of GW280430A did not vary significantly after various bolus doses or infusions, averaging 1.4-1.8 min in the monkey, significantly shorter than the same time interval (4.8-5.7 min) for mivacurium. Dose ratios for autonomic versus neuromuscular blocking properties in the cat were greater than 25 for both GW280430A and mivacurium. The ratio ED Hist:ED95 Neuromuscular Block in the monkey was significantly greater (approximately 53 vs. 13) for GW280430A, indicating approximately four times less relative prominence of the side effects of skin flushing and decrease of blood pressure, which are associated with release of histamine.     

Preclinical pharmacology of GW280430A (AV430A) in the rhesus monkey and in the cat: a comparison with mivacurium

BACKGROUND: No replacement for succinylcholine is yet available. GW280430A (AV430A) is a representative of a new class of nondepolarizing neuromuscular blocking drugs called asymmetric mixed-onium chlorofumarates. It undergoes rapid degradation in plasma by chemical hydrolysis and inactivation by cysteine adduction, resulting in a very short duration of effect. The neuromuscular, cardiovascular, and autonomic pharmacology of GW280430A is compared herein with that of mivacurium. METHODS: Adult male rhesus monkeys and adult male cats were anesthetized with nitrous oxide-oxygen-halothane and chloralose-pentobarbital, respectively. The neuromuscular blocking properties of GW280430A and mivacurium were compared at a stimulation rate of 0.15 Hz in the extensor digitorum of the foot (monkey) and the tibialis anterior (cat). Sympathetic responses were assayed in the cat in the nictitating membrane preparation, and vagal effects were evaluated in the cat via observation of bradycardic responses after stimulation of the cervical right vagus nerve. RESULTS: GW280430A and mivacurium were equipotent in the monkey (ED95 was 0.06 mg/kg in each case). GW280430A was half as potent as mivacurium in the cat. The total duration of action of GW280430A was less than half that of mivacurium in the monkey; recovery slopes were more than twice as rapid. The 25-75% recovery index of GW280430A did not vary significantly after various bolus doses or infusions, averaging 1.4-1.8 min in the monkey, significantly shorter than the same time interval (4.8-5.7 min) for mivacurium. Dose ratios for autonomic versus neuromuscular blocking properties in the cat were greater than 25 for both GW280430A and mivacurium. The ratio ED Hist:ED95 Neuromuscular Block in the monkey was significantly greater (approximately 53 vs. 13) for GW280430A, indicating approximately four times less relative prominence of the side effects of skin flushing and decrease of blood pressure, which are associated with release of histamine. CONCLUSIONS: These experiments show a much shorter neuromuscular blocking effect and much-reduced side effects in the case of GW280430A vis-à-vis mivacurium. These results, together with the novel chemical degradation of GW280430A, suggest further evaluation in human subjects.     

Clinical pharmacology of GW280430A in humans

BACKGROUND: An ultrashort-acting nondepolarizing neuromuscular blocking agent that could be an alternative to succinylcholine has been the focus of a concerted effort in the field of muscle relaxants. GW280430A showed a promising pharmacodynamic profile in preclinical work and a wide margin of safety and so was selected for study in humans. METHODS: Thirty-one volunteers participated in this study, which determined the dose producing 95% block (ED95) and the safety and pharmacodynamics of increasing ED95 multiples. Anesthesia was induced and maintained with propofol, midazolam, and fentanyl. Neuromuscular transmission was measured at the adductor pollicis using ulnar nerve stimulation, and responses were recorded continuously by standard mechanomyographic monitoring. RESULTS: The ED95 for GW280430A is 0.19 mg/kg. The time to onset of 90% block ranged from 1.3 to 2.1 min, depending on the dose. Clinical durations ranged from 4.7 to 10.1 min and increased with increasing dose. Five to 95% and 25-75% recovery rates were approximately 7 and 3 min, respectively, and were independent of the dose administered. Transient cardiovascular side effects were observed at doses beginning at 3 x ED95 and above and were suggestive of histamine release. Most volunteers receiving 4 x ED95 exhibited plasma histamine concentrations indicative of significant histamine release. CONCLUSIONS: GW280430A has a rapid onset and ultrashort duration of action. The recovery rate is rapid, predictable, and independent of dose. Doses at least up to 2.5 x ED95 seem to be free of side effects and seem to be able to provide relaxation within 60-90 s.     

