Twitch Depression Research Articles

Sevoflurane increases fade of neuromuscular response to TOF stimulation following rocuronium administration in children. A PK/PD analysis

Sevoflurane enhances neuromuscular block produced by rocuronium, affecting not only single twitch response but also the response to high-frequency stimulation, increasing tetanic [or train-of-four (TOF)] fade. We compared the degree of fade during spontaneous recovery from rocuronium-induced neuromuscular block in 24 children (3-11 years old, ASA groups I and II), anesthetized with nitrous oxide-sevoflurane (one MAC, endtidal concentration) or nitrous oxide-fentanyl. Neuromuscular transmission was monitored electromyographically (EMG), stimulating the ulnar nerve at the wrist with TOF, 2 Hz for 2 s, repeated at 20-s intervals and recording EMG potential from adductor pollicis brevis. Depression of the fourth twitch, T4, was used as a measure of fade. Following an intubating dose of rocuronium, 0.6 mgxkg(-1), continuous infusion of rocuronium was given to maintain stable 90-99% T1 depression. Plasma concentration of rocuronium was determined with high performance liquid chromatography with electrochemical detection (HPLC-EC) method at the moment of discontinuation of rocuronium infusion and 10, 20, 30, 40, 50, 60, and 75 min afterwards. A two compartment model was used for pharmacokinetic (PK) calculations. PK parameters were fixed and pharmacodynamic data were fitted to effect compartment model proposed by Sheiner. Sevoflurane reduced rocuronium concentration in effect compartment producing 50% inhibition of both T1 and T4 response and significantly delayed not only T1, but also T4 recovery. Potentiating effect of sevoflurane on rocuronium-induced neuromuscular block influences not only postsynaptic, but also the presynaptic part of the neuromuscular junction, enhancing fade of neuromuscular response to high-frequency stimulation. The intensity of this latter effect is clinically relevant.

Effect of Storage Temperature of Rocuronium on Intubating Condition and Clinical Duration after Low-dose Technique

Background: Rocuronium bromide is a monoquaternary amino steroidal muscle relaxant. Rocuronium is structurally stable and no metabolites of rocuronium have not been observed in humans. The manufacturer recommends that rocuronium can be stored in room temperature for 12 weeks. The aim of this study was to determine if the storage temperature of rocuronium could influence the pharmacodynamics of rocuronium. Methods: One hundred of patients with a class I or II ASA physical status were enrolled in this study. It was divided to two groups. One (Group '0', n = 50) consists of those who had intravenously administered the rocuronium which had been stored in refrigerator and the other (Group '14', n = 50) consists of those who had intravenously administered the rocuronium which had been stored in room temperature (20-29℃, median 25.1℃) for 14 days. Before an anesthesia was induced, TOF-Watch® was attached and calibrated. The anesthesia was induced with 1μg/kg of fentanyl and 1.5 mg/kg of propofol intravenously. While the 0.1 Hz of single twitch was applied, 0.45 mg/kg of rocuronium, which is appointed to each group, was injected. Intubation is performed 90 seconds after injection of rocuronium and evaluated the intubating condition as excellent, good, poor, and impossible. Results: There was a statistically significant difference in intubating condition at 90 seconds between two groups. The onset time to twitch depression of 0% in group '14' was prolonged compared to group '0' (P ＜ 0.05). Clinical duration was also shortened in group '14' (P ＜ 0.05). Conclusions: Compared with the use of rocuronium stored in refrigerator, that stored at room temperature can be expected to have unfavorable intubating condition at 90 seconds after rocuronium injection. Therefore, the storage temperature has some influences on the efficacy of rocuronium.

