Pharmacokinetic-pharmacodynamic modeling of rocuronium in case of a decreased number of acetylcholine receptors: a study in myasthenic pigs

BACKGROUND: In myasthenic patients, the sensitivity for nondepolarizing relaxants is increased and the time course of effect is prolonged due to a reduced number of functional acetylcholine receptors at the neuromuscular junction. The authors investigated both the performance of the link model proposed by Sheiner and a pharmacodynamic-pharmacokinetic model taking into account the number of unbound acetylcholine receptors in myasthenic pigs. METHODS: After obtaining the approval of the Animal Experiments Committee of their institution, the authors studied eight myasthenic pigs and eight control pigs. Myasthenia gravis was induced by injecting Torpedo acetylcholine receptors in weeks 1 and 4. On the day of the experiments, the pigs were anesthetized and intubated, and the appropriate muscles and nerves were prepared for the measurements. Rocuronium was administered by infusion to reach 90% twitch height block. Arterial blood was sampled during onset and offset of effect, and the plasma concentration of rocuronium was measured with high-performance liquid chromatography. Plasma concentration-time effect data were analyzed using two different pharmacokinetic-pharmacodynamic models, the link model according to Sheiner and a pharmacokinetic-pharmacodynamic model taking into account the unbound receptor concentration. Muscles were removed after the experiment for laboratory analysis of the acetylcholine receptor concentration. RESULTS: All eight pigs of the myasthenic group developed clinical signs of myasthenia gravis (muscle weakness) and showed increased sensitivity toward rocuronium. Pharmacokinetic modeling revealed no significant differences between myasthenic and control pigs. In pharmacokinetic-pharmacodynamic analysis, visual inspection as well as the Akaike Information Criterion (3,605 3,769) and the residual SD (3.2 3.6%) revealed a better fit for the unbound receptor model in myasthenic animals compared to the Sheiner model. Pharmacokinetic-pharmacodynamic analysis with the unbound receptor model demonstrated a decreased EC50 of 0.27 micro m (ranging from 0.17 to 0.59 micro m) compared to 2.71 micro m (ranging from 2.42 to 4.43 micro m) in control animals. The results of the Sheiner pharmacokinetic-pharmacodynamic analysis were in the same range. Both the laboratory analysis and pharmacokinetic-pharmacodynamic modeling showed a decrease in receptor concentration of more than 75%. CONCLUSION: Both the Sheiner model and the unbound receptor model may be used to fit plasma concentration-effect data of rocuronium in pigs. The unbound receptor concentration model, however, can explain the observed differences in the time course of effect, based on receptor concentration.     

Pharmacokinetic-Pharmacodynamic Modeling of Rocuronium in Case of a Decreased Number of Acetylcholine Receptors: A Study in Myasthenic Pigs

Background: In myasthenic patients, the sensitivity for nondepolarizing relaxants is increased and the time course of effect is prolonged due to a reduced number of functional acetylcholine receptors at the neuromuscular junction. The authors investigated both the performance of the link model proposed by Sheiner and a pharmacodynamic-pharmacokinetic model taking into account the number of unbound acetylcholine receptors in myasthenic pigs.

Methods: After obtaining the approval of the Animal Experiments Committee of their institution, the authors studied eight myasthenic pigs and eight control pigs. Myasthenia gravis was induced by injecting Torpedo acetylcholine receptors in weeks 1 and 4. On the day of the experiments, the pigs were anesthetized and intubated, and the appropriate muscles and nerves were prepared for the measurements. Rocuronium was administered by infusion to reach 90% twitch height block. Arterial blood was sampled during onset and offset of effect, and the plasma concentration of rocuronium was measured with high-performance liquid chromatography. Plasma concentration-time effect data were analyzed using two different pharmacokinetic-pharmacodynamic models, the link model according to Sheiner and a pharmacokinetic-pharmacodynamic model taking into account the unbound receptor concentration. Muscles were removed after the experiment for laboratory analysis of the acetylcholine receptor concentration.

