Twitch Depression Research Articles

Pharmacodynamic modeling of muscle relaxants: effect of design issues on results.

Pharmacodynamic studies of muscle relaxants use different dosing regimens (such as administration by bolus vs. infusion and doses that produce complete vs. incomplete paralysis). The authors used published data to evaluate the effect of modeling assumptions on pharmacodynamic estimates. The authors used a pharmacokinetic-pharmacodynamic dataset in which patients received cisatracurium, 75 or 300 microg/kg (1.5 or 6 x ED95), to generate plasma concentration (Cp) and twitch depression (effect) curves. They then evaluated the impact of the following: assuming that Cp decreased monotonically versus increasing initially before decreasing monotonically; misrecording effect data by 6 s or less; and doses targeting incomplete versus complete paralysis. Parameters evaluated were the steady state Cp depressing twitch tension 50% (C50) and the rate constant for equilibration between plasma and effect site concentrations (k(e0)). With the large dose, increasing the time at which Cp peaked from 0.0 to 1.5 min decreased C50 and increased k(e0) markedly; with the small dose, changes in both were small. Misrecording the timing of effect had a larger impact with the large dose compared with the small dose. Doses smaller than ED50 or those producing prolonged, complete twitch depression yielded biased and variable estimates. The erroneous assumption that Cp decreases monotonically after bolus administration affects accuracy of pharmacodynamic estimates with doses producing rapid, complete twitch depression. Other errors (e.g., misrecording the time of drug administration) impact on pharmacodynamic estimates, particularly with large doses. The authors' findings suggest that investigators performing neuromuscular (and other) pharmacodynamic studies should carefully consider the impact of study design on their parameter estimates.

Reduction of quantal size and inhibition of neuromuscular transmission by bafilomycin A

The energy for uphill transport of neurotransmitters into synaptic vesicles is created by bafilomycin A- and concanamycin A-sensitive vacuolar H +-ATPase (V-ATPase). Both blockers (at 0.1–5 μM) depressed twitch tension and induced tetanic fade of mouse diaphragm on stimulation of the phrenic nerve. Axonal impulse conduction and depolarization of motor endplate by exogenous acetylcholine were not inhibited. The IC 50s for bafilomycin A and concanamycin A were 1.1±0.2 and 0.7±0.1 μM, respectively. Contractile response evoked by stimulation of diaphragm, muscle resting membrane potential and membrane resistance were not altered. V-ATPase blockers decreased quantal size and shifted the distribution of miniature endplate potentials (mepps) to low amplitude direction. The increase of mepp events in high KCl medium was suppressed slightly. The blockers depressed endplate potentials (epps) with IC 50s of 0.7±0.2 μM (bafilomycin A) and 0.4±0.1 μM (concanamycin A). On high frequency stimulation, the coefficient of variance and run-down of epps were increased. The inhibitory effects on mepps and epps were irreversible and augmented by nerve stimulation. The results suggest that inhibition of V-ATPase reduces the acetylcholine content of synaptic vesicles, leading to suppression of neuromuscular transmission.

No Substitute for the Intravenous Route

No Substitute for the Intravenous Route

Evaluation of Presynaptic Action of Depolarizing Neuromuscular Blocking Agents with Single Twitch Response in Vitro

Background: This study was performed to evaluate the presynaptic effects of depolarizing neuromuscular blocking drugs by using slow and fast frequencies of indirect stimulation on partial twitch depression in vitro. Methods: A rat phrenic nerve hemidiaphragm was dissected and was mounted in an organ bath containing an oxygenated Krebs solution. The phrenic nerve was stimulated supramaximally and the twitch response (0.1 Hz) was stabilized for at least 30 minutes. T200/T1 ratio (twitch height of the 200th stimuli divided by that of the first stimuli) at frequencies of 0.2, 0.5, 1.0, and 2.0 Hz using a drug concentration which provided approximately 20% twitch depression at 0.1 Hz was calculated. To compare T200/T1 ratios with TOF ratios, a 2.0 Hz TOF response was measured immediately after the 200th stimuli at either frequency of stimulation. Results: T200/T1 ratios produced by succinylcholine (SCC) and decamethonium (C10) were located between α-bungarotoxin (ABX) and hexamethonium (C6), however, significant differences among the four drugs were found at 2.0 Hz. The propensity for a decrease in T200/T1 ratios at 2.0 Hz might differ from this study: C6 > C10 > SCC > ABX. T200/T1 ratios at 2.0 Hz were not different from TOF ratios. Conclusions: It is concluded that small doses of C10 have a greater presynaptic activity than that of SCC, when the observed effects in this study were compared with the result of ABX acting predominantly at postsynaptic receptors and C6 acting predominantly at presynaptic receptors. (Korean J Anesthesiol 2001; 40: 532∼537) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ

Neuromuscular Blocking Properties of beta-Bungarotoxin, Hexamethonium and Verapamil in the Rat Phrenic Nerve-Hemidiaphragm Preparation

Background: β-Bungarotoxin irreversibly changes the presynaptic membrane, hexamethonium acts on the presynaptic nicotinic receptor, and verapamil blocks the ion channels on the presynaptic membrane. The effect of these drugs on twitch height and train of four (TOF) ratio were investigated, as well as the reversal effects of neostigmine, pyridostigmine or 4-aminopyridine (4-AP) on the partial neuromuscular blockade induced by these drugs. Methods: Square wave, 0.1 Hz supramaximal stimuli or 2 Hz, 0.2 ms train of four stimuli, was applied to the phrenic nerve-hemidiaphragm preparation of the rat, and the twitch height response was recorded mechanomyographically. The cumulative concentration effects and TOF ratios at each point of twitch depression after β-bungarotoxin, hexamethonium or verapamil were measured. TOF ratios were observed at 75, 50 and 25% of the control twitch height value during observation of the concentration effect. The EC50 and EC95 of β-bungarotoxin, hexamethonium or verapamil were calculated using an inhibitory sigmoid Emax model. The reversal effect of some doses of neostigmine, pyridostigmine or 4-aminopyridine to the partial neuromuscular block produced by EC50 of βbungarotoxin, hexamethonium or verapamil was determined. Results: The EC50 and EC95 of β-bungarotoxin, hexamethonium and verapamil were 0.0695 and 0.1160μg/ml, 1267.0 and 2033.5μg/ml and 29.45 and 37.99μg/ml respectively. TOF fade was marked with hexamethonium or verapamil but small with β-bungarotoxin. Neostigmine or pyridostigmine did not reverse the partial neuromuscular block induced by β-bungarotoxin, hexamethonium or verapamil. However, 4-AP produced a dose-dependent recovery of the twitch response (P < 0.05). Conclusions: β-Bungarotoxin, hexamethonium and verapamil produced different degree of TOF fade, and this may be due to different sites of action of these drugs. 4-AP reversed effectively the partial

Studies of Interaction between Hexamethonium and Lidocaine, alpha-Bungarotoxin or Decamethonium in Vitro