Clinical Pharmacology of GW280430A in Humans

Background: An ultrashort-acting nondepolarizing neuromuscular blocking agent that could be an alternative to succinylcholine has been the focus of a concerted effort in the field of muscle relaxants. GW280430A showed a promising pharmacodynamic profile in preclinical work and a wide margin of safety and so was selected for study in humans.

Methods: Thirty-one volunteers participated in this study, which determined the dose producing 95% block (ED95) and the safety and pharmacodynamics of increasing ED95 multiples. Anesthesia was induced and maintained with propofol, midazolam, and fentanyl. Neuromuscular transmission was measured at the adductor pollicis using ulnar nerve stimulation, and responses were recorded continuously by standard mechanomyographic monitoring.

Results: The ED95 for GW280430A is 0.19 mg/kg. The time to onset of 90% block ranged from 1.3 to 2.1 min, depending on the dose. Clinical durations ranged from 4.7 to 10.1 min and increased with increasing dose. Five to 95% and 25-75% recovery rates were approximately 7 and 3 min, respectively, and were independent of the dose administered. Transient cardiovascular side effects were observed at doses beginning at 3 x ED95 and above and were suggestive of histamine release. Most volunteers receiving 4 x ED95 exhibited plasma histamine concentrations indicative of significant histamine release.     

Comparative Pharmacology of Cisatracurium (51W89), Atracurium, and Five Isomers in Cats

Background: Atracurium has four chiral centers and the marketed product is a mixture of ten optical and geometric isomers. Six of the isomers were prepared and evaluated for neuromuscular blocking activity and autonomic effects in anesthetized cats. This study reports the comparative pharmacology of the six isomers and atracurium that led to the selection of one isomer, cisatracurium (Nimbex, 51W89) for clinical development.

Methods: Purpose bred cats, anesthetized with alpha-chloralose (80 mg/kg) and pentobarbital sodium (7 mg/kg) administered intraperitoneally, were used in this study. Neuromuscular blocking effects were assessed from the effects on the tibialis anterior twitch evoked at 0.15 Hz. Inhibition of the autonomic nervous system was assessed from the effects on the nictitating membrane contraction, in response to preganglionic sympathetic nerve stimulation and the bradycardia/vasodepressor responses to vagal nerve stimulation. Cardiovascular effects and plasma histamine concentrations were determined after a bolus injection of cisatracurium or atracurium.

Results: Like atracurium, all six isomers produced dose-dependent neuromuscular block (NMB). The calculated ED95 NMB values varied approximately tenfold (43+/-2 micro gram/kg-488+/-56 micro gram/kg). The "R-series" isomers were more potent than the corresponding "S series" isomers. With the exception of the S,Trans-S', Trans isomer, the NMB effects, i.e., onset times (range 2.6+/-0.2 min to 4.7+/-0.3 min) and total durations (range 9.9+/- 1.4 min to 14+/-0.9 min), of the other five isomers were very similar to that of atracurium. The former isomer had a relatively short duration of action. The 25-75% recovery times after cisatracurium at 1x ED sub 95 (4.4+/-0.4 min), 4x ED95 (4.5+/-0.4 min), and continuous infusions lasting at least 60 min that maintained 95-99% NMB (4.8+/-0.4 min) indicated a noncumulative effect. The vagal ID50: NMB ED95 ratios for atracurium and the six isomers ranged from 2 to 27. The sympathetic ID25: NMB ED95 ranged from 2.7 to 60. Atracurium and all of the isomers, except cisatracurium, produced cardiovascular effects after intravenous bolus administration at large doses (700-4,800 micro gram/kg). In contrast to atracurium, there were no changes in plasma histamine concentrations associated with the administration of doses of cisatracurium equivalent to 60x the NMB ED95 (62+/-8 micro gram/kg).     

