Is time to peak effect of neuromuscular blocking agents dependent on dose? Testing the concept of buffered diffusion.

BACKGROUND AND OBJECTIVES: For neuromuscular blocking agents, an inverse relationship between potency and time to peak effect has been observed. To test the hypothesis that this relationship is due to buffered diffusion, we investigated the influence of dose on time to peak effect. Pharmacokinetic-pharmacodynamic simulations were performed to support the expected relationships between potency, dose, peak effect and time to peak effect. METHODS: Pigs (20-28 kg body weight) were anaesthetized with ketamine and midazolam, followed by pentobarbital and fentanyl intravenously. Neuromuscular block was measured by stimulating the peroneal nerve supramaximally at 0.1 Hz and measuring the response of the tibialis anterior muscle mechanomyographically. After an initial dose to establish the individual ED90 of a neuromuscular blocking agent (rocuronium, vecuronium, pipecuronium or d-tubocurarine), five different doses of the same compound were administered to each animal, aiming at 20%, 40%, 60%, 75% or 90% block, in a random order. Doses were given 45 min after complete recovery of the twitch response. RESULTS: For rocuronium and pipecuronium, time to peak effect increased with dose, whereas dose did not affect time to peak effect of vecuronium and d-tubocurarine. Simulations predict that time to peak effect decreases with dose if buffered diffusion is taken into account. CONCLUSIONS: The results suggest that buffered diffusion does not play a dominant role in the time to peak effect of neuromuscular blocking agents. Therefore it is unlikely that the observed inverse relationship between potency and time to peak effect of neuromuscular blocking agents in the clinical range is due to buffered diffusion.

Quantifying allodynia in patients suffering from unilateral neuropathic pain using von frey monofilaments.

OBJECTIVES: The aim of this study is to investigate whether quantitative sensory testing with Von Frey monofilaments (VFMs) can be used for the quantification of allodynia in patients with chronic neuropathic pain, and how the pain threshold of affected skin differs from healthy skin. METHODS: Using VFMs, we aimed to determine the pain threshold in 22 patients suffering from allodynia as a consequence of a chronic unilateral neuropathic pain syndrome. We performed quantitative sensory testing according to the Method of Limits protocol. We used the patient's own contralateral side and 5 healthy control participants to obtain reference values. RESULTS: On the affected side, we found in 20 out of 22 patients that the pain threshold could be determined with the monofilaments. On average, these 20 patients indicated pain upon the application of monofilament with logarithmic nr. 4.56, whereas no pain threshold could be determined on the contralateral, unaffected side, and in the healthy control participants for any monofilament. DISCUSSION: We showed that although etiology and pathophysiology of allodynia vary individually, with VFMs the clinical symptom allodynia can be quantified in a simple and practical fashion in almost all patients.

A temporary decrease in twitch response during reversal of rocuronium-induced muscle relaxation with a small dose of sugammadex.

BACKGROUND: We present a case in which a temporary decrease in train-of-four (TOF) response was observed after reversal of muscle relaxation with a small dose (0.5 mg/kg) of sugammadex administered 42 min after 0.9 mg/kg of rocuronium. At the end of the operation, the TOF ratio was >0.9, and the patient woke normally, without signs of muscle weakness. We describe this temporary decrease in muscle response during muscle relaxation reversal as muscle relaxation rebound and hypothesize that it occurs when the dose of sugammadex is sufficient for complex formation with rocuronium in the central compartment, but insufficient for redistribution of rocuronium from peripheral to central compartments. METHODS: To investigate our hypothesis, we developed and fit a simple pharmacokinetic- pharmacodynamic model of rocuronium, sugammadex, and their interaction to the patient TOF response data. RESULTS: Simulations using the fitted model indicate that muscle relaxation rebound can occur for doses of sugammadex in a limited critical range. CONCLUSIONS: Sufficiently large doses of sugammadex eliminate the possibility for muscle relaxation rebound, which does not require dissociation of the sugammadex/ rocuronium complex.

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

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

Pharmacokinetics and neuromuscular blocking effects of atracurium besylate and two of its metabolites in patients with normal and impaired renal function.