Background: Interactions of neuromuscular blocking agents are antagonistic in a combination of depolarizing and nondepolarizing agents, additive in a combination of relative two compounds or synergistic in a combination of different two nondepolarizing agents. However, the interactions of neuromuscular blocking agents with a different site of action from each other have not been studied clearly. This study was designed to examine the interaction between hexamethonium and lidocaine, α-bungarotoxin or decamethonium with markedly different pre and postsynaptic sites of action. Methods: Square wave, 0.1 Hz supramaximal stimuli or 2 Hz, 0.2 ms train of four (TOF) stimuli, was applied to the rat phrenic nerve-hemidiaphragm preparation, and the twitch height response was recorded mechanomyographically. The cumulative concentration effect and TOF ratio at each point of twitch depression after hexamethonium, lidocaine, α-bungarotoxin or decamethonium given were measured. The EC50 and EC95 of hexamethonium, lidocaine, α-bungarotoxin and decamethonium were calculated using an inhibitory sigmoid E model. In the experiment of each combination of two drugs, three points of the isobole for hexamethonium-lidocaine, hexamethonium-α-bungarotoxin and hexamethonium-decamethonium were established using ratios of 1: 3, 1: 1 and 3: 1 of their EC50. Points on the line of theoretical additivity and 95% canfidence intervals were calculated according to Tallarida et al. TOF ratios were observed at 75, 50 and 25% of the control twitch height value during each combination ratio of their EC50. Results: Significant deviations of points on the isobole from the line of additivity to the left were found at all EC50 ratios of hexamethonium-lidocaine (P<0.05 respectively), that to the right was found at all EC50 ratios of a hexamethonium-α-bungarotoxin and hexamethonium-decamethonium (P<0.05 respectively). The magnitude of TOF fade depended upon the mixed ratios for their EC50. Conclusions: The interaction was found to be synergistic in the combination of hexamethonium-lidocaine, and antagonistic in the combination of hexamethonium-α-bungarotoxin and hexamethonium-decamethonium. (Korean J Anesthesiol 2001; 40: 645~654)

Neuromuscular Blocking Properties of alpha-Bungarotoxin, Decamethonium and Lidocaine in the Rat Phrenic Nerve-Hemidiaphragm Preparation

Background: α-Bungarotoxin, decamethonium or lidocaine has a neuromuscular blocking effect. The aim of this study was to evaluate the pharmacodynamic properties of these drugs at the neuromuscular junction and the reversal effects of antagonists in vitro. Methods: The effects of evoked twitch tension response have been studied on the isolated phrenic nerve hemidiaphragm preparation of the rat, using a single twitch (0.1 Hz) and the train of four (TOF; 2 Hz for 2 s) stimulation. The cumulative concentration effect and TOF ratio at each point of twitch depression after α-bungarotoxin, decamethonium or lidocaine were measured mechanomyographically. The EC50 and EC95 of α-bungarotoxin, decamethonium or lidocaine were calculated using an inhibitory sigmoid Emax model. The reversal effects of various doses of neostigmine, pyridostigmine or 4-aminopyridine (4-AP) to the partial neuromuscula r block produced by EC50 of α-bungarotoxin, decamethonium or lidocaine were determined. Results: The EC50 and EC95 of α-bungarotoxin, decamethonium or lidocaine were 0.179 and 0.320μg/ml, 17.07 and 26.84μg/ml or 76.80 and 105.70μg/ml. TOF fade was produced by α-bungarotoxin or decamethonium but not by lidocaine. Neostigmine or pyridostigmine did not reverse the partial neuromuscular block induced by α-bungarotoxin, decamethonium or lidocaine. However, 4-AP produced a dose-dependent recovery of the twitch response (P < 0.05). Conclusions: α-Bungarotoxin, decamethonium or lidocaine produced different degree of TOF fade, and it means that this may be due to different site of action of these drugs. 4-AP reversed effectively the partial neuromuscular block induced by α-bungarotoxin, decamethonium or lidocaine, whereas neostigmine or pyridostigmine did not. (Korean J Anesthesiol 2001; 40: 763∼772) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ

Cardiac contractile impairment associated with increased phosphorylation of troponin I in endotoxemic rats.

The subcellular mechanisms underlying intrinsic myocardial depression during sepsis remain poorly defined, in particular the relative roles of altered intracellular Ca2+ transients versus changes in myofilament properties. We studied contractile function of cardiac myocytes isolated 12 h after induction of endotoxemia (5 mg/kg intravenous E. coli lipopolysaccharide [LPS]) in conscious rats. Cardiomyocytes from LPS-injected rats had depressed twitch shortening compared with control cells (4.10.2% versus 7.80.3%; P2+ transients (peak indo-1 ratio 1.130.02 versus 1.120.02; P = NS). Contractile depression was unaffected by inhibitors of nitric oxide synthase. Steady-state myofilament response to Ca2+, assessed by tetanization of intact cells over a range of [Ca2+], was reduced significantly in the LPS group (P2+ was unaffected by isoproterenol (3 nmol/L) in endotoxemic cells, whereas there was a rightward shift in control cells. A reduction in myofilament response to Ca2+ is the major determinant of intrinsic cardiac depression in systemic endotoxemia. This condition appears to be related to an increase in myocardial troponin I phosphorylation.

