Hermann Mellinghoff

Mivacurium: Dose-Response Relationship and Administration by Repeated Injection or Infusion

The dose-response relationship and neuromuscular blockade after infusion or repeated injection of mivacurium were studied in 65 patients in nitrous oxide-narcotic anesthesia. The ED95 (twitch tension) was determined in 45 patients by intravenous injection of a single bolus of 30, 39, 47, 54, or 60 μg/kg (9 patients per dose). Another 20 patients received an initial bolus of 2 × ED95 followed either by an infusion started at 5% twitch recovery (i.e., 95% depression) and adjusted to sustain 95% twitch depression (n = 10) or by repeated injection of 0.6 × ED95 whenever twitch tension had recovered to 25% of control (n = 10). Five patients in each of these two groups received 7 μg/kg of neostigmine at 25% twitch recovery, and the others recovered twitch tension spontaneously. The mean ED95 was 73 μg/kg. A 2 × ED95 bolus was followed by complete twitch depression within 2.2 ± 0.7 min. The mean infusion rate resulted in 6 ± 2 μg · kg−1 ± min−1. The ensuing recovery index was 6 ± 3 min. A 6 ± 2 min recovery index was found after up to 10 repeat injections given every 9 ± 3 min. There was no significant effect of neostigmine in both groups. In conclusion, the recovery indices after the infusion or repeat injection of near-equal doses of mivacurium were identical.

A comparison of cisatracurium and atracurium : Onset of neuromuscular block after bolus injection and recovery after subsequent infusion

Cisatracurium is a new nondepolarizing muscle relaxant.In patients randomized to receive either cisatracurium (n = 40) or atracurium (n = 20) we compared the time course of neuromuscular block. The initial bolus dose of cisatracurium was 0.1 mg/kg, that of atracurium 0.5 mg/kg. Neuromuscular block, maintained with an infusion of either drug, was reversed with neostigmine 45 micro g/kg and atropine 20 micro g/kg in one half of the patients. Neuromuscular transmission was assessed by recording the mechanical twitch response to train-of-four nerve stimulation. Onset times were 3.1 +/- 1.0 min with cisatracurium and 2.3 +/- 1.1 min with atracurium (P = 0.008). The infusion rates for a 95% +/- 4% neuromuscular block were 1.5 +/- 0.4 micro g [centered dot] kg-1 [centered dot] min-1 for cisatracurium and 6.6 +/- 1.7 micro g [centered dot] kg-1 [centered dot] min-1 for atracurium, 3.3 times those of cisatracurium when referenced to the active cations. After the infusion, the spontaneous recovery intervals 25%-75% of 18 +/- 11 min and 18 +/- 8 min for cisatracurium and atracurium (P = 0.896) were shortened to 5 +/- 2 min and 4 +/- 3 min (P = 0.921) after neostigmine. While attributing different onset times also to differences in the initial doses, we conclude that time profiles for neuromuscular block of both muscle relaxants, when given in equipotent doses, are not different. (Anesth Analg 1996;83:1072-5)

Clinical efficacy of controlled-release oxycodone 20 mg administered on a 12-h dosing schedule on the management of postoperative pain after breast surgery for cancer.

SUMMARY Objective: To assess clinical efficacy of controlled-release oxycodone (CRO) 20 mg on a 12-h dosing schedule in this prospective, randomised, placebo-controlled, double-blinded study of 40 ASA physical status I-III women undergoing breast surgery for cancer. Research design and methods: General anaesthesia using remifentanil and propofol was performed for surgery. Both groups received premedication with oral midazolam 7.5 mg 1 h before surgery. In the controlled-release oxycodone group, one tablet of 20 mg CRO was administered with the premedication, and 12 h after the premedication another 20 mg CRO. In the placebo (PL) group, a placebo tablet was administered with the premedication, and 12 h later another placebo tablet. All patients had access to opioid rescue medication via an IV patient-controlled analgesia (PCA) device. Main outcome measures: Area under the curve (AUC), based on IV opioid rescue consumption over 24 h postoperatively. Results: The AUC for IV PCA opioid consumption was significantly lower in the CRO group than in the PL group (p = 0.01). The CRO group required less IV opioid loading dose (p < 0.001), and consumed less opioid rescue medication 4h (p = 0.036), 16h (p = 0.01), and 24 h (p = 0.005) postoperatively. AUC for VAS scores at rest was significantly lower in the CRO group than in the PL group (p = 0.05). VAS scores at rest were lower in the CRO group 16 h (p = 0.04) and 24h (p = 0.03) postoperatively. There was no difference in AUC for pain scores on movement (p = 0.103) and for quality of analgesia (p = 0.139). There was no difference in nausea between groups (p = 0.34). Pruritus, arterial hypotension or hypertension, bradycardia, and tachycardia were not observed in either treatment group. None of the patients showed signs of confusion, agitation, or respiratory depression. Conclusion: The administration of CRO 20 mg on a 12-h dosing schedule halves postoperative IV PCA opioid consumption. CRO 20mg is effective in preventing pain after breast surgery for cancer with only mild side-effects.