The pharmacokinetics of atracurium, laudanosine and the quaternary alcohol were studied in patients with normal and impaired renal function following intravenous administration of atracurium. Anaesthesia consisted of thiopental, fentanyl, halothane and nitrous oxide in oxygen. Plasma and urine concentrations of the parent compound and its degradation products were measured by high performance liquid chromatography. Renal failure was defined as a creatinine clearance of less than 5 ml/min; it caused no significant differences in the pharmacokinetics of atracurium but did result in a different pharmacokinetic profile of laudanosine, with a 3-fold increase in the mean ( +/- SD) terminal half-life (176 +/- 84 and 516 +/- 262 minutes for patients with normal and impaired renal function, respectively). Moreover, the half-life of the quaternary alcohol increased from 27.1 +/- 8.3 minutes in patients with normal renal function to 42.5 +/- 8.3 minutes in those with impaired renal function (mean +/- SD). Renal elimination of unchanged atracurium accounted for 11% of the administered dose and at least 27% of the total degradation of atracurium occurred via ester hydrolysis. The neuromuscular function was monitored by measuring the twitch tension of the adductor pollicis muscle elicited by stimulation of the ulnar nerve at 0.1 Hz. The total duration of neuromuscular blockade (51.8 +/- 11.5 minutes) and the recovery index (9.6 +/- 2.0 minutes) are shortened in patients with impaired renal function, compared with those with normal renal function (64.1 +/- 7.2 and 16.7 +/- 4.1 minutes, respectively), indicating that sensitivity to the neuromuscular blocking action of atracurium may be altered by renal failure.

Clinical pharmacokinetics of neuromuscular blocking drugs.

Neuromuscular blocking agents provide muscle relaxation for a great variety of surgical procedures with light planes of general anaesthesia. Besides having a significant impact in the development of anaesthesia and surgery, these agents continue to play an important role as pharmacological tools in the elucidation of the physiological and pharmacological regulation of neuromuscular transmission and the morphofunctional organisation of the neuromuscular junction. In the daily practice of anaesthesia, muscle relaxants are considered to be safe drugs with predictable, straightforward pharmacological actions. However, the use of relaxants constitutes a deliberate encroachment on respiration, one of the most important physiological mechanisms. The pharmacokinetic behaviour of this class of agents is little influenced by age or anaesthetic agents; however, hepatic or renal disease may profoundly alter their excretion pattern, resulting in prolonged duration of neuromuscular blockade. Biotransformation plays an important role in the total elimination of recently introduced compounds. Consequently, knowledge of the disposition pharmacokinetics, excretion and biotransformation of this class of drugs is indispensable for their rational choice for various surgical procedures. In this review, the known pharmacokinetics of standard compounds (introduced before 1980) are briefly summarised and new information generated by the development of vecuronium, rocuronium, pipecuronium (steroidal agents) and atracurium, mivacurium, doxacurium (benzylisoquinolinium esters) is discussed in more detail.

Pharmacokinetics of pancuronium in patients undergoing coronary artery surgery with and without low dose dopamine.

Pancuronium is frequently used in coronary artery surgery, but its pharmacokinetics in these patients are still unknown. It is possible that dopamine, administered to prevent renal impairment induced by the surgery, might promote the elimination of pancuronium. Therefore, the pharmacokinetics of a bolus dose of pancuronium were studied in 2 groups of coronary artery surgery patients, with and without dopamine 2 micrograms/kg/min, administered during and after cardiopulmonary bypass. Dopamine in the administered dose did not influence the systemic haemodynamics. The pharmacokinetic variables in both groups did not differ from those found in an earlier study in healthy normothermic patients. Total renal clearance was not influenced by dopamine, due to post-bypass rebound hyperperfusion in the control group. Pancuronium was shown to be subject to considerable tubular reabsorption, and its elimination was found to be increased during hypothermia. Dopamine increases pancuronium elimination by an increase in glomerular filtration rate. The dopamine-induced decrease in tubular solute reabsorption did not enhance the elimination of pancuronium.

Different homing pattern of isolated mouse lymphoma cells correlates with a different chromosomal pattern.

After 5-20 weeks of in vitro culture of mouse lymphoma cells, a characteristic and reproducible change in cell morphology, clonogenic ability, and homing pattern after intraperitoneal or intravenous injection was observed. Cytogenetic comparison of the two cell populations present before and after the "switch" revealed that the phenotypic changes cannot be due to in vitro karyotype evolution because their chromosomal pattern differed in such a way that it is impossible that they can evolve from each other. It was concluded that two different cell populations are present in the lymphoma and their growth and behavior are influenced by certain circumstances and/or interactions. Apparently one population predominates in the peripheral blood circulation, whereas the other will predominate after prolonged in vitro culturing.

The isolated heart-lung preparation in the cat. An in situ model to study the role of the lungs in the disposition of drugs.