Mivacurium: dose-response relationship and administration by repeated injection or infusion.

The dose-response relationship and neuromuscular blockade after infusion or repeated injection of mivacurium were studied in 65 patients in nitrous oxide-narcotic anesthesia. The ED95 (twitch tension) was determined in 45 patients by intravenous injection of a single bolus of 30, 39, 47, 54, or 60 micrograms/kg (9 patients per dose). Another 20 patients received an initial bolus of 2 x ED95 followed either by an infusion started at 5% twitch recovery (i.e., 95% depression) and adjusted to sustain 95% twitch depression (n = 10) or by repeated injection of 0.6 x ED95 whenever twitch tension had recovered to 25% of control (n = 10). Five patients in each of these two groups received 7 micrograms/kg of neostigmine at 25% twitch recovery, and the others recovered twitch tension spontaneously. The mean ED95 was 73 micrograms/kg. A 2 x ED95 bolus was followed by complete twitch depression within 2.2 +/- 0.7 min. The mean infusion rate resulted in 6 +/- 2 micrograms.kg-1.min-1. The ensuing recovery index was 6 +/- 3 min. A 6 +/- 2 min recovery index was found after up to 10 repeat injections given every 9 +/- 3 min. There was no significant effect of neostigmine in both groups. In conclusion, the recovery indices after the infusion or repeat injection of near-equal doses of mivacurium were identical.     

Large bolus dose vs. continuous infusion of cisatracurium during hypothermic cardiopulmonary bypass surgery

BACKGROUND AND OBJECTIVE: We investigated whether a high bolus dose of cisatracurium (8x ED95) given at induction can provide muscle relaxation for the major part of a cardiac procedure with hypothermic cardiopulmonary bypass, avoid important postoperative residual curarization and cause no waste of product. METHODS: Twenty patients were randomly assigned either to Group 1 (n = 10) or Group 2 (n = 10). Those in Group 1 were given cisatracurium in a high bolus dose (0.4 mg kg(-1)). Those in Group 2 received cisatracurium 0.1 mg kg(-1) at induction followed after 30 min by a continuous infusion of cisatracurium. As an escape medication in case of patient movement, a bolus dose of cisatracurium 0.03 mg kg(-1) was given. RESULTS: In Group 1 (large cisatracurium bolus dose), the clinical duration of effect (until T1/T0 = 25%) was 110 min. Six of 10 patients in Group 1 required additional boluses of cisatracurium intraoperatively. Four of these six had received an additional bolus near the end of surgery and had a train-of-four (TOF) ratio = 0 at the end. The other four patients in Group 1 had a final TOF ratio >0.9. In Group 2 (continuous cisatracurium infusion), only two patients had a TOF ratio >0.9 at the end of surgery, no patient moved and none received additional boluses. The total amount of cisatracurium used in the bolus and infusion Groups was 34.5 +/- 7.8 and 21.3 +/- 5.7 mg, respectively (P = 0.0004). CONCLUSIONS: For continued neuromuscular block during hypothermic cardiac surgery, a high bolus dose of cisatracurium appears to be safe, although it is not an alternative to a continuous infusion, as its neuromuscular blockade does not cover the intraoperative period and a high incidence of movements occurs. In the patients who received a high bolus dose of cisatracurium, postoperative residual curarization appeared after additional boluses had been given. The consumption of cisatracurium by high bolus was significantly greater than with continuous infusion.     

Atracurium and vecuronium: repeated bolus injection versus infusion.