Results: All eight pigs of the myasthenic group developed clinical signs of myasthenia gravis (muscle weakness) and showed increased sensitivity toward rocuronium. Pharmacokinetic modeling revealed no significant differences between myasthenic and control pigs. In pharmacokinetic-pharmacodynamic analysis, visual inspection as well as the Akaike Information Criterion (3,605 vs. 3,769) and the residual SD (3.2 vs. 3.6%) revealed a better fit for the unbound receptor model in myasthenic animals compared to the Sheiner model. Pharmacokinetic-pharmacodynamic analysis with the unbound receptor model demonstrated a decreased EC50 of 0.27 [mu]m (ranging from 0.17 to 0.59 [mu]m) compared to 2.71 [mu]m (ranging from 2.42 to 4.43 [mu]m) in control animals. The results of the Sheiner pharmacokinetic-pharmacodynamic analysis were in the same range. Both the laboratory analysis and pharmacokinetic-pharmacodynamic modeling showed a decrease in receptor concentration of more than 75%.     

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Neuromuscular effects of isoflurane in patients with myasthenia gravis

Seventeen myasthenia gravis and seven control patients were studied mechano (MMG)- and electromyographically (EMG) during isoflurane/oxygen/air anaesthesia. In myasthenic patients the mean train-of-four ratio and neuromuscular block (by MMG) during 1.9 MAC isoflurane anaesthesia were 55 +/- 9% and 46 +/- 12%, respectively. The correlation between simultaneous MMG and EMG measurements was excellent (r2 = 0.933, P less than 0.001). The occurrence of HLA-B8 together with acetylcholine receptor antibodies seems to predispose myasthenic patients to a neuromuscular depression produced by isoflurane. Our current and prior results show that isoflurane possesses approximately twice as strong a neuromuscular blocking effect as halothane in myasthenic patients.     

Decreased number of acetylcholine receptors is the mechanism that alters the time course of muscle relaxants in myasthenia gravis: a study in a rat model

BACKGROUND: In myasthenic patients, the time course of action of non-depolarizing neuromuscular blocking agents is prolonged and the sensitivity is increased. We used our antegrade perfused rat peroneal nerve anterior tibialis muscle model to investigate if this altered time course of effect and sensitivity can be explained by the decreased acetylcholine receptor concentration that is caused by the disease. METHODS: Functional acetylcholine receptors were reduced by administration of alpha-bungarotoxin or by injecting monoclonal antibodies against rat acetylcholine receptors (experimental autoimmune myasthenia gravis). After induction of anaesthesia, the model was set up and perfusion of the tibialis anterior muscle with blood was started. After stabilization of the twitch, rocuronium or pancuronium were infused until 90% block was obtained. Twitch data and infusion data were recorded and used to calculate the time course of effect and potency. RESULTS: The potency of neuromuscular blocking agents was increased and the offset of the neuromuscular block was prolonged in both the alpha-bungarotoxin groups and the experimental autoimmune myasthenia gravis groups compared to controls. CONCLUSION: This study shows that the increased sensitivity to neuromuscular-blocking agents in myasthenia gravis can be accounted for by a decreased number of acetylcholine receptors. It also shows that the antegrade perfused rat peroneal nerve anterior tibialis muscle model is a suitable model to study the effects of myasthenia gravis on the time course of effect of neuromuscular blocking agents.     

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.     

Randomized, multicenter study of interaction between Org 9426 (rocuronium bromide) and anesthetic agents in Japanese population

BACKGROUND: The purpose of this randomized, multi-center phase III trial was to investigate the influence of sevoflurane and propofol on the neuromuscular blocking effects and pharmacokinetic parameters of Org 9426 (rocuronium bromide) in Japanese population. METHODS: Thirty-nine adult Japanese patients participated in this randomized, multi-center study. Neuromuscular function was monitored continuously with TOF-Watch SX (Organon NV, Netherlands) after anesthetic induction with propofol. These subjects randomly received either 0.6 mg x kg(-1) or 0.9 mg x kg(-1) of rocuronium for endotracheal intubation. These two groups were further divided to two anesthetic regiments : sevoflurane group and propofol group. The difference in onset and recovery of rocuronium-induced neuromuscular block was statistically analyzed with two-way ANOVA. RESULTS: Mean duration for maximal block was 76 seconds and 66 seconds, respectively. The duration between Org 9426 administration and 25% recovery of first twitch response was significantly prolonged in patients given 0.9 mg x kg(-1) of Org 9426. Sevoflurane also significantly increased this duration. However, the serum concentration of Org 9426 was not statistically different between the four study groups. CONCLUSIONS: The duration of Org 9426-induced neuromuscular blockade was significantly increased under sevoflurane anesthesia compared to propofol anesthesia. This difference may be attributed to pharmacodynamic change.     