Time course of action of sugammadex (Org 25969) on rocuronium-induced block in the Rhesus monkey, using a simple model of equilibration of complex formation

Reversal of neuromuscular block can be accomplished by chemical encapsulation of rocuronium by sugammadex (Org 25969), a synthetic gamma-cyclodextrin derivative. The present study determined the time course of the reversal action of sugammadex on rocuronium-induced block in the anaesthetized Rhesus monkey using train-of-four stimulation. A bolus injection of rocuronium 100 microg kg(-1) (about 1xED(90)) was given to determine the degree of neuromuscular block reached by this dose. After complete spontaneous recovery, a rapid bolus injection of sugammadex, 1 mg kg(-1), was given and at different time intervals (15, 30 or 60 min, in three different experiments) the effect of another rocuronium bolus injection of 100 microg kg(-1) was determined. Injection of the first dose of rocuronium resulted in a mean neuromuscular block (depression of first twitch) of 93 (SEM=1.6)%. Fifteen minutes after injection of sugammadex the same rocuronium dose resulted in 17% (SEM=5.6) block. After 30 and 60 min these maximum blocks amounted to 49% (SEM=7.6) and 79% (SEM=4.2), respectively. The estimated half-life of sugammadex in Rhesus monkey is 30 (SEM=4.9) min. The half-life of sugammadex (Org 25969), a new fast and efficient reversal agent for rocuronium-induced block, is relatively short in the Rhesus monkey, implying the possibility to perform neuromuscular block by rocuronium shortly after reversal of a prior block. In translation to the human situation differences in rocuronium sensitivity and kinetics should be taken into account.

Twitch Potentiation Influences the Time Course of Twitch Depression in Muscle Relaxant Studies: A Pharmacokinetic-Pharmacodynamic Explanation

The time course of twitch depression following neuromuscular blocking agent (NMBA) administration is influenced by the duration of control neuromuscular monitoring (twitch stabilization). The physiological mechanism for this interaction is not known. During twitch stabilization twitch response often increases to a plateau, this is known as twitch potentiation or the staircase phenomenon. Since twitch potentiation contributes to the observed twitch response it may also influence the time course of twitch depression following NMBA administration. Our objective was to estimate the degree that twitch potentiation influences the time course of twitch depression following NMBA administration under conditions typical for muscle relaxation studies. We used previousy described pharmacokinetic-pharmacodynamic (PK-PD) and twitch potentiation models to simulate twitch data. Simulations consisted of twitch stabilization followed by a NMBA bolus dose and subsequent onset and recovery from muscle relaxation. Twitch data were analyzed for onset and recovery characteristics and the results compared to clinical muscle relaxation studies in existing literature. We found that twitch potentiation likely plays a minor role in shortened onset time and increased duration of twitch depression observed with long periods of twitch stabilization.

Modeling of Twitch Fade Based on Slow Interaction of Nondepolarizing Muscle Relaxants with the Presynaptic Receptors

Nondepolarizing muscle relaxants (MRs) diminish the indirectly evoked single twitch due to their binding to the postsynaptic receptors. Additionally, the MRs produce progressive diminution of successive twitches upon repetitive stimulation (fade). Our study addresses the generation of fade as observed under clinical situation. The study was conducted in two phases. In the clinical part, we have evaluated the time course of twitch depression and fade following the administration of several doses of three MRs (rocuronium, pancuronium, and cisatracurium). In the second part, we have modified our model of neuromuscular transmission to simulate the time course of twitch depression and fade. The MR was assumed to bind to a single site on the presynaptic receptor to produce fade. The rates of interaction with the presynaptic receptors were characterized in terms of the arbitrarily assigned equilibrium dissociation constant and the half-life for dissociation of the presynaptic complex. A method was developed to relate the release of acetylcholine to the occupancy of the presynaptic receptors. The strength of the first and the fourth twitch was calculated from the peak concentration of the activated postsynaptic receptors, i.e., of those receptors with both sites occupied by acetylcholine. Our results indicate that, while the affinity of the MR for the presynaptic receptor plays little role in the time course of fade, the rate of dissociation of the complex between the presynaptic receptors and the muscle relaxant may be critical in determining the time course of fade. Tentative estimates of this parameter are offered.