In the search for drugs with an extreme short time course of action, compounds should be developed that are rapidly distributed to and temporarily stored in well-perfused organs. Since the lungs receive the complete cardiac output and have the ability to temporarily store drugs, we have developed an in situ, isolated lung preparation in the cat to study the contribution of the lungs to the disposition of drugs. The cat's own heart perfuses the lung in situ with autologous blood. The circulation between the left ventricle and the right atrium is short-circuited via an aorta-caval shunt. The right forelimb is added to study pharmacodynamics simultaneously (only for muscle relaxants). Validation of the model for 180 min of perfusion showed complete isolation of the organs without major biochemical changes or edema and a stable muscle response. In pilot experiments with two structurally related muscle relaxants, initial muscle relaxation was followed by spontaneous recovery of neuromuscular function and a gradually decreasing plasma concentration, indicating partial disposition by the lungs. This was confirmed by direct concentration measurements in the lung. The present model may provide a powerful experimental tool to elucidate the role of the lungs in the disposition of drugs.

Prevention of hypotension after induction of anesthesia after preoperative tune-up. A preliminary report of the Groningen Tune-up Study.

OBJECTIVE: To investigate whether the frequently occurring hypotension after induction of anesthesia can be prevented by preoperative treatment at the ICU guided by hemodynamic data obtained from a pulmonary artery (PA) catheter. DESIGN: Prospective controlled open randomized single center study. SETTING: University tertiary referral hospital. PATIENTS: Thirty-one patients undergoing major vascular- or abdominal surgery. INTERVENTIONS: Patients were randomized to either the control group or the ICU group. Patients allocated for the ICU group were admitted to the ICU the day before the operation and treatment was started aimed at a CI > or = 4.0 l/min/m2. No special treatment was given to the control group the day before the operation. Anesthesia was induced with etomidate, rocuronium and sufentanil. MEASUREMENTS AND MAIN RESULTS: Seventeen patients were allocated for the control group and 14 for the ICU-group. Mean ages were 65 +/- 2.5 and 66 +/- 2.5 years, respectively. Both groups were comparable regarding age, sex, blood pressure and type of operation. Filling pressures at admission on the ICU were: central venous pressure 3 +/- 2 mm Hg and pulmonary capillary wedge pressure 8 +/- 3 mm Hg while CI was 3.2 +/- 0.8 l/min/m2. The hemodynamic goal was achieved in all 14 patients of the ICU-group preoperatively with a background infusion of three l/24 h crystalloids, after a mean infusion of 1623 +/- 552 ml colloids, and in seven patients a median dose of 3 micrograms/kg/min (range 2-6) dopamine. Blood pressure before induction was comparable in both groups. The fall in systolic BP 10 min after induction of anesthesia was 22 +/- 18 in the ICU-group versus 41 +/- 17 mm Hg in the control group (p = 0.004). The fall in diastolic BP was 11 +/- 6 mm Hg in the ICU group versus 25 +/- 11 mm Hg in the control group (p = 0.0003). No differences between the groups in changes of heart rate were observed: a decrease of 13 +/- 7 bpm (95% confidence intervals 8.5 to 17.0) in the ICU group versus 15 +/- 14 (95% confidence intervals 7.6 to 21.9) bpm in the control group (p = 0.6). CONCLUSIONS: Hypotension after induction of anesthesia is significantly attenuated by preoperative treatment aiming at a CI > or = 4.0 l/min/m2 in high risk patients planned for major vascular- or abdominal surgery.

Clinical pharmacology of rocuronium (Org 9426): study of the time course of action, dose requirement, reversibility, and pharmacokinetics.

STUDY OBJECTIVE: To evaluate the time course of action, dose requirement, reversibility, and pharmacokinetics of rocuronium (Org 9426) under 3 anesthetic techniques (nitrous oxide-fentanyl supplemented with propofol, halothane, or isoflurane). DESIGN: Prospective, randomized study. SETTING: Operating suite at a university hospital. PATIENTS: 36 ASA physical status I-III patients aged 18 to 65 years who were scheduled for elective surgery. INTERVENTIONS: The time course of action of an intubation dose of rocuronium 600 micrograms/kg was investigated in 36 patients. In 18 of these patients, the maintenance dose requirement of rocuronium and reversibility by neostigmine were evaluated. In the remaining 18 patients, the pharmacokinetics of rocuronium after the intubating dose were studied. Neuromuscular transmission was monitored by mechanomyography. Venous blood samples and urine were analyzed by high-performance liquid chromatography. MEASUREMENTS AND MAIN RESULTS: With the exception of a longer clinical duration of rocuronium-induced neuromuscular block in the isoflurane group compared with the propofol group (p = 0.03), time course of action variables were similar in the 3 groups. In patients receiving maintenance doses of rocuronium, the dose requirement until reversal was 636 +/- 191 micrograms/kg/hr, 496 +/- 107 micrograms/kg/hr, and 384 +/- 127 micrograms/kg/hr for the propofol, halothane, and isoflurane groups, respectively (p = 0.02 for the isoflurane group vs. the propofol group). With respect to the reversal of a rocuronium-induced neuromuscular block, there were no differences in the percentage recovery or rate of recovery among the 3 groups. Pharmacokinetic analysis showed no significant differences for rocuronium during the 3 anesthetic techniques. CONCLUSION: Isoflurane potentiates the rocuronium-induced neuromuscular block, resulting in a longer clinical duration and lower maintenance dose requirement. This difference is not explained by differences in pharmacokinetics but is probably due to increased sensitivity of the neuromuscular junction to rocuronium during isoflurane anesthesia.