Effective reversal of muscle relaxation by rocuronium using sugammadex in a patient with myasthenia gravis undergoing laparoscopic cholecystectomy

As myasthenia gravis affects neuromuscular transmission, these patients show various responses to neuromuscular blocking drugs. We report a successful use of the sugammadex in a myasthenic patient to reverse rocuronium-induced neuromuscular block. A 69-year-old woman was scheduled for laparoscopic cholecystectomy and total of rocuronium 20 mg was administered. After spontaneous recovery of T1, we administered sugammadex 200mg intravenously, reversing neuromuscular blockade to a train-of-four ratio (T4/T1) of 100% within 30 sec. Sugammadex can be used to reverse rocuronium-induced neuromuscular blockade in patients with myasthenia gravis, thereby avoiding the need for reversal with acetylcholinesterase inhibitors.     

Systemic inflammation leads to resistance to atracurium without increasing membrane expression of acetylcholine receptors

BACKGROUND: Systemic inflammation may be associated with resistance to nondepolarizing neuromuscular blocking drugs, the mechanisms of which are, however, uncharacterized. The authors therefore investigated the pharmacodynamics of atracurium and its relation to the expression of nicotinic acetylcholine receptors and alpha1 -acid glycoprotein in a rat model of systemic inflammation. METHODS: To induce a systemic inflammation, male CD rats received 56 mg/kg corynebacterium parvum intravenously. On days 2, 4, 6, 8, 10, 12, 14, or 16 after infection, neuromuscular transmission was measured. The individual effective dose of atracurium was determined, followed by an atracurium infusion at a rate to establish a steady state neuromuscular block of 50%. Total and unbound plasma concentrations of atracurium for 50% paralysis were measured using high-performance liquid chromatography. Acetylcholine receptors were quantitated using 125I-alpha-bungarotoxin. alpha1 -Acid glycoprotein concentrations in the serum were measured using a competitive chemiluminescence immunoassay. RESULTS: The effective dose of atracurium was increased on days 4, 6, and 8. Total atracurium plasma concentrations at 50% neuromuscular paralysis were increased on days 4, 6, 8, and 10, with a peak at day 8 (8.0 +/- 1.3 micro g/ml) compared with control rats (4.23 +/- 0.82 micro g/ml). The alpha1 -acid glycoprotein concentrations were increased between days 2 and 10, with a peak on day 4 (6.52 +/- 1.45 mg/ml), and recovered to control values (0.61 +/- 0.33 mg/ml) on day 12. Unbound plasma concentrations of atracurium to achieve 50% depression, as well as the expression of acetylcholine receptors, did not differ between groups. CONCLUSION: Resistance to atracurium during corynebacterium parvum-induced systemic inflammation is due to increased drug binding to alpha1 -acid glycoprotein and is unrelated to changes in acetylcholine receptor expression.     

Vecuronium dose-response and maintenance requirements in patients with myasthenia gravis

Eleven myasthenia gravis and seven control patients were studied during N2O/O2-fentanyl anesthesia to determine the ED50, ED95, and maintenance requirement of vecuronium using both mechanomyography and electromyography. The ED95 of vecuronium was 17 (range 8-34) micrograms/kg in patients with myasthenia gravis, and this was significantly related to patient's acetylcholine receptor antibody titer (r = -0.75, P less than 0.01). The average ED95 value was 250% greater in control than in myasthenic patients (P less than 0.01). The hourly requirement of vecuronium to maintain an 80-90% neuromuscular blockade was 38 +/- 10 micrograms/kg in myasthenic and 120 +/- 27 micrograms/kg in control patients (P less than 0.001). When these requirements were related to individual ED95 doses, they were comparable indicating similar time durations of effect of vecuronium following an equipotent dose in myasthenic and in control patients.     