Acute desflurane or sevoflurane exposure on a previously stabilized atracurium-induced neuromuscular block

The aim of this prospective study was to compare the effect of the administration of desflurane or sevoflurane to a fixed neuromuscular block. After written consent, 12 patients were anaesthetized with propofol and sufentanil. Atracurium was administered via a continuous infusion in order to obtain 85% twitch depression of the control value assessed by repeated accelerometric stimulation at the adductor pollicis. Once stabilized over the course of 30 min, propofol was discontinued and either desflurane (n = 6) or sevoflurane (n = 6) was delivered at 1 MAC in a mixture of 50% O(2) in air. Study parameters were the magnitude and the time of twitch height variations. Results are presented in mean +/- SD. Exposure to halogenated agents led to a significant reduction in twitch height with similar magnitude between the two agents. However, interaction with desflurane showed an initial and transient rise (35 +/- 22%) in twitch height before subsequent depression occurred. The time to reach 50% of the signal depression in the desflurane group was significantly delayed (25 +/- 7 vs. 11 +/- 4 min in the sevoflurane group; P < 0.01). On a stable neuromuscular block elicited by continuous infusion of atracurium, the abrupt administration of desflurane or sevoflurane reduces the accelerometric responses of the adductor pollicis in a similar way. This potentiating effect is produced faster after sevoflurane than after desflurane. With desflurane, a biphasic effect (of a transient and moderate increase followed by depression of the signal) was recorded.

Geographic Regional Differences in Rocuronium Bromide Dose–Response Relation and Time Course of Action

Geographic location is not acknowledged as a stratifying factor that can directly affect drug potency, because drugs are still licensed with the same recommended dose for different geographic regions. The aim of the current study was to compare the potency and duration of action of rocuronium bromide in 54 patients in three countries with different life habits, diet, and ambient conditions, namely white Austrians, white North Americans, and Han Chinese in China. Neuromuscular block of six consecutive 50-microg/kg rocuronium incremental doses followed by 300 microg/kg was evaluated using the Relaxometer mechanomyograph (Groningen University, Groningen, Holland). Dose-response curves were created using log-dose-probit transformation. The authors compared rocuronium bromide ED50, ED90, and ED95 (effective doses required for 50%, 90%, and 95% first twitch depression, respectively) as well as Dur25 and Dur0.8 (times from last incremental dose administration until 25% first twitch and 0.8 train-of-four ratio recovery, respectively) in patients of the three countries. Rocuronium ED50, ED90, and ED95 were significantly higher in Austrian patients (258 +/- 68, 530 +/- 159, and 598 +/- 189 microg/kg) and Chinese patients (201 +/- 59, 413 +/- 107, and 475 +/- 155 microg/kg) compared with American patients (148 +/- 48, 316 +/- 116, and 362 +/- 149 microg/kg, respectively). Dur25 and Dur0.8 were significantly shorter in Austrian patients (22.3 +/- 5.5 and 36.9 +/- 12.8 min) and Chinese patients (30.4 +/- 7.5 and 45.7 +/- 15.9 min) compared with American patients (36.7 +/- 8.5 and 56.2 +/- 16.7 min, respectively). The authors demonstrated a significant difference in rocuronium potency and duration of action among patients in the three countries. Larger studies are required for determining dosage recommendations for different geographic regions.

Rocuronium 0.3 mg·kg−1 (ED95) induces a normal peak effect but an altered time course of neuromuscular block in patients with Duchenne's muscular dystrophy

In patients with Duchenne's muscular dystrophy (DMD) recovery from neuromuscular block is delayed. It has been assumed that this is because of a higher potency of muscle relaxants in this patient cohort. We determined the peak effect, and the time course of action of rocuronium 0.3 mg x kg(-1) (ED(95)) in DMD patients. Twenty-four patients (12 with DMD and 12 controls; aged 10-18 years) were studied. All patients were anesthetized with propofol and fentanyl/remifentanil. Neuromuscular transmission was monitored by acceleromyography. After induction all patients received a single dose of rocuronium 0.3 mg x kg(-1). The complete time course of action as onset, peak effect and spontaneous recovery was recorded. The onset time (s) to maximum block was significantly (P < 0.01) prolonged in DMD patients (median: 315; range: 120-465) compared with controls (195, 75-270). The peak effect (% twitch depression relative to baseline) was not different between the groups (DMD: 59-100; controls: 28-100). In the DMD group, recovery was significantly (P < 0.01) delayed compared with controls at all recorded time points. The clinical duration (min) was 40.3 (22-89) in the DMD group vs 9.8 (6-17) in the control group (P < 0.01). The similar peak effect in both groups does not confirm the thesis of rocuronium having a higher potency in DMD patients. The documented very long recovery after the ED(95) of rocuronium emphasizes the need for careful assessment of neuromuscular function in DMD patients.