The purpose of this study was to compare the characteristics of recovery from neuromuscular blockade after either atracurium or vecuronium given by intravenous infusion or by repeated injection. Four groups of 10 patients each were studied during nitrous oxide narcotic anesthesia. An initial intravenous dose of 2 x ED95 of either muscle relaxant was followed by an intravenous infusion started at 5% recovery of control twitch tension and adjusted for 95% block or by repeated injection of 0.6 x ED95 administered whenever twitch tension had returned to 25% of control. There were no significant differences between the maintenance doses required based on method of administration: atracurium repeated injection, 1.6 +/- 0.3 x ED95 h-1; atracurium infusion, 1.7 +/- 0.3 x ED95 h-1; vecuronium repeated injection, 1.8 +/- 0.5 x ED95 h-1; and vecuronium infusion, 1.6 +/- 0.4 x ED95 h-1. Nevertheless, differences of up to 20 min were noted in the recovery indices in the following order: atracurium repeated injection = atracurium infusion less than vecuronium repeated injection less than vecuronium infusion. A single dose of neostigmine (7 micrograms/kg) significantly reduced the recovery indices, thereby eliminating their differences.     

Effect of volatile anesthetics on vecuronium-induced neuromuscular blockade in children

We studied 60 children undergoing elective surgery to evaluate the effect of interactions between vecuronium and isoflurane or halothane on the potency and duration of neuromuscular blockade, as measured by electromyography. Vecuronium was first administered by a logarithm-based cumulative method (14, 22, 35, 56, 89 micrograms/kg) in 10 children anesthetized with thiopental (5 mg/kg), alfentanil (15 micrograms/kg first dose, then 10 micrograms/kg), and N2O/O2 (60:40) until a 95% +/- 2% twitch depression (ED95) was obtained. Thirty children given the same balanced anesthesia were then randomly assigned to three groups (n = 10 in each) to receive a single ED20 (21 micrograms/kg), ED50 (33 micrograms/kg), or ED80 (47 micrograms/kg) intravenous bolus of vecuronium calculated from the mean regression line of twitch responses of the first 10 children. In the second part of the study, 20 children were anesthetized with isoflurane (1.2%) or halothane (0.7%) and compared with the previous 10 children anesthetized with alfentanil-N2O. Potency of vecuronium determined by single-bolus or logarithm-based cumulative techniques was not significantly different. Isoflurane and halothane significantly decreased ED50 (22.3 +/- 1.6 and 25.4 +/- 1.4 micrograms/kg, respectively; mean +/- SE) and ED95 (41.5 +/- 3.3 and 46.7 +/- 3.2 micrograms/kg, respectively) compared with alfentanil-N2O (ED50: 32.8 +/- 0.8 micrograms/kg, ED95: 70.5 +/- 2.6 micrograms/kg). Recovery rate from vecuronium-induced neuromuscular blockade was significantly longer with isoflurane than with alfentanil-N2O or halothane. We conclude that in children single-bolus and logarithm-based cumulative techniques give similar potency estimates for vecuronium. Isoflurane and halothane increase by similar amounts the neuromuscular potency of vecuronium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Muscle relaxation does not influence venous oxygen saturation during cardiopulmonary bypass

STUDY OBJECTIVE: To examine whether the omission of neuromuscular blocking drugs during cardiopulmonary bypass (CPB) is associated with increased anesthetic requirements, higher frequency of intraoperative movements, and lower venous oxygen saturation (SvO(2)). DESIGN: Prospective, randomized study. SETTING: Large community hospital. PATIENTS: 30 ASA physical status III and IV patients scheduled for cardiac surgery. INTERVENTIONS: Patients were randomized to one of two groups: group 1 (n = 15) received a 3xED(95) bolus dose of cisatracurium at induction and thereafter no more neuromuscular blocking drug; group 2 (n = 15) received a continuous infusion of cisatracurium during the entire procedure. INTERVENTIONS: Both groups received a standardized anesthetic with bispectral index-guided propofol target-controlled infusion and a remifentanil infusion steered by hemodynamic changes. Venous oxygen saturation was continuously determined during CPB. MEASUREMENTS AND MAIN RESULTS: Propofol consumption was 5.4 +/- 1.7 and 4.4 +/- 1.0 mg/(kg/h) in groups 1 and 2, respectively (P = 0.07). Remifentanil consumption was 0.15 +/- 0.05 and 0.17 +/- 0.05 mug/(kg/min) in groups 1 and 2, respectively (P = 0.19). In groups 1 and 2, no patient recalled any intraoperative phenomena; none moved or had diaphragmatic contractions. During CPB, SvO(2) was 81.3 +/- 3.2% (76%-85%) in group 1 and 80.6 +/- 3.1% (73%-85%) in group 2 (P = 0.53). CONCLUSIONS: Omitting the continuous administration of neuromuscular blocking drugs during CPB did not increase anesthetic requirements. No intraoperative movements occurred, nor was there decreased SvO(2).     