Effect of renal failure and cirrhosis on the pharmacokinetics and neuromuscular effects of rapacuronium administered by bolus followed by infusion.

Recent trials indicate that rapacuronium's pharmacokinetic characteristics are influenced by both renal failure and cirrhosis but the time course of a single bolus dose of 1.5 mg/kg is affected minimally. The authors reassessed these pharmacokinetic findings and examined the time course of the same bolus dose followed by a 30-min infusion. During nitrous oxide-isoflurane anesthesia, patients with normal renal and hepatic function (n = 25), those with renal failure (n = 28), and those with cirrhosis (n = 6) received a bolus dose of rapacuronium (1.5 mg/kg) followed by a 30-min infusion adjusted to maintain 90-95% twitch depression. At 25% recovery, neostigmine was administered. Blood was sampled until 8 h after the infusion to determine concentrations of rapacuronium and its active metabolite ORG9488. Rapacuronium's pharmacokinetic parameters were determined using mixed-effects modeling. Onset and facilitated recovery of twitch depression were similar in the three groups. Patients with renal failure required 22% less rapacuronium to maintain target twitch depression during the infusion. Rapacuronium's plasma clearance was 24% smaller in renal failure and decreased 0.5%/yr of age; rapid distribution clearance was 51% smaller in men than in women. After the infusion, ORG9488 concentrations decreased markedly more slowly in patients with renal failure. Cirrhosis did not alter the pharmacokinetics of rapacuronium. Rapacuronium's plasma clearance and infusion requirement were decreased by renal failure. By dosing to maintain target twitch depression, recovery was not prolonged. Cirrhosis does not affect the pharmacokinetics or neuromuscular effects of rapacuronium. Persistence of ORG9488 in patients with renal failure might prolong recovery after rapacuronium if target twitch depression is not maintained or with administration of rapacuronium for more than 30 min.

Dose–Response and Onset/Offset Characteristics of Rapacuronium

A rigorous study of the dose-response relation of rapacuronium has, to our knowledge, yet to be performed. In addition, there is little information available regarding the onset or offset profile of rapacuronium when administered in subparalyzing doses. These issues necessitate further study. Forty-seven adult patients, American Society Anesthesiologists physical status I or II, were studied. Tracheal intubation was accomplished without muscle relaxants. Anesthesia was maintained with use of nitrous oxide, propofol, and alfentanil. The electromyogram of the first dorsal interosseous muscle was measured using a monitor. Single stimuli at 0.10 Hz were administered. A single dose of rapacuronium was administered. After log-dose or logit transformation of the data, the best-fit line of regression was determined using the method of least squares. For each subject, the authors estimated the 50% effective dose (ED50) and 95% effective dose (ED95) from the Hill equation using the slope obtained from regression analysis. The onset times to 50 and 90% of peak effect were estimated in a subset of 10 individuals in which peak twitch depression decreased to the range of 90-99%. The calculated ED50 and ED95 values for rapacuronium were 0.39 +/- 0.08 (SD) and 0.75 +/- 0.16 mg/kg, respectively. After a single ED95 dose, 90% of the drug's peak effect was evident in 77 +/- 17 s. After this dose, rapacuronium has a clinical duration of 6.1 +/- 1.1 min. The authors found the ED95 of rapacuronium to be substantially less than suggested by previous estimates. Rapacuronium has an onset profile that is not different from that previously reported for succinylcholine. The rate of spontaneous recovery was faster after rapacuronium than the authors previously observed after mivacurium administration but was slower than after succinylcholine, using an identical protocol.

Inhibition of mouse neuromuscular transmission and contractile function by okadaic acid and cantharidin.

