Pharmacodynamics and pharmacokinetics of rocuronium in intensive care patients.

We have studied dose requirements, recovery times and pharmacokinetics of rocuronium in 32 intensive care patients. After an initial dose of 50 mg, rocuronium was administered as maintenance doses of 25 mg whenever two responses to train-of-four (TOF) stimulation reappeared (bolus group; n = 27) or by continuous infusion to maintain one response in the TOF (infusion group; n = 5). Median requirements for rocuronium were 27.4 (range 14.5-68.3) mg h-1 and 43.7 (30.9-50.3) mg h-1 in patients in the bolus and infusion groups, respectively. Median total duration of rocuronium administration was 29.0 (12.4-95.5) h and 63.4 (24.0-140.3) h, respectively. Median time from administration of the last bolus dose and end of infusion to recovery of the fourth twitch in the TOF was 100 (45-300) min and 60 (15-155) min, respectively. Arterial blood samples were obtained for up to 10 h after cessation of rocuronium administration, and concentrations of the parent compound and its putative metabolites were measured using high pressure liquid chromatography (HPLC). The plasma concentration profile (n = 12) was described adequately by a two-compartment model. Mean plasma clearance (Cl), steady-state distribution volume (Vss), mean residence time (MRT) and elimination half-life (T1/2 beta) were 3.16 (SD 1.15) ml kg-1 min-1, 769 (334) ml kg-1, 262 (120) min and 337 (163) min, respectively. Recovery times, Vss, MRT, and T1/2 beta differed from previously published data obtained after rocuronium infusion of moderate duration in surgical patients.

Clinical pharmacokinetics of rocuronium bromide.

A new aminosteroidal neuromuscular blocking agent, rocuronium bromide, has recently been introduced into clinical practice. Its main advantage over other currently used drugs of this kind is its fast onset of action, which could render rocuronium the muscle relaxant of choice for rapid facilitation of tracheal intubation. A further advantage of the new compound over vecuronium bromide is the less extensive formation of breakdown products, reducing the contribution of active metabolites to the neuromuscular blocking effects of the parent compound. Thorough knowledge of the pharmacokinetics of any new drug is highly desirable for the anaesthesiologist because absorption, distribution to the tissue, as well as elimination by biotransformation and excretion, are closely related to its effects. Due to its chemical relationship to other aminosteroidal neuromuscular blocking agents such as pancuronium bromide or vecuronium, rocuronium is expected to display pharmacokinetic behaviour similar to that of its predecessors. Hepatic and renal disease may prolong the effect of rocuronium, but to a lesser extent than seen with pancuronium or vecuronium, because the plasma clearance of rocuronium is not significantly influenced by dysfunction of the liver or kidneys. On the contrary, in elderly or hypothermic patients the reduction in plasma clearance results in a prolonged duration of the action of rocuronium. All information on the pharmacokinetics of this new nondepolarising neuromuscular blocking agent which has been made available to date is presented in this review, with a discussion of the significance of these data for clinical use of the drug.

The onset of pipecuronium following application of the priming principle.

Pipecuronium bromide, a long acting non-depolarizing neuromuscular blocking agent was administered to four groups of 10 patients using the priming technique. The effects of the combination of two different priming doses (0.01 or 0.015 mg kg-1) given at two different time intervals (3 or 4 min) before the 'main' intubating dose (0.07 or 0.065 mg kg-1) were investigated. Onset times were recorded and the intubation conditions were scored and compared with a group of patients receiving the same total amount of pipecuronium (0.08 mg kg-1) in a single bolus injection. Intubating conditions at 90 s after administration of the intubating dose were found to be significantly improved in all primed groups but the onset times, evaluated using the response of the adductor pollicis muscle to a single twitch stimulation, were similar to that observed after the single bolus injection. The optimal priming combination is considered to be 0.01 mg kg-1 of pipecuronium followed 3 to 4 min later by 0.07 mg kg-1.

Rocuronium bromide: time-course of action in underweight, normal weight, overweight and obese patients.

The duration of action and recovery of 0.6 mg kg-1 rocuronium in underweight, normal weight, overweight and obese patients were investigated. Forty-eight patients were divided into four groups, according to their body mass index, and were given 0.6 mg kg-1 rocuronium. The onset time, the duration 25% and either the spontaneous or induced recovery were measured according to the random assignment. The onset time in the obese group was shorter 60 (50-90) s compared to the other groups (underweight: 95 (40-320) s, normal: 95 (50-200) s, overweight: 90 (50-260) s, but the difference did not reach the level of statistical significance. The duration 25% was slightly prolonged in the obese patients (31.5 (21.0-61.0) min) when compared to the underweight (25.0 (15.0-37.0) min), normal weight (26.0 (20.0-36.0) min) and overweight (27.0 (19.0-35.0) min) patients. No differences were observed in spontaneous (9.5-12.5 min) and induced (2.5-3.5 min) recovery.

Rocuronium bromide in the ICU: dose finding and pharmacokinetics.

