Jmkh Wierda

Time course of action and endotracheal intubating conditions of Org 9487, a new short-acting steroidal muscle relaxant; a comparison with succinylcholine.

In a randomized study, we evaluated lag time (time from the end of injection of muscle relaxant until the first depression of the train-of-four response [TOF]), onset time (time from the end of injection of muscle relaxant until the maximum depression of the first twitch of the TOF [TJ), neuromuscular block, and endotracheal intubating conditions at 1 min after 1 mg/kg succinylcholine (n = 15) and 1.5 mg/kg Org 9487 (n = 30). Two minutes after administration of Org 9487, 15 of the 30 patients received neostigmine for reversal. Recovery of neuromuscular block after succinylcholine, Org 9487 without and Org 9487 with neostigmine were compared using the time until T1 was 90% for the succinylcholine group, and the time until TOF was 70% for the Org 9487 groups. Neuromuscular transmission was monitored mechanomyographically. Onset time was similar (67 [20] and 83 [38] s for succinylcholine and Org 9487, respectively) and endotracheal intubating conditions were also similar after both muscle relaxants. Times until clinically sufficient recovery of neuromuscular block induced by succinylcholine (time until T, = 90%: 10.6 [3.3] min) and Org 9487 with neostigmine (time until TOF = 70%: 11.6 [1.4] min) were not different. In contrast, in the Org 9487 without neostigmine group, more time was required until complete recovery (24.1 [6.2] min) (P < 0.05). In conclusion, Org 9487 is a muscle relaxant suitable for endotracheal intubation and short-lasting interventions.

Pharmacokinetics and pharmacodynamics of rocuronium at the vocal cords and the adductor pollicis in humans

The pharmacokinetic‐pharmacodynamic relationship of rocuronium at the laryngeal adductor muscles and the adductor pollicis was determined in eight patients during general anesthesia. Rocuronium was administered as an infusion at a rate of 100 μg · kg−1 · min−1 over 5 minutes. The half‐life of transport between plasma and biophase (effect compartment) was significantly shorter at the adductor laryngeal muscles (2.7 ± 0.6 minutes, mean ± SD) than at the adductor pollicis (4.4 ± 1.5 minutes, p = 0.003). The concentration in the effect compartment producing 50% of the maximum effect was significantly greater at the adductor laryngeal muscles (1424 ± 148 μg · L−1) than at the adductor pollicis (823 ± 157 μg · L−1, p = 0.0001). The shorter onset of neuromuscular blockade at the laryngeal muscles than at the adductor pollicis may be explained by a faster transfer rate at the laryngeal adductor muscles neuromuscular junction than at the adductor pollicis neuromuscular junction.

Pharmacokinetics and pharmacokinetic-dynamic relationship between rapacuronium (Org 9487) and its 3-desacetyl metabolite (Org 9488)

UNLABELLED Rapacuronium (Org 9487) is a rapid-onset and short- to intermediate-acting muscle relaxant. Its 3-desacetyl metabolite, Org 9488, also exerts neuromuscular-blocking activity that may become apparent after prolonged maintenance of relaxation with rapacuronium. In this study, the pharmacokinetic behavior (n = 7) of this metabolite and the pharmacokinetic/pharmacodynamic (PK/PD) relationship of rapacuronium (n = 10) and Org 9488 (n = 7) were investigated in humans. Similar protocols were used for three study groups regarding the anesthetic technique, blood and urine sampling, and pharmacokinetic and PK/PD analyses. The time course of action was measured mechanomyographically using the adductor pollicis muscle. The median clearance of rapacuronium was 7.28 mL x kg(-1) x min(-1) x with an excretion fraction in the urine of 6.2%. The clearance (studied in two groups) of Org 9488 was 1.28 and 1.06 mL x kg(-1) x min(-1) with an excretion fraction in the urine of 51.9% and 53.5%, respectively. The median rate constant of transport between plasma and the biophase of rapacuronium (0.449 min(-1)) is markedly larger than that for Org 9488 (0.105 min(-1)). The modeled concentration in the biophase at 50% effect as a measure of potency is higher for rapacuronium (4.70 microg/mL) than for Org 9488 (1.83 microg/mL). The lower clearance of the metabolite will gradually prolong the time course of the neuromuscular blockade during maintenance with rapacuronium. IMPLICATIONS We investigated the concentration-time-effect relationship of the relaxant rapacuronium and the contribution of its metabolite. Clearance, rate constant of transport between plasma and the biophase, and modeled concentration in the biophase at 50% effect of rapacuronium are consistent with its rapid onset and short to intermediate duration. The lower clearance of the metabolite will gradually prolong the time course of the neuromuscular blockade during maintenance with rapacuronium.