What is the Optimal Dosage of Remifentanil for Minimizing the Hemodynamic Change to Tracheal Intubation during Induction with Propofol Target-Controlled Infusion?

Background: Laryngoscopy and tracheal intubation are associated with hemodynamic pressor responses, which lead to adverse effect. Opioids have been used to reduce the hemodynamic change. The purpose of this study was to investigate an optimal dosage of remifentanil for attenuating hemodynamic change. Methods: 120 ASA class 1-2 patients, scheduled for elective surgery, were divided randomly into 4 groups. Anesthesia was induced with vecuronium priming dose (0.01 mg/kg) and TCI of propofol target concentration 8/ml. This was reduced to 4/ml when the effect-site concentration had been 3/ml. After the effect-site concentration had reached 4/ml, vecuronium (0.09 mg/kg) was given. At the same time, control group received normal saline, group R0.25 received remifentanil 0.25/kg, group R0.5 received remifentanil 0.5/kg, group R1 received remifentanil 1/kg over 60s and an infusion 0.2/kg/min. Intubation was performed after maximum depression of the single twitch was shown by single twitch stimulation test. Sytolic blood pressure, mean arterial pressure, diastolic blood pressure, heart rate and BIS value were measured preinduction, after propofol induction, immediately before and after intubation and 1, 2, 3, 4 minutes after intubation, respectively. Results: Post-intubation mean arterial pressure decreased significantly from pre-intubation value in group R0.5 and R1 (P /kg bolus and an infusion of 0.2/kg/min attenuate the pressor response to tracheal intubation in patients anesthetized with propofol TCI.

The Effect of Phenytoin on Rocuronium-Induced Neuromuscular Block in the Rat Phrenic Nerve-Hemidiaphragm Preparation

Anticonvulsant therapy alters the action of nondepolarizing muscle relaxants. We determined the effects of acute and chronic administration of phenytoin on rocuronium-induced neuromuscular block using the rat phrenic nerve-hemidiaphragm preparation. Rats were divided into 3 groups: a saline control group (n = 10), an acute phenytoin-treated group (n = 30), and a chronic phenytoin-pretreated group (n = 30). Phrenic nerve-hemidiaphragm was dissected, mounted in a bath containing oxygenated Krebs solution, and the nerve was stimulated at supramaximal intensity. Single twitch responses were recorded by physiogram. In the acute phenytoin-treated group, acute effects of phenytoin were determined based on the phenytoin concentration of 1, 10, or 100 microg/mL in the bath. The chronic effects of phenytoin were determined using phrenic nerve-diaphragms from rats pretreated with phenytoin (50 mg/kg/d) for 1, 7, or 28 days. In rats with phenytoin 100 microg/mL in the bath, all concentrations of rocuronium produced twitch depression significantly different from those of other groups (P < 0.05), and the concentration-response curve shifted to the left. In rats with phenytoin 10 microg/mL in the bath, the effective concentrations for 50%, 90%, and 95% twitch depression values were significantly different from those of the control group (P < 0.05). In chronically (28 days) phenytoin-pretreated rats, the concentration-response curve significantly shifted to the right (P < 0.05). These findings show that acute administration of phenytoin augmented the neuromuscular blocking effects of rocuronium, whereas chronic phenytoin treatment causes resistance to the neuromuscular blocking effects of rocuronium in target organs.

Neuromuscular blocking properties of atracurium during sevoflurane or propofol anaesthesia in dogs