Mivacurium for Muscle Relaxation in a Child with Duchenne's Muscular Dystrophy

In a 5-yr-old boy with Duchenne’s muscular dystrophy (DMD), the repeated administration of mivacurium 0.13 mg/kg was associated with a normal dose-response relationship and time from end of injection to twitch recovery to 25% of control (DUR25%) and a twofold normal recovery index (time from 25% to 75% recovery). There was no difference between electromyogram (EMG) and mechanical twitch tension recording. Thus, the characteristics of mivacurium neuromuscular block in patients with DMD may be more favorable than those of atracurium and vecuronium previously reported in the literature. In patients with Duchenne’s muscular dystrophy (DMD), after atracurium and vecuronium, the recovery from neuromuscular block is 3‐6 times longer than that in healthy individuals (1,2). Similar results in patients with dystrophia myotonica led to the recommendation to use the shortest acting nondepolarizing muscle relaxant available (3). Mivacurium is the shortest acting nondepolarizing muscle relaxant in current clinical use. There has been no account in the literature of its use in patients with DMD. We describe a patient with DMD in whom mivacurium was used for muscle relaxation monitored by simultaneous recording of the evoked twitch tension and the evoked compound EMG.

Atracurium and vecuronium : repeated bolus injection versus infusion

The purpose of this study was to compare the characteristics of recovery from neuromuscular blockade after either atracurium or vecuronium given by intravenous infusion or by repeated injection. Four groups of 10 patients each were studied during nitrous oxide narcotic anesthesia. An initial intravenous dose of 2 × ED95 of either muscle relaxant was followed by an intravenous infusion started at 5% recovery of control twitch tension and adjusted for 95% block or by repeated injection of 0.6 × ED95 administered whenever twitch tension had returned to 25% of control. There were no significant differences between the maintenance doses required based on method of administration: atracurium repeated injection, 1.6 ± 0.3 × ED95 h−1; atracurium infusion, 1.7 ± 0.3 × ED95 h−1; vecuronium repeated injection, 1.8 ± 0.5 × ED95 h−1; and vecuronium infusion, 1.6 ± 0.4 × ED95 h−1. Nevertheless, differences of up to 20 min were noted in the recovery indices in the following order: atracurium repeated injection = atracurium infusion < vecuronium repeated injection < vecuronium infusion. A single dose of neostigmine (7 μg/kg) significantly reduced the recovery indices, thereby eliminating their differences.