Thirty patients requiring elective ventilation in the ICU received either intermittent boluses (25 patients) or a continuous infusion (five patients) of rocuronium. Degree of block was monitored by train-of-four stimuli and maintained at one twitch either observed or palpated. All patients were sedated with intermittent doses or an infusion of 0.14-0.4 microgram kg-1 h-1 of midazolam and received a continuous infusion of either sufentanil or fentanyl (0.25-2.0 micrograms kg-1 h-1). Control of ventilation was better with the continuous infusion of rocuronium, but these patients also had a more intense block receiving 9.9 +/- 1.3 micrograms kg-1 min-1 as compared to 6.4 +/- 2.3 micrograms kg-1 min-1 in the bolus group. Elimination half-time, volume of distribution at steady-state, and mean residence time were significantly greater than in surgical patients receiving comparable infusions, but plasma clearance was similar.

Long-term administration of pancuronium and pipecuronium in the intensive care unit.

This study was performed to determine the optimum dose of pancuronium (n = 30) and pipecuronium (n = 30) under continuous sedation and analgesia in the intensive care unit (ICU). This was an open clinical investigation in 60 critically ill patients with head injury, multiple trauma (in some complicated with sepsis and multi-organ failure), requiring neuromuscular block for ventilation for at least 48 h. Emphasis was placed on the neuromuscular monitoring with a peripheral nerve stimulator and adequate sedation and analgesia. Satisfactory block was achieved in all cases with an average dose of 3 mg/h with either compound. None of the patients experienced prolonged paralysis, muscle weakness, or other neuromuscular dysfunctions in the postventilatory period. We suggest that adequate use of sedative hypnotics and opioids plus neuromuscular monitoring allowed us to optimize the dose of muscle relaxants according to the need of individual patients.

Pharmacodynamics and pharmacokinetics of rocuronium following continuous infusion in patients during intravenous anaesthesia.

After an initial bolus dose (0.6 mg kg-1), 10 patients received a continuous infusion of rocuronium, initially at 0.5 mg kg-1h-1, and then adjusted to maintain 90% twitch depression. Blood samples were analysed for 420 min after switching off the infusion. The dose required to maintain the block was 595 +/- 146 micrograms kg-1h-1, 7-9 times that reported for vecuronium under similar conditions. The pharmacokinetic parameters (volume of distribution at steady state, 309 +/- 80 ml kg-1, plasma clearance 4.5 +/- 1.96 ml kg-1 min-1, and elimination half-life 107 +/- 37 min) were similar to those previously reported after a large single bolus.

[Rocuronium, the "ideal" nondepolarizing muscle relaxant?]. / Rocuronium, das "ideale" nicht depolarisierende Muskelrelaxans?

Rocuronium bromide (Org 9426) is a new, non-depolarising steroidal muscle relaxant that is currently undergoing extensive clinical trials worldwide. Since it is expected to be introduced into clinical practice in the near future, the purpose of this review is to give a summary of the currently available information on this promising new compound. The search for the so-called ideal muscle relaxant [34] in the last years was focused on a non-depolarising compound that could replace succinylcholine for rapid intubation. The currently most frequently used agents vecuronium and atracurium have an onset of action that usually does not allow intubation earlier than 3 min after its injection. Recent animal [40] and human [10] studies have shown that development of neuromuscular blockade of the vocal cords and laryngeal muscles can be faster than that of the peripheral skeletal muscles. This would mean that intubation can be performed before complete relaxation of the adductor muscle of the thumb is achieved. Rocuronium is the 2-morpholino, 16 N-allyl-pyrrolidino derivative of the 3-hydroxy metabolite of vecuronium. In initial clinical studies [13, 42] its most impressive features appeared to be rapid onset time and, more importantly, the rapid development of good intubating conditions. Thirty to 90 s after the injection of 0.6 mg/kg (2 x ED90), rocuronium provided intubating conditions that were equal to those observed after succinylcholine [9, 17, 31, 38]. Although the onset time of rocuronium at the adductor pollicis muscle is slower than that of succinylcholine, intubation with this compound can be performed faster than with any other non-depolarising agent.(ABSTRACT TRUNCATED AT 250 WORDS)

The use of rocuronium (ORG 9426) in patients with chronic renal failure.

The pharmacodynamics of an initial dose of 0.6 mg.kg-1 rocuronium followed by three maintenance doses of 0.15 mg.kg-1 were studied during nitrous oxide/oxygen/isoflurane anaesthesia in patients with normal renal function (n = 12) and chronic renal failure (n = 12). The mean (SD) duration (min) of block after the initial dose was 28.0 (5.5) and 25.6 (11.7) respectively. The mean (SD) duration (min) of the effect of the three maintenance doses was 15.3 (4.0) and 14.2 (7.0); 17.3 (3.2) and 17.4 (8.7); 18.1 (2.8) and 19.1 (10.1) for the normal and renal failure patients respectively. The induced and spontaneous recovery indices were 3.7 (0.7) and 17.1 (6.9) in the normal group compared with 3.9 (0.5) and 19.0 (12.5) in the renal failure group and these values did not differ between the two groups. In this small study rocuronium appears to be suitable for patients with chronic renal failure. There is no evidence of prolonged block even when the drug is given in repeated doses for maintenance.