ObjectiveTo quantify the neuromuscular blockade (NMB) produced by atracurium in either sevoflurane or propofol-anaesthetized dogs. AnimalsTwelve healthy, female adult mixed-breed dogs weighing 13 ± 3 kg (range 10–22 kg). Materials and methodsThree doses of atracurium (0.1, 0.2 and 0.3 mg kg−1) were tested at 1-week intervals. Anaesthesia was induced with inhaled sevoflurane or intravenous propofol and maintained with end-tidal sevoflurane concentrations of 1.95% (1.25 × MAC) or propofol 0.6 mg kg−1 minute−1 respectively. Acceleromyography and train-of-four stimulation of the fibular nerve were used for the assessment of NMB. The percentage depression of the first twitch (T1) and the fourth to the first twitch ratio (T4/T1), the maximum degree of neuromuscular block achieved and surgical muscle relaxation were recorded. Before and during neuro muscular blockade (at 10 minute intervals) body temperature, ECG, arterial blood pressure, inspired and expired CO2 concentrations and SpO2 were recorded. ResultsAtracurium produced a dose-dependent duration of NMB in both propofol and sevoflurane-anaesthetized dogs. Duration of block was longer in dogs anaesthetized with sevoflurane. All studied doses of atracurium caused twitch depression ≥95% with little or no cardiovascular changes. ConclusionsSevoflurane produces a clinically relevant potentiation of atracurium-induced NMB in dogs compared with propofol. Clinical relevanceSignificant differences in the potentiation of NMB drugs are encountered with commonly used anaesthetics in the dog.

Dose‐response relationship of rocuronium: A comparison of electromyographic vs. acceleromyographic‐derived values

Acceleromyography (AMG) is being employed with increasing frequency as a research tool. However, there is almost no information available regarding the accuracy of values for drug potency obtained using AMG. This study was an attempt to determine if AMG-derived ED(50/95) values are interchangeable with those measured with a more traditional neuromuscular monitor. Thirty adult patients were studied. Anesthesia was induced and maintained with N20, propofol, and supplementation opioid. Tracheal intubation was accomplished without muscle relaxants. Simultaneous ipsilateral AMG and EMG responses to 0.10 Hz stimulation was recorded. Following instrument calibrations, a single dose of rocuronium was administered. The first patient received a bolus of 0.17 mg kg(-1) of rocuronium. Using the Hill equation with a postulated slope of 4.50, the ED(50) was calculated. The second subject received a dose which approximated the calculated ED(50) for patient no. 1. Successive subjects were given a dose based on the running average of the estimated ED(50). The AMG-derived ED50/95 values for rocuronium (0.163 +/- 0.055 and 0.314 +/- 0.105 mg mg(-1)) were virtually identical to those established using EMG (0.159 +/- 0.043 and 0.306 +/- 0.084 mg kg(-1)). While mean peak twitch depression (Delta T1) was the same in both groups for individual subjects Delta T1 differed by +/- 20% (95% confidence interval). Acceleromyography-derived twitch heights for individual patients are not necessarily interchangeable with information obtained using electromyography. Nevertheless, acceleromyography appears to be a valid methodology for determining the drug potency when a population rather than an individual subject is being studied.

Cisatracurium-Induced Neuromuscular Blockade Is Affected by Chronic Phenytoin or Carbamazepine Treatment in Neurosurgical Patients

The effect of chronic anticonvulsant therapy (CAT) on the maintenance and recovery profiles of cisatracurium-induced neuromuscular blockade has not been adequately studied. In this study, we compared the pharmacokinetics and pharmacodynamics of cisatracurium after a prolonged infusion in patients with or without CAT. Thirty patients undergoing intracranial surgery were enrolled in the study: 15 patients under CAT (carbamazepine and phenytoin, Group A) and 15 controls receiving no anticonvulsant therapy (Group C). Anesthesia was standardized and both groups received a bolus of cisatracurium followed by an infusion to maintain a 95% twitch depression. A steady-state was obtained and the infusion was kept constant for 2 additional hours. Neuromuscular blockade was then allowed to spontaneously recover. Blood samples were taken for measurement of cisatracurium plasma concentration during the steady-state period (Cp(ss)95) and at various times during recovery. Demographic and intraoperative data were similar. CAT resulted in faster 25% and 75% recovery of the first twitch. The rate of infusion of cisatracurium needed to maintain a 95% twitch depression at steady-state was 44% faster in Group A (P < 0.001). The clearance of cisatracurium was significantly faster in Group A when compared with Group C (7.12 +/- 1.87 versus 5.72 +/- 0.70 L . kg(-1) . min(-1), P = 0.01). The Cp(ss)95 was also significantly larger in Group A (191 +/- 45 versus 159 +/- 36 ng/mL, P = 0.04). In addition, patients receiving CAT had a 20% increase in the clearance of cisatracurium that, in turn, resulted in a faster recovery of neuromuscular blockade after an infusion of the drug. Also, patients under CAT had a 20% increase in their Cp(ss)95, indicating an increased resistance to the effect of cisatracurium.