Clinical pharmacology of doxacurium chloride. A new long-acting nondepolarizing muscle relaxant

Doxacurium chloride (BW A938U) is a bis-quaternary benzylisoquinolinium 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 micrograms/kg were studied in 81 consenting ASA physical status I and II patients anesthetized with nitrous oxide-oxygen-fentanyl-thiopental. The neuromuscular and cardiovascular effects of doxacurium were compared with those of eight patients receiving 100 micrograms/kg of pancuronium receiving identical anesthesia. The calculated ED95 for evoked twitch inhibition of the adductor pollicis at 0.15 Hz was 30 micrograms/kg. At 1.3 times the ED95 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 micrograms/kg). Doxacurium administration did not result in any elevation of plasma histamine at doses up to and including 2.7 times the ED95. 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.     

Preanesthetic Train-of-four Fade Predicts the Atracurium Requirement of Myasthenia Gravis Patients

Background: The most sensitive diagnostic criterion of myasthenia gravis is a decrement in the muscular response to repetitive stimulation. The authors hypothesized that myasthenia gravis patients who show a train-of-four ratio (T4/T1) < 0.9 in the preanesthetic period will have increased sensitivity to nondepolarizing neuromuscular blocking agents compared with myasthenia gravis patients with preanesthetic T4/T1 >= 0.9.

Methods: After institutional review board approval was obtained, 20 electrophysiologically documented myasthenia gravis patients were studied. Current pyridostigmine therapy was continued until the morning of surgery. Before induction of anesthesia, neuromuscular transmission was recorded from the hypothenar muscles using electromyography with train-of-four stimulation of the ulnar nerve. According to the T4/T1 ratio, patients were assigned to the "normal" group (T4/T1 >= 0.9) or the "decrement" group (T4/T1 < 0.9). After induction of intravenous anesthesia, the effective dose to achieve a 95% neuromuscular blockade (ED95) for atracurium was assessed with a cumulative bolus technique. Postoperatively, pyridostigmine was titrated to obtain a T4/T1 > 0.75 and to treat residual myasthenic symptoms.

Results: In 14 patients, preanesthetic T4/T1 was >= 0.9 (normal), whereas 6 patients presented with T4/T1 < 0.9 (decrement). Decrement patients had a lower ED95 of 0.07 +/- 0.03 mg/kg atracurium (mean +/- SD) compared with normal patients with an ED95 of 0.24 +/- 0.11 mg/kg atracurium (P = 0.002). All patients were extubated within 30 min after surgery. Postoperative pyridostigmine infusion did not differ significantly between groups.     