1. Phosphorylations of cellular proteins modulate biological activities. The effects of okadaic acid (0.1 - 10 microM) and cantharidin (1 - 100 microM), inhibitors of protein phosphatases, on the synaptic transmission at the mouse neuromuscular junction were explored. 2. Both inhibitors almost completely depressed twitch forces elicited by electrical stimulation of diaphragm muscles (the IC(50)s for okadaic acid and cantharidin were 1.1+/-0.2 and 13+/-1 microM, n=5, respectively) and suppressed contractures evoked by high K(+) and ryanodine more than 70%. Contractures caused by cardiotoxin, which destroys the integrity of sarcolemma, were not depressed. 3. Both okadaic acid (10 microM) and cantharidin (100 microM) depolarized muscle membranes from approximately -80 to approximately -60 mV in a partially reversible and tetrodotoxin-sensitive manner. The initial short-term enhancement of twitch responses (up to approximately 40%) was correlated with the inhibitors-induced repetitive firings of muscle action potential. 4. Treatment with either agent resulted in nearly complete inhibitions of endplate potential (epp). The IC(50)s were 0.8+/-0.2 and 9+/-2 microM (n=5), respectively, for okadaic acid and cantharidin. On high frequency stimulation, the coefficient of epps was increased more than 10 fold and the extent of epp run-down during stimulations intensified from approximately 25 to approximately 75%. Analyses of presynaptic quantal releases revealed decreases in epp quantal content and the immediately available vesicle pool. 5. The frequency of miniature epp was initially elevated up to 2 fold then suppressed down to approximately 30%. The small reduction in the amplitude was antagonized when the membrane of endplate area was repolarized. 6. The data suggest that okadaic acid and cantharidin inhibit mobilizations of synaptic vesicles and depress Ca(2+) release from sarcoplasmic reticulum and that protein phosphatases participate in the modulation of motor function.

A New Method of Monitoring the Effect of Muscle Relaxants on Laryngeal Muscles Using Surface Laryngeal Electromyography

A New Method of Monitoring the Effect of Muscle Relaxants on Laryngeal Muscles Using Surface Laryngeal Electromyography

Propofol enhances a d-tubocurarine-induced twitch depression in septic rat diaphragm.

We estimated the effect of d-tubocurarine (dTc) on neuromuscular transmission and the action of propofol on dTc-induced twitch depression by using sham control and septic rat nerve-hemidiaphragm preparations in vitro. Isometric twitch tension elicited by indirect (phrenic nerve) or direct (muscle) stimulation at 0.1 Hz was evaluated. Sepsis induced by panperitonitis attenuated the twitch tension elicited by indirect and direct stimulation (P < 0.01 in each group) in the absence of significant morphological inflammatory damage to the diaphragm. dTc (1 microM) decreased the twitch tension elicited by indirect stimulation (P < 0.01) less intensely in the septic group than in the sham group (P < 0.01). Propofol accentuated dTc-induced depressed twitch more intensely in the septic group (P < 0.01 or 0.05). These results demonstrate that sepsis attenuates both muscle contractile force and the effect of a neuromuscular blocker and that propofol more intensely enhances dTc-induced twitch depression during sepsis. Propofol and nondepolarizing muscle relaxants are widely used for various clinical cases, including sepsis. Interactions between nondepolarizing muscle relaxants and propofol during sepsis are interesting from a clinical point of view. We demonstrated that propofol significantly enhances d-tubocurarine-induced twitch depression in vitro in the septic rat model compared with that in the nonseptic rat model.

Rocuronium potency and recovery characteristics during steady-state desflurane, sevoflurane, isoflurane or propofol anaesthesia