Innervator NS 252, a new, constant current and programmable peripheral nerve stimulator.

A peripheral nerve stimulator should be able to deliver a constant current to provide supramaximal nerve stimulation even under conditions of increasing resistance. We tested a new programmable peripheral nerve stimulator, the Innervator NS 252. It was able to maintain a constant current of 80 mA up to a resistance of 3.9 kohm. The pulse appearance was correct and there were only small variations in stimulation time intervals. The different type of double burst stimulation and the lack of synchronization with the previously applied stimulus pattern may be regarded as slight disadvantages.

[Headache following laparotomy; chronic subdural haematoma following epidural anaesthesia]. / Hoofdpijn na een laparotomie: een chronisch subduraal hematoom na epidurale anesthesie.

A 63-year-old man underwent an exploratory laparotomy because of rectal carcinoma. The operation was performed under general anaesthesia in combination with epidural anaesthesia. Since the operation the patient complained of a headache. Eight weeks after the operation he was hospitalized because of worsening of the headache and also drowsiness. A physical examination showed a slight tendency to incline to the left. A CT scan showed a subdural haematoma, which was relieved with surgery. We suspected that accidental puncture of the dura caused the haematoma. The incidence, causes, symptoms, diagnosis and treatment of this rare complication are discussed.

Assessment of the clinical relevance of quantitative sensory testing with Von Frey monofilaments in patients with allodynia and neuropathic pain. A pilot study.

BACKGROUND: Allodynia is a common and disabling symptom in many patients with neuropathic pain. Whereas quantification of pain mostly depends on subjective pain reports, allodynia can also be measured objectively with quantitative sensory testing. In this pilot study, we investigated the clinical relevance of quantitative sensory testing with Von Frey monofilaments in patients with allodynia as a consequence of a neuropathic pain syndrome, by means of correlating subjective pain scores with pain thresholds obtained with quantitative sensory testing. METHODS: During a 4-week trial, we administered a cannabis extract to 17 patients with allodynia. We quantified the severity of the allodynia with Von Frey monofilaments before, during and after the patients finished the trial. We also asked the patients to rate their pain on a numeric rating scale at these three moments. RESULTS: We found that most of the effect of the cannabis occurred in the last 2 weeks of the trial. In this phase, we observed that the pain thresholds, as measured with Von Frey monofilaments, were inversely correlated with a decrease of the perceived pain intensity. CONCLUSION: These preliminary findings indicate clinical relevance of quantitative sensory testing with Von Frey monofilaments in the quantification of allodynia in patients with neuropathic pain, although confirmation of our data is still required in further studies to position this method of quantitative sensory testing as a valuable tool, for example, in the evaluation of therapeutic interventions for neuropathic pain.

Simultaneous versus sequential pharmacokinetic-pharmacodynamic population analysis using an iterative two-stage Bayesian technique.

A method for simultaneous pharmacokinetic-pharmacodynamic (PK-PD) population analysis using an Iterative Two-Stage Bayesian (ITSB) algorithm was developed. The method was evaluated using clinical data and Monte Carlo simulations. Data from a clinical study with rocuronium in nine anesthetized patients and data generated by Monte Carlo simulation using a similar study design were analysed by sequential PK-PD analysis, PD analysis with nonparametric PK data and simultaneous PK-PD analysis. Both PK and PD data sets were 'rich' with respect to the number of measurements per individual. The accuracy and precision of the estimated population parameters were evaluated by comparing their mean error (ME) and root mean squared error (RMSE), respectively. The influence of PD model misspecification on the results was also investigated. The simultaneous PK-PD analysis resulted in slightly more precise population parameter estimates than the sequential PK-PD analysis and the nonparametric PK method. In the presence of PD model misspecification, however, simultaneous analysis resulted in poor PK parameter estimates, while sequential PK-PD analysis performed well. In conclusion, ITSB is a valuable technique for PK-PD population analysis of rich data sets. The sequential PK-PD method is better suited for the analysis of rich data than the simultaneous analysis.

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.

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.

Evaluation of a closed-loop muscle relaxation control system.

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