Effect of laudanosine on catecholamine release in dogs

It is well established that a large dose of atracurium (more than twice ED95) produces significant release of histamine in the blood accompanying hypotension but recovery to control level within a few minutes after the administration of atracurium. We speculated that laudanosine, a metabolite of atracurium may play an important role in preventing this cardiovascular disaster due to histamine release. From this concept, we investigated the effect of laudanosine on the release of epinephrine and norepinephrine in dogs, anesthetized with halothane, nitrous oxide and oxygen. Two different doses of laudanosine (1 microgram.kg-1 and 10 micrograms.kg-1) were selected and serum catecholamine levels were measured with HPLC in six dogs. Intravenous injection of 1.0 microgram.kg-1 laudanosine increased NE level from 0.11 +/- 0.03ng.ml-1 to 0.13 +/- 0.04ng.ml-1 at 3 minutes after the injection. Blood pressure, heart rate, pulmonary arterial pressure, pulmonary wedge pressure and central venous pressure did not change significantly. The intravenous injection of 10 micrograms.kg-1 laudanosine increased NE level from 0.09 +/- 0.02ng.ml-1 to 0.14 +/- 0.02ng.ml-1 at 1 minutes after the injection, but there was no remarkable cardiovascular effect. From this study we conclude that the intravenous injection of laudanosine increased serum NE level, but there was no significant hemodynamic change in the dogs.     

Dose-response relationship and infusion requirement of cisatracurium besylate in infants and children during nitrous oxide-narcotic anesthesia

BACKGROUND: To determine the effect of age on the dose-response relation and infusion requirement of cisatracurium besylate in pediatric patients, 32 infants (mean age, 0.7 yr; range, 0.3-1.0 yr) and 32 children (mean age, 4.9 yr; range, 3.1-9.6 yr) were studied during thiopentone-nitrous oxideoxygen-narcotic anesthesia. METHODS: Potency was determined using a single-dose (20, 26, 33, or 40 microg/kg) technique. Neuromuscular block was assessed by monitoring the electromyographic response of the adductor pollicis to supramaximal train-of-four stimulation of the ulnar nerve at 2 Hz. RESULTS: Least-squares linear regression analysis of the log-probit transformation of dose and maximal response yielded median effective dose (ED50) and 95% effective dose (ED95) values for infants (29+/-3 microg/kg and 43+/-9 microg/kg, respectively) that were similar to those for children (29+/-2 microg/kg and 47+/-7 microg/kg, respectively). The mean infusion rate necessary to maintain 90-99% neuromuscular block during the first hour in infants (1.9+/-0.4 microg x kg(-1) x min(-1); range: 1.3-2.5 microg x kg(-1) x min(-1)) was similar to that in children (2.0+/-0.5 microg x kg(-1) x min(-1); range: 1.3-2.9 microg x kg(-1) x min(-1)). CONCLUSION: The authors conclude that cisatracurium is equipotent in infants and children when dose is referenced to body weight during balanced anesthesia.     

Spasmolytic effect of magnesium sulfate on serotonin-induced pulmonary hypertension and bronchoconstriction in dogs

BACKGROUND: Magnesium (Mg2+) has relaxant effects on histamine-induced bronchoconstriction. In addition, Mg2+ has been reported to reduce vascular smooth muscle tone and be clinically useful for treatment of persistent pulmonary hypertension of the newborn. In this study, we evaluated the relaxant effect of Mg2+ on serotonin (5HT)-induced bronchoconstriction and pulmonary hypertension. METHODS: Seven mongrel dogs were anesthetized with pentobarbital (30 mg x kg(-1) + 2 mg x kg(-1) x h(-1)) and paralyzed by pancuronium (0.2 mg x kg(-1) x h(-1)). Bronchoconstriction and pulmonary hypertension were elicited with 5HT (10 microg x kg(-1) + 1 mg x kg(-1) x h(-1)). Airway caliber was evaluated by changes in bronchial cross-sectional area (BCA) of the 3rd bronchial bifurcation measured by a fiberoptic bronchoscope method as previously reported. Pulmonary hypertension was assessed by changes in pulmonary vascular resistance (PVR). The BCA and PVR were expressed as per cent of the basal level. Thirty minutes after start of 5HT infusion, magnesium sulfate (MgSO4): 0 (saline), 1, 10, 100 and 1000 micromol x kg(-1) was given i.v.. Arterial blood was also collected to measure plasma level of Mg2+ and catecholamines. RESULTS: 5HT increased %PVR to 163+/-25% and decreased % BCA by 39.2+/-4.5%. Plasma level of Mg2+ following MgSO4 1000 micromol x kg(-1) i.v. exceeded its toxic level. The ED50s of MgSO4 (dose producing 50% relaxation of maximal constriction) was 47.8 micromol x kg(-1) and 1.09 mmol x kg(-1) for pulmonary hypertension and bronchoconstriction, respectively. The ratio of %PVR to %SVR was about 1.0 after MgSO4 0-100 micromol x kg(-1) i.v., although the ratio significantly increased after 1000 micromol x kg(-1) i.v.. CONCLUSION: In dogs, 5HT-induced pulmonary hypertension but not bronchoconstriction was significantly reduced by an iv bolus of MgSO4, resulting in a plasma concentration within the assumed therapeutic level.     