We have studied the potency and recovery characteristics of rocuronium during 1.25 MAC of isoflurane, desflurane, sevoflurane or propofol anaesthesia in 84 patients using electromyography. Potency was determined by a cumulative bolus technique. The mean ED50 of rocuronium was 169 (SD 41), 126 (32), 121 (28) and 136 (25) micrograms kg-1 during propofol, isoflurane, sevoflurane and desflurane anaesthesia, respectively (ns), and ED90 values were 358 (62), 288 (29), 289 (28) and 250 (28) micrograms kg-1, respectively. The reduction in ED90 was statistically significant for all three inhalation anaesthetics (P < 0.05) compared with propofol. After 120 min, the cumulative infusion rate of rocuronium to obtain twitch depression of 90-95% was 9.0 (1.9), 6.3 (1.6), 6.1 (2.0) and 6.1 (1.1) micrograms kg-1 min-1 during propofol, isoflurane, sevoflurane and desflurane anaesthesia, respectively (P < 0.01). Recovery index was 22 (13), 27 (10), 28 (13) and 26 (14) min under propofol, isoflurane, sevoflurane and desflurane anaesthesia, respectively (ns). There were no significant differences between the three potent inhalation anaesthetics in relation to potency, infusion requirements or recovery characteristics of rocuronium.

Oita International Electrocardiology Symposium 2000 “Electrophysiology and Management of Lethal Arrhythmias in the New Millennium: From Genes to Bedside”

Recent clinical studies show that pulmonary veins (PVs) are important foci of atrial tachyarrhythmias. Autonomic nervous system was known to play a role in the genesis of atrial tachyarrhythmias. The present experiments aimed to investigate the actions of autonomic agents in dog PVs and to explore the arrhythmogenic activity in these tissues. Transmembrane action potentials were recorded with the conventional microelectrode techniques and tension was detected by a transducer. In PV driven electrically, isoproterenol (Isop, 1μM) increased while ACh (1-10μM) depressed twitch force but elevated resting tension. In PV active spontaneously, Isop increased the automatic rate and induced high frequency irregular rhythms while ACh suppressed them. The actions of Isop and ACh were antagonized by propranolol and atropine, respectively. Quite often a single microelectrode impalement recorded 2 and more types of action potentials with wide range of durations (APD), indicating presence of multiple cells with different electrophysiological properties and electrical uncoupling of neighboring cells in PV strips. Activation of β-adrenoceptor stimulated while cholinergic agonist suppressed spontaneous action potentials or high frequency irregular rhythms in PV.

The Potency (ED50) and Cardiovascular Effects of Rapacuronium (Org 9487) During Narcotic-Nitrous Oxide-Propofol Anesthesia in Neonates, Infants, and Children

We studied the neuromuscular blocking effects of rapacuronium (Org 9487) (dose-response curve, onset, and 50% effective dose [ED50] value), and changes in heart rate and blood pressure, as well as evidence of histamine release in neonates, infants, and children in an open-label, randomized, two-center study. Fifteen neonates, 30 infants, and 30 children were studied. Anesthesia was induced and maintained with propofol, nitrous oxide:oxygen (60:40), and fentanyl. Mechanomyographic monitoring of neuromuscular function was performed at the thumb. The potency (ED50) for neonates, infants, and children were 0.32 (95% confidence interval [CI] 0.15–0.61), 0.28 (95% CI 0.11–0.61), and 0.39 (95% CI 0.17–0.85) mg/kg, respectively. Neonates who received 0.3, 0.6, or 0.9 mg/kg Org 9487 developed a maximum T1 twitch depression of 34 ± 28%, 98 ± 3%, and 99 ± 2%, respectively. Time-to-peak effect (onset time) for 0.9 mg/kg Org 9487 was 57 ± 20 s. Maximum percent T1 twitch depression (±SD) in infants who received 0.3, 0.6, or 0.9 mg/kg rapacuronium was 41 ± 34%, 96 ± 7%, and 100 ± 1%, respectively. Time-to-peak effect for 0.9 mg/kg Org 9487 was 62 ± 29 s. In children 0.3, 0.6, and 0.9 mg/kg rapacuronium resulted in an average percent T1 twitch suppression of 29 ± 23, 83 ± 11, and 90 ± 16, respectively. Time-to-peak effect of 0.9 mg/kg Org 9487 was 96 ± 33 s, respectively. There was no evidence of histamine release or significant changes in heart rate or blood pressure in either group at any dose. Rapacuronium is a low-potency nondepolarizing muscle relaxant with a fast onset of relaxation and minimal cardiovascular effects. Its potency (ED50) is similar in neonates (0.32 mg/kg), infants (0.28 mg/kg), and children (0.39 mg/kg). T1 suppression (90% ± 16) is less and time to peak effect (96 ± 33 s) is greater (0.9 mg/kg rapacuronium) in children, compared with the combined group of infants and neonates. Implications This study assesses the potency of rapacuronium (Org 9487) in pediatric patients. The potency of rapacuronium is similar in neonates (0.32 mg/kg), infants (0.28 mg/kg), and children (0.39 mg/kg).