Time course of action and intubating conditions following vecuronium, rocuronium and mivacurium

The purpose of this study was to compare the time course of action and tracheal intubating conditions of vecuronium, rocuronium and mivacurium in anaesthetised patients. Anaesthesia consisted of thiopentone, fentanyl, N2O/O2 and isoflurane. After a 2 × ED90 dose the first attempt at tracheal intubation was made at 90s. If required, maintenance doses of 0.5 × ED90 were administered. The intubating conditions after rocuronium were significantly better than those after vecuronium and mivacurium. The average onset times of rocuronium (172 s) and vecuronium (192 s) were significantly shorter than that of mivacurium (229 s). The clinical duration and recovery time were significantly shorter after mivacurium (13 and 6min, respectively) than with vecuronium (33 and 14min, respectivelys) and rocuronium (28 and 11 min, respectively). We conclude that rocuronium might be of advantage whenever the interval between the administration of the muscle relaxant and tracheal intubation must be short, whereas mivacurium may be of benefit if fast spontaneous recovery is required.

Evaluation of a closed-loop muscle relaxation control system

Automatic muscle relaxation control may reduce anesthesiologists’ workload freeing them for other patient care requirements. In this report we describe a muscle relaxation controller designed for routine clinical application using rocuronium and the train-of-four count. A muscle relaxation monitor (TOF Watch SX) was connected to a laptop computer running a controller algorithm program that communicates with a syringe pump to form a closed-loop muscle relaxation system. The control algorithm uses proportional-integral and lookup table components and is designed to avoid the usability restrictions of existing controllers. The controller is optimized using an objective method to avoid the uncertainties of ‘‘hand-crafted’’ controller algorithms. Controller target was train-of-four count 1 or 2 and controller performance was evaluated in 15 patients. During 39 hours of closed-loop control, 96.1% of all twitches recorded were in the target range. Average rocuronium infusion rate was 0.36 mg·kg−1·h−1 (sd 0.18 mg·kg−1·h−1). We show that the controller remains useful even in the presence of disturbances that can arise in routine clinical conditions. The muscle relaxation controller maintained the target train-of-four count values and may serve as a basis for the design of hardware and user interfaces for closed-loop muscle relaxation control in clinical conditions.

Effect of hypothermia on the hepatic uptake and biliary excretion of vecuronium in the isolated perfused rat liver.

BackgroundHypothermia prolongs the time course of action of nondepolarizing muscle relaxants. It is not known whether this prolongation is caused by a reduced rate of extrahepatic distribution or elimination, liver uptake, metabolic clearance, or biliary excretion. Therefore, the authors studied the effects of hypothermia on the net hepatic uptake, metabolism, and biliary excretion of vecuronium in isolated perfused rat liver. MethodsLivers of Wistar rats were perfused with Krebs Ringer solution (1% albumin, 3.3% carbon dioxide in oxygen, pH 7.36–7.42, 38°C). Each perfusion experiment (recirculatory perfusion system) was divided into three phases. In phase 1, a bolus dose of vecuronium (950 &mgr;g) was followed by a continuous infusion of vecuronium (63 &mgr;g/min) throughout the perfusion experiment. In phase 2, the temperature was reduced to 28°C. In phase 3, temperature was restored. In controls, the temperature was kept constant throughout the perfusion. Concentrations of vecuronium and its metabolites were measured in perfusion medium, bile, and liver homogenate. Parameters of a multicompartmental liver model were fitted to the concentration patterns in perfusion medium and in bile. ResultsHypothermia increased vecuronium concentrations in the perfusion medium from 4.0 &mgr;g/ml (range, 2.5–6.6) to 15.6 &mgr;g/ml (11.5–18.4 &mgr;g/ml;P = 0.018). Hypothermia reduced the biliary excretion rate of 3-desacetyl vecuronium from 18% (range, 6–37%) to 16% (range, 4–19%) of that of vecuronium (P = 0.018). Pharmacokinetic analysis confirmed that hypothermia reduced the rate constants of hepatic uptake and metabolism from 0.219 to 0.053 and from 0.059 to 0.030, respectively. ConclusionsHypothermia significantly and reversibly reduced the net hepatic uptake of vecuronium. Hypothermia reduced the metabolism of vecuronium and the biliary excretion rate of 3-desacetyl vecuronium.