Preanesthetic train-of-four fade predicts the atracurium requirement of myasthenia gravis patients

BACKGROUND: The most sensitive diagnostic criterion of myasthenia gravis is a decrement in the muscular response to repetitive stimulation. The authors hypothesized that myasthenia gravis patients who show a train-of-four ratio (T4/T1) < 0.9 in the preanesthetic period will have increased sensitivity to nondepolarizing neuromuscular blocking agents compared with myasthenia gravis patients with preanesthetic T4/T1 > or = 0.9. METHODS: After institutional review board approval was obtained, 20 electrophysiologically documented myasthenia gravis patients were studied. Current pyridostigmine therapy was continued until the morning of surgery. Before induction of anesthesia, neuromuscular transmission was recorded from the hypothenar muscles using electromyography with train-of-four stimulation of the ulnar nerve. According to the T4/T1 ratio, patients were assigned to the "normal" group (T4/T1 > or = 0.9) or the "decrement" group (T4/T1 < 0.9). After induction of intravenous anesthesia, the effective dose to achieve a 95% neuromuscular blockade (ED95) for atracurium was assessed with a cumulative bolus technique. Postoperatively, pyridostigmine was titrated to obtain a T4/T1 > 0.75 and to treat residual myasthenic symptoms. RESULTS: In 14 patients, preanesthetic T4/T1 was > or = 0.9 (normal), whereas 6 patients presented with T4/T1 < 0.9 (decrement). Decrement patients had a lower ED95 of 0.07 +/- 0.03 mg/kg atracurium (mean +/- SD) compared with normal patients with an ED95 of 0.24 +/- 0.11 mg/kg atracurium (P = 0.002). All patients were extubated within 30 min after surgery. Postoperative pyridostigmine infusion did not differ significantly between groups. CONCLUSIONS: The requirement for atracurium is significantly reduced in myasthenia gravis patients with a T4/T1 ratio < 0.9 before anesthesia. This study indicates that routine neuromuscular monitoring in myasthenia gravis patients should be extended into the preinduction period to identify patients who require less atracurium.     

Cardiovascular and neuromuscular effects of three steroidal neuromuscular blocking drugs in dogs (ORG 9616, ORG 9426, ORG 9991)

Developmental research has been directed toward creating nondepolarizing muscle relaxants with an onset time and duration of actions shorter than that of vecuronium or atracurium. We determined the cardiovascular and neuromuscular effects of three new and promising nondepolarizing muscle relaxants in six dogs anesthetized with halothane. Each dog was anesthetized four times (each time separated from the others by at least 1 wk); one muscle relaxant was studied each time. Three doses (one, three, and five times the ED90) were given as intravenous bolus injections. ORG 9616 and ORG 9991 had shorter durations of action than ORG 9426. The duration of action of the doses that were five times the ED90 was 18 +/- 5.88 and 15.8 +/- 4.41 min (mean +/- SD) with ORG 9616 and ORG 9991, respectively, as compared with 39.7 +/- 17.15 min with ORG 9426 (P less than 0.05). ORG 9426 was virtually free of cardiovascular effects. The ED90 doses of ORG 9616 and ORG 9991 did not cause cardiovascular effects; the doses of three and five times the ED90 caused small decreases in mean arterial blood pressure and increases in heart rate. Mean arterial blood pressure decreased from 99 +/- 10.2 to 88 +/- 13.1 mm Hg and from 98 +/- 11.7 to 77 +/- 8.1 mm Hg with five times the ED90 dose of ORG 9616 and ORG 9991, respectively. The authors conclude that ORG 9426 has a duration of neuromuscular blockade that is probably similar to vecuronium, and one that is free of cardiovascular effects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Rocuronium pharmacokinetic-pharmacodynamic relationship under stable propofol or isoflurane anesthesia