The use of sugammadex in a patient with myasthenia gravis

Myasthenia gravis, affecting neuromuscular transmission, leads to a large variability in sensitivity to depolarising and non‐depolarising neuromuscular blocking drugs. We report the successful use of the modified μ‐cyclodextrin sugammadex in a myasthenic patient to reverse a rocuronium‐induced deep level of neuromuscular block. After spontaneous neuromuscular recovery of T2 (second twitch of the train‐of‐four series), we administered 2 mg.kg^?1 of sugammadex intravenously, reversing neuromuscular blockade to a train‐of‐four ratio (T4/T1) > 90% within 210 s. Sugammadex, in combination with objective neuromuscular monitoring, can be used to reverse rocuronium‐induced neuromuscular blockade in patients with myasthenia gravis, thereby avoiding the need for reversal with acetylcholinesterase inhibitors.     

Cisatracurium in a myasthénic patient undergoing thymectomy

PURPOSE: The report investigates cisatracurium neuromuscular block in a myasthenic patient undergoing thymectomy. CLINICAL FEATURES: A myasthenic patient (Osserman II B) was prepared preoperatively with 240 mg x day(-1) pyridostigmine. The neuromuscular block produced by 0.05 mg x kg(-1) cisatracurium was monitored by Datex electromyography. The electromyographic response was compared with that in a control group of five non-myasthenic patients. In the myasthenic patient, cisatracurium resulted in a rapid onset of complete (97-98%) neuromuscular block, while a slow onset of partial (80-90%) block was achieved in the control group. Also, administration of 0.05 mg x kg(-1) neostigmine at the end of surgery reversed the neuromuscular block of cisatracurium in the non-myasthenic patients, but did not change the rate of spontaneous recovery in the myasthenic patient. CONCLUSION: The myasthenic patient is sensitive to cisatracurium, as evidenced by a more rapid onset and more marked neuromuscular block compared with the control non-myasthenic patients. This may be attributed to the decreased number of functional endplate acetylcholine receptors in the myasthenic patient, with a consequent decrease of the safety margin of neuromuscular transmission. Also, in contrast with the control group, the rate of recovery from neuromuscular block in the myasthenic patient was not enhanced by neostigmine at the end of surgery. This may be attributed to the prior inhibition of acetylcholinesterase by the preoperative pyridostigmine, as well as by possible desensitization of the cholinergic receptors secondary to prolonged pyridostigmine therapy.     

Precurarization and priming: a theoretical analysis of safety and timing.

The priming principle suggests that the onset of neuromuscular block may be accelerated if an intubating dose is preceded by a priming dose administered a few minutes earlier. We thought it would be instructive to use a pharmacodynamic/pharmacokinetic model to estimate the risk associated with different priming doses and intervals. In any normal population, there is wide variability in the response to neuromuscular blocking drugs. For most relaxants, the coefficient of variation for the 50% effective dose (ED(50)) approximates 20%-25%. Thus, 1 patient in 50 (-2.05 SD) may have an ED(50) only half of the commonly cited value. By using published pharmacodynamic/pharmacokinetic data, we calculated the effect of administering 10%, 20%, or 30% of the ED(95) on the response of the adductor pollicis muscle in a population normally distributed with respect to drug sensitivity. A dose equivalent to 10% of the ED(95) will rarely produce a measurable neuromuscular effect. As this dose is increased, the potential for clinical weakness rapidly escalates. In 1 in 50 individuals, the usual recommendation of 10% of the intubation dose will produce measurable neuromuscular depression. For vecuronium, the optimal priming interval is 5 min. The safety and dependability of the priming principle is very much subject to the laws of probability. IMPLICATIONS: When using the priming principle to accelerate the onset of neuromuscular block, the initial dose should not exceed 10% the drug's ED(95). For drugs other than rocuronium, the optimal priming interval is not <5 min.     

The effect of environmental tobacco smoke on the dose requirements of rocuronium in children

BACKGROUND: Smoking affects the pharmacodynamic and pharmacokinetic behaviour of several drugs. The aim of this study was to evaluate the effects of environmental tobacco smoke on onset and recovery time after single dose rocuronium in children. METHODS: Forty children between 4 and 10 years were enrolled into the study. Children who have no familial smoking history were included in the first group whereas passive smokers included in the second group. Sevoflurane in 50% O2 and 50% N2O was used for induction of anaesthesia. Evoked adductor pollicis electromyography was used to monitor neuromuscular block. The T95 and T25 values were recorded. RESULTS: The T95 values (+/-sd) for rocuronium were 110.1 +/- 39.3 s and 79.3 +/- 35.6 s for group 1 and group 2, respectively (P < 0.05). The T25 value of group 2 was 40.1 +/- 10.6 min and compared with group 1 values (30.85 +/- 7.02 min) it was significantly longer (P < 0.01). CONCLUSION: This study shows that passive smoking children consume less rocuronium than nonsmokers during similar anaesthesia. We think that a history of passive smoking must also be taken into consideration during preoperative evaluation of paediatric patients.     