The Potency (ED50) and Cardiovascular Effects of Rapacuronium (Org 9487) During Narcotic-Nitrous Oxide-Propofol Anesthesia in Neonates, Infants, and Children

We studied the neuromuscular blocking effects of rapacuronium (Org 9487) (dose-response curve, onset, and 50% effective dose [ED50] value), and changes in heart rate and blood pressure, as well as evidence of histamine release in neonates, infants, and children in an open-label, randomized, two-center study. Fifteen neonates, 30 infants, and 30 children were studied. Anesthesia was induced and maintained with propofol, nitrous oxide:oxygen (60:40), and fentanyl. Mechanomyographic monitoring of neuromuscular function was performed at the thumb. The potency (ED50) for neonates, infants, and children were 0.32 (95% confidence interval [CI] 0.15-0.61), 0.28 (95% CI 0.11-0.61), and 0.39 (95% CI 0.17-0.85) mg/kg, respectively. Neonates who received 0.3, 0.6, or 0.9 mg/kg Org 9487 developed a maximum T1 twitch depression of 34 +/-28%, 98 +/- 3%, and 99 +/- 2%, respectively. Time-to-peak effect (onset time) for 0.9 mg/kg Org 9487 was 57 +/- 20 s. Maximum percent T1 twitch depression (+/-SD) in infants who received 0.3, 0.6, or 0.9 mg/kg rapacuronium was 41 +/- 34%, 96 +/- 7%, and 100 +/- 1%, respectively. Time-to-peak effect for 0.9 mg/kg Org 9487 was 62 +/- 29 s. In children 0.3, 0.6, and 0.9 mg/kg rapacuronium resulted in an average percent T1 twitch suppression of 29 +/- 23, 83 +/- 11, and 90 +/- 16, respectively. Time-to-peak effect of 0.9 mg/kg Org 9487 was 96 +/- 33 s, respectively. There was no evidence of histamine release or significant changes in heart rate or blood pressure in either group at any dose. Rapacuronium is a low-potency nondepolarizing muscle relaxant with a fast onset of relaxation and minimal cardiovascular effects. Its potency (ED50) is similar in neonates (0.32 mg/kg), infants (0.28 mg/kg), and children (0.39 mg/kg). T1 suppression (90% +/- 16) is less and time to peak effect (96 +/- 33 s) is greater (0.9 mg/kg rapacuronium) in children, compared with the combined group of infants and neonates. This study assesses the potency of rapacuronium (Org 9487) in pediatric patients. The potency of rapacuronium is similar in neonates (0.32 mg/kg), infants (0.28 mg/kg), and children (0.39 mg/kg).