PURPOSE: To compare the pharmacokinetics, pharmacodynamics and the concentration-effect relationship of rocuronium in patients under stable propofol or isoflurane anesthesia. METHODS: Ten patients were randomized to receive fentanyl, propofol and nitrous oxide (60%) or fentanyl, thiopental, isoflurane (1.2% end-tidal concentration) and nitrous oxide (60%). To obtain good intubation conditions and maintain adequate muscle relaxation during surgery, patients received two bolus doses of rocuronium: 0.5 mg x kg(-1) (1.7 x ED95) at induction followed one hour later by 0.3 mg x kg(-1) (1 x ED95). Arterial blood samples were obtained over six hours after the second bolus dose. Plasma concentrations of rocuronium were measured using high pressure liquid chromatography. Muscle twitch tension was monitored by mechanomyography for the two doses. Pharmacokinetic and pharmacodynamic parameters were determined. RESULTS: No differences in rocuronium pharmacokinetic parameters were observed between both groups. After the second bolus, clinical duration was 20 +/- 6 min in the propofol group vs 39 +/- 8 min in the isoflurane group (P <0.05). The effect compartment concentration corresponding to 50% block, EC50, was higher under propofol anesthesia: 1008 vs 592 microg x L(-1) (P <0.05). CONCLUSION: Rocuronium body disposition is similar under stable propofol or isoflurane anesthesia. In contrast to isoflurane, propofol does not prolong the neuromuscular block. Therefore, the potentiating effect of isoflurane is of pharmacodynamic origin only, as explained by an increased sensitivity at the neuromuscular junction. In contrast with isoflurane anesthesia where the dose of rocuronium has to be decreased under stable conditions, no dose adjustment is required under propofol anesthesia.     

Effects of bolus administration of ORG-9426 in children during nitrous oxide-halothane anesthesia.

ORG-9426 is a new steroidal nondepolarizing neuromuscular blocking drug. We determined the dose-response relationship of ORG-9426 in 62 children (aged 1-5 yr) during nitrous oxide-halothane anesthesia by means of log-probit transformation and least-squares linear regression of the initial dose and response. Twelve additional patients received a bolus of 600 micrograms/kg (2 X the dose estimated to produce 95% depression of neuromuscular function [ED95]) of ORG-9426. Neuromuscular blockade was monitored by recording the electromyographic activity of the adductor pollicis muscle resulting from supramaximal stimulation of the ulnar nerve at 2 Hz for 2 s at 10-s intervals. To determine the dose-response relationship, patients randomly received initial bolus doses of 120 (n = 15), 160 (n = 16), 200 (n = 16), or 240 (n = 15) micrograms/kg ORG-9426. The resulting dose estimated to produce 50% depression of neuromuscular function (ED50) and ED95 were 179 and 303 micrograms/kg, respectively. Time from administration of 600 micrograms/kg to onset of 90% and 100% neuromuscular block was 0.8 +/- 0.1 (0.5-1.3) and 1.3 +/- 0.2 (0.7-2.8) min. The time to recovery of neuromuscular transmission to 25% (T25) was 26.7 +/- 1.9 (17.2-39.0) min. The recovery index (T25-75) was 11.0 +/- 1.6 (6.0-22.8) min, and the time to complete recovery of the magnitude of the fourth response to a train-of-four stimuli divided by the magnitude of the first response (T4/T1) greater than or equal to 0.75 was 41.9 +/- 3.2 (26.5-57.7) min.(ABSTRACT TRUNCATED AT 250 WORDS)