Early reversal of profound rocuronium-induced neuromuscular blockade by sugammadex in a randomized multicenter study: efficacy, safety, and pharmacokinetics

BACKGROUND: Sugammadex reverses the neuromuscular blocking effects of rocuronium by chemical encapsulation. The efficacy, safety, and pharmacokinetics of sugammadex for reversal of profound rocuronium-induced neuromuscular blockade were evaluated. METHODS: Ninety-eight male adult patients were randomly assigned to receive sugammadex (1, 2, 4, 6, or 8 mg/kg) or placebo at 3, 5, or 15 min after 0.6 mg/kg rocuronium. Patients were anesthetized with propofol and fentanyl. The primary endpoint of the study was the time to achieve a recovery of train-of-four ratio to 0.9. Neuromuscular blockade was measured using acceleromyography. Concentrations of rocuronium and sugammadex were determined in venous blood and urine samples. A population pharmacokinetic model using NONMEM (GloboMax LLC, Hanover, MD) was applied. RESULTS: The mean time to recovery of the train-of-four ratio to 0.9 after dosing at 3, 5, and 15 min decreased from 52.1, 51.7, and 35.6 min, respectively, after administration of placebo to 1.8, 1.5, and 1.4 min, respectively, after 8 mg/kg sugammadex. Sugammadex was safe and well tolerated. However, 20.4% of patients showed signs of inadequate anesthesia after its administration. The median cumulative excretion of rocuronium in the urine over 24 h was 26% in the placebo group and increased to 58-74% after 4-8 mg/kg sugammadex. The mean plasma clearances of sugammadex and rocuronium were 0.084 and 0.26 l/min, respectively. CONCLUSIONS: In male subjects, sugammadex safely reversed profound neuromuscular blockade induced by 0.6 mg/kg rocuronium in a dose-dependent manner. Sugammadex enhanced the renal excretion of rocuronium, and its clearance is approximately one third that of rocuronium.     

Pharmacokinetics and pharmacokinetic-dynamic modelling of rocuronium in infants and children

We have determined the pharmacokinetics and pharmacokinetic- pharmacodynamic relationship of rocuronium in infants and children. We studied infants (n = 5, 0.1-0.8 yr) and children (n = 5, 2.3-8 yr), ASA II, in the ICU while undergoing artificial ventilation under i.v. anaesthesia with an arterial cannula in situ and the EMG of the adductor pollicis muscle was monitored. Rocuronium 0.06 (infants) and 0.09 (children) mg kg-1 min-1 was given i.v. over +/- 5 min until 85% neuromuscular block was obtained. Arterial blood samples were obtained over 240 min. Plasma concentrations were measured by HPLC. Pharmacokinetic-dynamic variables were calculated using the Sheiner model and the Hill equation. Statistical analysis was performed using the Mann-Whitney U test (P < 0.05). The mean administered dose was 0.32 (SD 0.08) mg kg-1 and 0.4 (0.1) mg kg-1 for infants and children, respectively. Infants differed from children in plasma clearance (4.2 (0.4) vs 6.7 (1.1) ml min-1 kg-1), distribution volume at steady state (231 (32) vs 165 (44) ml kg-1), mean residence time (56 (10) vs 26 (9) min), concentration in the effect compartment at 50% block (1.2 (0.4) vs 1.7 (0.4) mg litre-1) and the slope of the concentration-effect relationship (5.7 (1.3) vs 3.9 (0.5)). Calculated mean ED90 values were 0.26 and 0.34 mg kg-1 for infants and children, respectively. The time course of neuromuscular block after equipotent doses did not differ.      