Molar Potency is Not Predictive of the Speed of Onset of Atracurium

In an effort to determine the extent to which atracurium may represent an exception to the rule that molar potency predicts onset time, we studied the onset profile of atracurium after a dose selected to produce approximately 95% twitch depression. We compared these results with data obtained in a previous study after the administration of vecuronium, rocuronium, and cisatracurium. Eighteen ASA physical status I and II patients were studied. After the induction of anesthesia, tracheal intubation was accomplished without relaxants. The evoked electromyographic response to 0.10-Hz single stimuli was continuously recorded. After baseline stabilization, a single bolus of atracurium, averaging 0.21 mg/kg, was administered. If peak twitch depression did not fall within the range of 90%–98%, the patient was excluded. The time to 50% and 90% of peak effect was recorded. The time to 90% of maximal effect (192 ± 23 s) was not different from that previously observed for vecuronium (201 ± 20 s). The time to 50% of peak effect (110 ± 15 s) was shorter (P< 0.05) after atracurium administration than after vecuronium (125 ± 9 s). The onset times recorded for atracurium were slower than previously observed after rocuronium and more rapid than that which was seen after cisatracurium (P< 0.001). The observed onset profile of atracurium was considerably slower than anticipated, based on the drug’s molar potency. The 95% effective dose (μM/kg) may not be a reliable predictor of a muscle relaxant’s onset time, when the drug administered is a mixture isomers of varying potency. Implications The speed of onset of atracurium is slower than predicted, based on its molar potency. Potency of a relaxant may not be a reliable predictor of its time to peak effect, when the drug administered is a mixture of isomers with widely different neuromuscular activities.

Influences of age and gender on dose response and time course of effect of atracurium in anesthetized adult patients

Study Objective: To determine the influences of age and gender on the dose response and the time course of effect of atracurium. Design: Prospective, nonrandomized, clinical comparison. Setting: Operating room, Plastic Surgery Hospital of the Chinese Academy of Medical Sciences and Peking Union Medical College. Patients: 72 adult ASA physical status I patients (38 male and 34 female), aged 15 to 59 years, scheduled for elective plastic surgery. Interventions: Patients were divided into the three groups on the basis of age: Group 1, patients aged 15–29 years (n = 32); Group 2, patients aged 30–40 years (n = 21); and Group 3, patients aged 41–59 years (n = 19). Anesthesia was maintained with 60% nitrous oxide in oxygen, thiopental, and incremental doses of fentanyl as required. The dose-response relationship of atracurium was determined by a cumulative dose-response technique. Measurements and Main Results: Neuromuscular function was assessed mechanomyographically with train-of-four stimulation at the wrist every 12 seconds and the percentage depression of first twitch (T 1) response was used as the study variable. Age and gender significantly affected the dose-response relationship and time course of recovery of atracurium. Advancing age was associated with a reduced effective doses (ED 50, ED 90, and ED 95) of atracurium and a longer duration of action. The effective doses of atracurium were greater, and its duration of action was shorter in men than in women. There were significant differences in the 50%, 90%, and 95% effective dose (ED 50, ED 90, and ED 95) of atracurium, and clinical duration and total duration following administration of atracurium 400 μg/kg among the three age groups, and between men and women. Conclusions: Age and gender have significant effects on the dose response and time course of effect of atracurium. Older patients and women are more sensitive to atracurium-induced neuromuscular block than are young patients and men.

Rabbits treated with chronic isepamicin are resistant to mivacurium and rocuronium.

We compared the dose-response relationships and the neuromuscular blocking effects of mivacurium and rocuronium after chronic isepamicin therapy for 7 days in 56 anesthetized rabbits. Train-of-four stimuli were applied every 10 s to the common peroneal nerve, and the force of contraction of the tibialis anterior muscle was measured. Chronic isepamicin therapy is associated with a rightward shift of the mivacurium and rocuronium dose-response curves. The effective dose for 50% twitch depression of mivacurium and rocuronium increased significantly, from 16.9 +/- 4.8 and 56.5 +/- 5.3 microg/kg, respectively, with placebo to 30.6 +/- 5.3 and 75.6 +/- 4.7 microg/kg, respectively, during isepamicin therapy. The isepamicin rabbits receiving mivacurium 0.18 mg/kg or rocuronium 0.6 mg/kg had an accelerated recovery from neuromuscular blockade compared with those receiving placebo. The results of this study show that mivacurium and rocuronium have both a decreased effect and a shorter duration of action in rabbits when used during concurrent isepamicin therapy. We studied the dose-response relationships and the neuromuscular blocking effects of mivacurium and rocuronium during chronic isepamicin therapy in rabbits. Mivacurium and rocuronium have both a decreased effect and a shorter duration of action during chronic aminoglycoside antibiotic therapy in rabbits.