Evaluation of the time course of action of maintenance doses of rocuronium (ORG 9426) under halothane anaesthesia.

The time course of action of rocuronium was compared using three different sizes of maintenance doses after at least three subsequent administrations of the same repeat dose in each patients under halothane anaesthesia. Following endotracheal intubation facilitated with 0.6 mg.kg-1 rocuronium (ORG 9426), muscle relaxation was maintained in three groups each consisting of ten patients, using increments of equal repeat doses of either 75 micrograms.kg-1, 150 micrograms.kg-1 or 225 micrograms.kg-1 equivalent to 1/4, 1/2 and 3/4 of the ED95 of this new compound, respectively. Maintenance doses were administered when the twitch height depression induced by the previous dose returned to 25% of its control value. The clinical duration of the intubating dose averaged 27 +/- 7.5 min (mean +/- s.d.). The time course of action of the various maintenance doses depended on their size, but not on the number of administrations. The durations of repeat doses averaged 8-9 min, 14-16 min and 19-23 min after the low, medium and high maintenance doses, respectively. No overt cumulative effects were observed.

Antagonism of vecuronium by one of its metabolites in vitro.

The neuromuscular-blocking agent vecuronium bromide undergoes hydrolysis to three pharmacologically active metabolites (3-desacetyl, 17-desacetyl and 3,17-desacetyl vecuronium) which might modify the neuromuscular-blocking action of their parent compound. In order to elucidate the possible role of the interaction between vecuronium and its metabolites in the complications reported after long-term use of vecuronium in intensive care unit (ICU) patients, the relative potency of vecuronium, 3-desacetyl and 3,17-desacetyl vecuronium was determined in the rat hemidiaphragm in vitro and the mode of interaction of the above-mentioned compounds investigated. Dose-response relationships were established for each substance alone and for combinations of vecuronium with its metabolites. The relative potency at the EDmax50 levels (% maximal effect) were in the order of 1:1.2:27 for vecuronium, the 3-desacetyl derivative and the 3,17-desacetyl derivative, respectively. The mode of interaction characterized by isobolographic and algebraic (functional) analysis showed vecuronium and 3-desacetyl vecuronium to interact in an additive fashion while the combined effect of the parent compound and its 3,17-desacetyl derivative was less than additive, indicating antagonism.

Evaluation of the endotracheal intubating conditions of rocuronium (ORG 9426) and succinylcholine in outpatient surgery.

The time-course of action and tracheal intubating conditions of rocuronium and succinylcholine under intravenous anesthesia with propofol, alfentanil, and nitrous oxide were studied in 30 patients undergoing outpatient surgery. The neuromuscular effects of both drugs were quantified by recording the indirectly evoked twitch response of the adductor pollicis muscle after ulnar nerve stimulation (0.1 Hz, 0.2 ms supramaximal stimuli). Patients were given either 0.6 mg/kg rocuronium (n = 20) or 1 mg/kg succinylcholine (n = 10) intravenously. Sixty seconds after the administration of the muscle relaxant, the trachea was intubated and the intubating conditions were scored by a "blinded" assessor. Intubating conditions were not different (P = 0.34) between the rocuronium and succinylcholine groups. The onset and duration of neuromuscular blockade were shorter with succinylcholine than with rocuronium. The depression of the twitch response to 5% of control value occurred in 0.8 +/- 0.1 min with 1 mg/kg succinylcholine and 1.2 +/- 0.5 min with 0.6 mg/kg rocuronium (P less than 0.01). The recovery of the twitch response to 25%, 75%, and 90% of its control value was shorter after succinylcholine (P less than 0.001) and occurred at 8.1 +/- 2.6, 10.3 +/- 3.9, 11.3 +/- 4.6 and 25.3 +/- 5.0, 33.1 +/- 5.9, 36.1 +/- 6.3 min after succinylcholine and rocuronium, respectively. Also the time required for spontaneous recovery from 25% to 75% of the control twitch response was significantly shorter (P less than 0.001) after succinylcholine (2.2 +/- 1.4 min) than after rocuronium (7.8 +/- 2.1 min). It is concluded that in spite of the pharmacodynamic differences between succinylcholine and rocuronium, the intubating conditions after administration of both compounds are similar and develop at the same rate.

Interaction of ORG 9426 and some of the clinically used intravenous anaesthetic agents in the cat.

The interaction of ORG 9426, a new non-depolarizing neuromuscular blocking agent, with intravenous anaesthetic drugs (fentanyl, thiopental, midazolam, droperidol and etomidate) has been investigated in cats. During an infusion of one of the above anaesthetics, the ED95 dose was determined by titration, and thereafter muscle relaxation was maintained with four subsequent doses of ORG 9426. Neither the potency nor the duration of action of the first dose nor that of the maintenance doses of ORG 9426 differed from those observed in a control group of cats anaesthetized with intraperitoneally administered pentobarbital. The recovery rates were similar in all groups. The authors conclude that, under the conditions of this study, commonly used intravenous anaesthetic drugs are not likely to influence the neuromuscular blocking potency and time course of action of ORG 9426 to any appreciable degree.