The Influence of Sevoflurane on the Antagonism Effect of Neostigmine for Rocuronium-induced Neuromuscular Blockade

Background: Some volatile anesthetics prolong the spontaneous recovery from neuromuscular blockade, and decrease the effect of neostigmine administrated for neuromuscular recovery. In addition, these effects differ among each volatile anesthetic. The aim of this study was to examine the effect of sevoflurane on the antagonism effect of neostigmine during the recovery period after administering rocuronium. Methods: Sixty-five adult patients were randomly allocated into 3 groups, using propofol and alfentanil, sevoflurane, and enflurane for the maintenance of anesthesia. Neuromuscular monitoring was performed using accelomyography. Tracheal intubation was performed at the maximum blockade after administering 0.6 mg/kg rocuronium. The infusion of rocuronium was initiated when a twitch was noticed and the infusion rate of rocuronium was determined to maintain a 155% twitch height. The acid-base balance was measured at a constant twitch height, and 20/kg neostigmine injection. After neostigmine, the initial twitch height, the maximum twitch height, the onset and duration of neostigmine were measured, and the antagonism effect was calculated as a percentage of the pre-existing twitch depression immediately before administering the neostigmine. Results: The maximum twitch heights and antagonism effects of the Sevoflurane and Propofol groups were larger than that of the Enflurane group and the durations of the neostigmine effect were longer. The rocuronium infusion rate was significantly higher in the Propofol group than in the other groups. Conclusions: The effects of sevoflurane on the antagonism effect and duration of neostigmine were less than enflurane, and there was no difference between sevoflurane and propofol.

Influence of chronic phenytoin administration on the pharmacokinetics and pharmacodynamics of vecuronium.

The duration of action of vecuronium is reduced in patients receiving phenytoin. In this study, the authors examined, simultaneously, the influence of phenytoin on both the pharmacokinetics and the pharmacodynamics of vecuronium. This study was approved by the institutional review board of the University of California, San Francisco, and patients gave written informed consent. Twenty-two patients, 11 taking phenytoin and all scheduled to undergo prolonged neurosurgical procedures with general anesthesia, participated in the study. In 12 patients (6 phenytoin, 6 control), vecuronium was infused at 7.5 microg x kg(-1) x min(-1) until the first response (T1) of each train-of-four decreased by 50%; in the remaining 10 patients (5 phenytoin, 5 control), 200 microg/kg vecuronium was infused over 10 min. Arterial blood samples were drawn at intervals over the next 5-7 h. Plasma concentrations of vecuronium and 3-desacetylvecuronium were measured by capillary gas chromatography. Pharmacokinetic and pharmacodynamic modeling was used to characterize the disposition of vecuronium and patient responses to it in the two groups. Clearance was typically increased by 138% (95% confidence interval, 93-183%) in patients taking phenytoin. The effect of vecuronium was well described using a sigmoid Emax model. The concentration of vecuronium giving 50% twitch depression was increased 124% (45-202%) in patients taking phenytoin. Chronic phenytoin therapy reduces the effect of vecuronium by mechanisms that include both increased vecuronium metabolism and reduced sensitivity of the patient to circulating concentrations of vecuronium.

Susceptibility to cartap-induced lethal effect and diaphragmatic injury via ocular exposure in rabbits.