Acute Late Sepsis Attenuates Effects of a Nondepolarizing Neuromuscular Blocker, Rocuronium, by Facilitation of Endplate Potential and Enhancement of Membrane Excitability In Vitro

Background: Sepsis attenuates the muscle-relaxing effects of nondepolarizing neuromuscular blockers. The authors investigated the effects of acute late sepsis on neuromuscular transmission and neuromuscular actions of rocuronium to clarify the mechanisms by which sepsis attenuates the effects of nondepolarizing neuromuscular blockers.

Methods: Sepsis was induced by cecal ligation and puncture operation. Endplate potentials, acetylcholine potentials, and electrotonic potentials were recorded from the motor endplates of isolated diaphragms from acute late septic and nonseptic rats.

Results: (1) Sepsis did not influence the effect of rocuronium to decrease endplate potential amplitude, which was increased by sepsis itself; (2) sepsis facilitated the effect of rocuronium to decrease quantal acetylcholine release, which was increased by sepsis itself; (3) sepsis did not influence the effect of rocuronium to decrease acetylcholine sensitivity, which was decreased by sepsis itself; (4) sepsis decreased critical depolarization, and rocuronium did not influence critical depolarization.     

Bioavailability of Intramuscular Rocuronium in Infants and Children

Background: Intramuscular rocuronium, in doses of 1,000 micro gram/kg in infants and 1,800 micro gram/kg in children, produces complete twitch depression in 5-6 min. To determine the rate and extent of absorption of rocuronium after intramuscular administration, blood was sampled at various intervals after rocuronium administration by both intramuscular and intravenous routes to determine plasma concentrations (Cp) of rocuronium.

Methods: Twenty-nine pediatric patients ages 3 months to 5 yr were anesthetized with N2 O and halothane. The trachea was intubated, ventilation was controlled, and adductor pollicis twitch tension was measured. When anesthetic conditions were stable, rocuronium (1,000 micro gram/kg for infants and 1,800 micro gram/kg for children) was injected either intramuscularly (in the deltoid muscle) or intravenously. Four venous plasma samples were obtained from each child 2-240 min after rocuronium administration. A mixed-effects population pharmacokinetic analysis was applied to these values to determine bioavailability, absorption rate constant, and time to peak Cp with intramuscular administration.

Results: With intramuscular administration, rocuronium's bioavailability averaged 82.6% and its absorption rate constant was 0.105 min sup -1. Simulation indicated that Cp peaked 13 min after rocuronium was given intramuscularly, and that 30 min after intramuscular administration, less than 4% of the administered dose remained to be absorbed from the intramuscular depot.     

Target controlled infusion of rocuronium: analysis of effect data to select a pharmacokinetic model

Background. We aimed to evaluate whether area under the curve(AUC) analysis of pharmacodynamic data can be used to comparepharmacokinetic models taken from the literature, during a targetcontrolled infusion (TCI) of rocuronium. Methods. Seventy-two patients scheduled for orthopaedic surgeryreceived a TCI of rocuronium (Stanpump) based on one of fourpharmacokinetic models: those described by Szenohradszky, Alvarez-Gomez,Wierda, and Cooper. The resulting theoretical plasma concentrationversus time curve was calculated for all patients based on allfour pharmacokinetic models. Predicted effect versus time curveswere calculated following the pharmacokinetic–pharmacodynamiclink model (Sheiner and colleagues). Neuromuscular block wasevaluated acceleromyographically. The difference between thearea under the observed effect (AUC_OE) and predicted effect(AUC_PE) versus time curves was used for comparison. Results. AUC_PE differed significantly from AUC_OE in the Szenohradszkyand Alvarez-Gomez models, both with the reference link-pharmacodynamicdata and with altered link-pharmacodynamic variables. AUC_PEand AUC_OE were comparable for the Wierda and Cooper models.The mean AUC_OE was 25.1 (SD 11.9)% blockxh. AUC_PE–AUC_OEwas significantly larger in the Szenohradszky model when comparedwith all other pharmacokinetic models. This difference remainedwhen link or pharmacodynamic variables were modified. The smallestAUC_PE–AUC_OE difference was found with the Wierda model. Conclusion. It was possible to use AUC analysis for identificationof the pharmacokinetic model that best predicted the pharmacodynamiccharacteristics of our patients. Br J Anaesth 2003; 90: 183–8