DOSE-RESPONSE RELATION, NEUROMUSCULAR BLOCKING ACTION, INTUBATION CONDITIONS, AND CARDIOVASCULAR EFFECTS OF ORG-9273, A NEW NEUROMUSCULAR BLOCKING-AGENT

The ED50 and the ED90, the time-course of the neuromuscular block, the intubation conditions, and the cardiovascular effects of Org 9273, a new steroidal nondepolarizing neuromuscular blocking agent, have been evaluated in 41 anesthetized patients. From cumulative dose-response curves the ED50 and ED90 were calculated to be 175 and 300 μg/kg, respectively. The time-course of neuromuscular blockade after 300− and 500-μg/kg doses of Org 9273 appeared to be similar to that of equipotent doses of vecuronium. The neuromuscular block was characterized by a fast initial rate of block development. High-dose Org 9273 (1 mg/kg = 3—4 times the ED90) had a clinical duration comparable to an intubating dose of pancuronium, but a considerably more rapid onset and recovery index. Three hundred micrograms per kilogram and 500 μg/kg Org 9273 produced good to excellent intubation conditions 1 min after administration. Org 9273 in a dose of 0.5—2 times the ED90 produced no cardiovascular changes; however, 3–4 times the ED90 increased heart rate 20%—25% (P < 0.001), probably due to a vagolytic effect.

Improving pharmacokinetic-pharmacodynamic models of muscle relaxants using potentiation modelling

Repeated motor nerve stimulation performed during neuromuscular monitoring enhances the evoked mechanical response of the corresponding muscle resulting in an increased twitch response. This is known as twitch potentiation or the staircase phenomenon. For neuromuscular modelling research twitch stabilisation techniques are often used to reduce the visible effect of potentiation, but such techniques are not always effective. Our objective was to model pharmacokinetic-pharmacodynamic (PK–PD) and twitch potentiation and to estimate neuromuscular block (NMB) in the presence of twitch potentiation. We combined a standard PK–PD model with a model describing the degree of twitch potentiation. The combined model was used to predict mechanomyographic twitch measurements and estimate NMB and twitch potentiation during muscle relaxation monitoring. Model parameters and prediction accuracy were compared to the standard PK–PD model with and without linear baseline correction. The PK–PD-potentiation model allows NMB to be estimated in the presence of twitch potentiation. It also accurately predicts data from twitch stabilisation, which is ignored with the standard PK–PD model. Compared to the standard PK–PD model, estimated PD parameters ec50 and gamma were found to be higher using the PK–PD-potentiation model. Compared to linear baseline correction, estimated PD parameters ke0 and ec50 were found to be higher. A PK–PD-potentiation model can estimate the degree of twitch potentiation and the degree of NMB during neuromuscular monitoring. This model leads to different PD parameter estimations than the standard PK–PD model however the differences are small enough to be unlikely to cause great concern among researchers.

POTENCY AND ONSET OF ACTION OF NEUROMUSCULAR BLOCKING-DRUGS

Dr. Kopman (l), in his reply to Bartkowski et al.‘s study (2), pointed out that the relatively fast onset of rocuronium cannot be satisfactorily explained by the difference in molar potency, expressed as ED,,, compared with the other neuromuscular blockers d-tubocurarine (d-TC), gallamine, pancuronium, vecuronium, and atracurium. We agree with Bartkowski and Witkowski in their response to Kopman (11, that a different stimulation mode and anesthetic technique may be of influence. In the past we repeated the study of Kopman (3) in 18 patients under thiopental/fentanyl anesthesia with a mixture of N,O and OZ. Three groups of six patients each received d-TC, gallamine, and pancuronium, respectively. In contrast to Kopman, who monitored the neuromuscular block with train-of-four (TOF) stimulation, 2 Hz every 20 s, we determined the TOF, 2 Hz every 12 s. We found only a weak relationship between onset and potency (y = -2.6432x + 4.7656; see Figure 1). Since the calculated ED, value for d-TC deviates significantly from the previous findings of Kopman (31, the higher potency of I-TC in our study may be related to its more pronounced intrinsic activity to prejunctional receptors, which is extensively described by Bowman et al. (4,5). Blockade of prejunctional receptors coincides with a more pronounced fade at higher stimulation frequencies, e.g., TOF and tetanic stimulation. This view is supported by several papers. Gibson and Mirakhur (6) demonstrated that d-TC and atracurium produce more fade than vecuronium and pancuronium, especially during onset (TOF 2 H.z every 10 s). Pearce et al (7) showed previously in their experiment that during onset atracurium produced significantly more fade than vecuronium, using TOF stimulation of 2 Hz with a stimulation-free interval of 12 s. With a little more intense TOF stimulation pattern of 4 Hz, Williams et al. (8) showed significant differences between pancuronium and d-TC and also between pancuronium and gallamine. This suggests that compounds with a more pronounced prejunctional affinity will display a higher potency with an increasing stimulation frequency and/or a decreasing stimulation-free interval. Consequently, the high correlation found by Kopman (3) is valid