Cartap is extensively used to control agricultural pests. Pertinent literatures have indicated that it causes no eye irritation [D.E. Ray, Insecticides derived from plants and other organisms, in: W.J. Hayes, E.R. Laws (Eds.), Handbook of Insecticide Toxicology, Classes of Insecticides, vol. 2, Academic Press, New York, 1991, p. 611; C. Tomlin, Cartap, in: C. Tomlin (Ed.), The Insecticide Manual, 12th ed., British Crop Protection Council, Surrey, UK, 2000, p. 144]; however, the instillation of a little cartap through the eye has caused death in rabbits. The aim of this study was to determine the ocular toxicity of cartap in New Zealand White rabbits. Cartap was directly instilled into the low conjunctival sac of eyes, at doses of 0, 5, 7.5, 10 and 12.5 mg/kg body weight. The changes in the enzymes and isoenzymes of creatine kinase (CK), lactate dehydrogenase (LD), as well as pathological changes in the muscles of the heart, thigh and diaphragm were determined in the cartap-treated rabbits. Moreover, the neuromuscular effect of cartap was examined using the isolated rabbit phrenic-nerve diaphragm model. The results indicated that rabbits developed severe signs and they died within 20 min of ocular instillation. The ocular LD50 of cartap was 8.1 mg/kg body weight. Treatment with cartap increased the activities of CK and LD enzymes and their isoenzymes, CK-1, CK-2, and CK-3 in serum, and CK-3 and LD-5 in the diaphragm. Microscopically, hypercontraction bands and the rupture of myofibers of the diaphragm were observed in dead rabbits. Cartap did not affect nerve-evoked twitch but induced irreversible contracture and twitch depression on the isolated rabbit's diaphragm. These results indicate that the rabbit is susceptible to cartap toxicity; the effect of cartap caused contracture and damage to the diaphragm might play a pivotal role in respiratory paralysis and death of rabbits during intoxication.

Endogenous adenosine prevents post-tetanic release facilitation mediated by α3β2 nicotinic autoreceptors

We investigated the modulatory role of endogenous adenosine on tetanic-induced (50 Hz for 5 s) nicotinic facilitation of [ 3H]acetylcholine release (5 Hz for 50 s) from rat motoneurons. Adenosine deaminase (0.5 U/ml) and the adenosine A 2A receptor antagonist, 3,7-dimethyl-1-propargyl xanthine (DMPX, 30 μM), facilitated post-tetanic [ 3H]acetylcholine release. Release inhibition caused by tubocurarine (1 μM), dihydro-β-erythroidine (1 μM) and α-conotoxin MII (0.1 μM) was attenuated after tetanic preconditioning. Nicotinic inhibitory action was fully restored after adenosine A 2A receptor block by DMPX or adenosine deaminase. DMPX (10 μM) caused a leftward shift of the inhibitory dose–response curves for d-tubocurarine (0.1–1 μM), dihydro-β-erythroidine (0.03–10 μM) and α-conotoxin MII (1–300 nM) on post-tetanic twitch amplitude. In contrast, the post-tetanic twitch depression caused by α-bungarotoxin (3–100 nM, which had no effect on transmitter release) was attenuated by DMPX (10 μM). It is concluded that activation of adenosine A 2A receptors by endogenously generated adenosine prevents the post-tetanic release facilitation mediated by nicotinic α3β2 autoreceptors.

Time course of neuromuscular blockade with rocuronium in children with intracardiac shunts

Objective: To evaluate the time course of neuromuscular blockade after rocuronium in children with intracardiac shunts. Design: Prospective study. Setting: University hospital. Participants: Consecutive children (n = 52) with intracardiac shunts scheduled for elective cardiac surgery. Participants were allocated to 2 groups according to the direction of the shunt. Interventions: Rocuronium, 0.6 mg/kg, was administered for muscle relaxation. The ulnar nerve was stimulated at 20-second intervals with a supramaximal 2-Hz train-of-4 stimulation (TOF-Guard nerve stimulator; Biomet International, Odense, Denmark). The onset time to maximal twitch depression and the time to clinical recovery were compared between the 2 groups. Measurements and Main Results: The time to maximal block was significantly faster in children with a right-to-left shunt: 56.8 ± 5.3 seconds versus 77.1 ± 6.6 seconds (p = 0.01). There was a tendency to shorter recovery in children with a right-to-left shunt: 42.3 ± 6.1 minutes versus 55.4 ± 4.9 minutes (p = NS). Conclusion: This study shows a more rapid onset of rocuronium in children with cyanotic congenital heart disease. In these patients, rocuronium is indicated, particularly for rapid airway control. Copyright 2002, Elsevier Science (USA). All rights reserved.

The Potency of New Muscle Relaxants on Recombinant Muscle-Type Acetylcholine Receptors

In Response: Dr. Nigrovic has raised some interesting points. First, our study did not attempt to investigate differences in the clinical onset and offset times of muscle relaxants measured by the twitch depression. These effects span the range of tens of seconds to minutes in vivo and incorporate variables such as blood flow, protein binding, and membrane permeability. In our study, muscle relaxants were applied directly onto the receptor in less than 1 second (chamber size of 25 μl, perfusion rate of 4–5 ml /min), and the peak-effect (i.e. the peak current) followed almost instantly. However, these drug application speeds were still not rapid enough to determine agent-specific differences in onset or offset at the receptor level. Second, Hill coefficients relate drug concentrations to effects and can only be compared when the effects are similar. In our study, the effect (namely the inhibition of acetylcholine-activated currents) was produced directly by ligand on the naked receptor, and the resulting Hill coefficient of about 1 was in agreement with blockade of one receptor-binding site. In vivo studies use force of muscle contraction as the effect, which is not directly produced by a ligand, but which is interposed between a current-contraction relationship. Thus, the two derived Hill coefficients are not comparable. In addition, presynaptic effects of nondepolarizing muscle relaxants may be involved that would have a significant effect on the Hill coefficient found with in vivo studies. Finally, the ultimate aim of our study was to examine the relative potencies of muscle relaxants using a postsynaptic model, not to find a model representing absolute potencies found in vivo. Any two models (recombinant nAChRs expressed in oocytes versus guinea pig hemidiaphragm) are likely to produce different absolute IC50 values. However, as suggested by Dr. Nigrovic, we have made a comparison between the relative IC50 values for different muscle relaxants from our study (nanomolar range) (1) and the relative IC50 values determined with guinea pig hemidiaphragm (micromolar range) (2), and the same potency relationships were found (Fig. 1). This striking correlation supports our conclusion that the differences in drug dosages needed to achieve clinically appropriate muscle relaxation appear to be governed by differences in drug-receptor affinity.Figure 1: Correlation of half-maximal response (IC50) values at the adult muscle-type nicotinic acetylcholine receptor (1) and published IC50 values for reduction of muscle twitch in a guinea-pig hemidiaphragm model (2).Matthias Paul Christoph H. Kindler C. Spencer Yost

The potency of new muscle relaxants on recombinant muscle-type acetylcholine receptors.

We studied the inhibition of fetal (gamma-nAChR) and adult (epsilon-nAChR) muscle-type nicotinic acetylcholine receptors by the two new nondepolarizing muscle relaxants (NDMRs) rocuronium and rapacuronium, the metabolite 3-desacetyl rapacuronium (Org 9488), and five other, longer-used NDMRs (pancuronium, vecuronium, mivacurium, d-tubocurarine, and gallamine). Receptors were expressed in Xenopus laevis oocytes by cytoplasmic injection of subunit complementary RNAs. Functional channels were activated with 10 microM acetylcholine, alone or in combination with various concentrations of the NDMRs. Currents were recorded with a whole-cell two-electrode voltage clamp technique. All NDMRs reversibly inhibited acetylcholine-activated currents in a dose-dependent fashion. Potencies of rapacuronium and Org 9488 were not statistically different at either gamma-nAChR (half-maximal response = 58.2 and 36.5 nM, respectively) or epsilon-nAChR (half-maximal response = 80.3 and 97.7 nM, respectively). The rank order of potencies at the epsilon-nAChR (pancuronium > vecuronium similar mivacurium > rocuronium similar d-tubocurarine > rapacuronium similar Org 9488 > gallamine) correlated highly with the clinical doses needed to produce 50% twitch depression at the adductor pollicis muscle in adults. Neuromuscular blockade by rapacuronium may be enhanced by its metabolite Org 9488. Different drug-receptor affinities of the tested NDMRs contribute to the differences in clinical dose requirements of these drugs needed to achieve appropriate muscle relaxation. Potencies of nondepolarizing muscle relaxants, studied at muscle nicotinic acetylcholine receptors expressed in a recombinant expression system, correlate highly with the clinical doses needed in adults to produce 50% twitch depression at the adductor pollicis muscle.