Muskelrelaxanzien Neue Substanzen und neuromuskuläres Monitoring

ZusammenfassungEinführung: In einer Übersicht werden die aktuellen Entwicklungen in der Messung der neuromuskulären Blockade sowie die neuen Muskelrelaxanzien dargestellt. Muskelrelaxanzien: Von den seit 1995/96 in Deutschland neu zugelassenen Muskelrelaxanzien Rocuronium, Cisatracurium und Mivacurium, bietet Rocuronium die kürzeste Anschlagszeit bei ansonsten gleichem neuromuskulär blockierenden Wirkprofil wie Vecuronium. Die 2fache ED95 führt innerhalb von 60 bis 90 s zu guten bis sehr guten Intubationsbedingungen. Cisatracurium ist eines der zehn Isomere von Atracurium mit etwa der fünffachen neuromuskulär blockierenden Potenz. Unter Bewahrung der atracuriumtypischen mittellangen Wirkdauer und der Metabolisierung durch den Hofmann-Abbau, zeichnet sich Cisatracurium durch eine sehr viel geringere unspezifische Histaminfreisetzung aus. Mivacurium ist ein kurzwirkendes Benzylisochinolin-Muskelrelaxans, das einer raschen enzymatischen Inaktivierung durch die Plasmacholinesterase unterliegt. Es füllt die pharmakodynamische Lücke zwischen Succinylcholin und den mittellang wirkenden Muskelrelaxanzien, ohne jedoch den kurzen Wirkungseintritt von Rocuronium oder Succinylcholin zu erreichen. Nachteilig sind die mögliche Histaminfreisetzung und die Wirkungsverlängerung bei verminderter bzw. atypischer Plasmacholinesterase.AbstractIntroduction: Recent developments in both the quantitative evaluation of neuromuscular blockade and new muscle relaxants are reviewed. With respect to nerve stimulation, neuromuscular recording, and definition of parameters, the results of the 1994 Copenhagen International Consensus Conference are highlighted. Future clinical studies should adhere to these standards. Muscle relaxants: Rocuronium, cisatracurium, and mivacurium are new muscle relaxants that were released for clinical use in 1995/1996. Of these, rocuronium has the shortest time of onset, whereas its recovery characteristics closely resemble those of vecuronium. Rocuronium is five times less potent than vecuronium. Twice the ED95 of rocuronium provides good or excellent intubating conditions within 60 to 90 s. Slight vagolytic effects were reported following injection of 0.6 mg/kg rocuronium, while histamine release was not observed. Cisatracurium is one of the ten steroisomers of atracurium. It is five times as potent as the chiral mixture while having a similar pharmacodynamic and -kinetic profile. Up to eight times the ED95 did not cause significant histamine release or clinically relevant cardiovascular effects. Mivacurium is a short-acting nondepolarizing benzylisoquinoline muscle relaxant that undergoes rapid breakdown by plasma cholinesterase (PChE). Its duration of action is about one-half as long as that of equipotent doses of atracurium and vecuronium and three times as long as succinylcholine. Mivacurium has a moderate histamine-releasing potential. In patients with atypical or reduced PChE activity, the duration of action of mivacurium is prolonged.

Muscle relaxants. New substances and neuromuscular monitoring

ZusammenfassungEinführung: In einer Übersicht werden die aktuellen Entwicklungen in der Messung der neuromuskulären Blockade sowie die neuen Muskelrelaxanzien dargestellt. Muskelrelaxanzien: Von den seit 1995/96 in Deutschland neu zugelassenen Muskelrelaxanzien Rocuronium, Cisatracurium und Mivacurium, bietet Rocuronium die kürzeste Anschlagszeit bei ansonsten gleichem neuromuskulär blockierenden Wirkprofil wie Vecuronium. Die 2fache ED95 führt innerhalb von 60 bis 90 s zu guten bis sehr guten Intubationsbedingungen. Cisatracurium ist eines der zehn Isomere von Atracurium mit etwa der fünffachen neuromuskulär blockierenden Potenz. Unter Bewahrung der atracuriumtypischen mittellangen Wirkdauer und der Metabolisierung durch den Hofmann-Abbau, zeichnet sich Cisatracurium durch eine sehr viel geringere unspezifische Histaminfreisetzung aus. Mivacurium ist ein kurzwirkendes Benzylisochinolin-Muskelrelaxans, das einer raschen enzymatischen Inaktivierung durch die Plasmacholinesterase unterliegt. Es füllt die pharmakodynamische Lücke zwischen Succinylcholin und den mittellang wirkenden Muskelrelaxanzien, ohne jedoch den kurzen Wirkungseintritt von Rocuronium oder Succinylcholin zu erreichen. Nachteilig sind die mögliche Histaminfreisetzung und die Wirkungsverlängerung bei verminderter bzw. atypischer Plasmacholinesterase.AbstractIntroduction: Recent developments in both the quantitative evaluation of neuromuscular blockade and new muscle relaxants are reviewed. With respect to nerve stimulation, neuromuscular recording, and definition of parameters, the results of the 1994 Copenhagen International Consensus Conference are highlighted. Future clinical studies should adhere to these standards. Muscle relaxants: Rocuronium, cisatracurium, and mivacurium are new muscle relaxants that were released for clinical use in 1995/1996. Of these, rocuronium has the shortest time of onset, whereas its recovery characteristics closely resemble those of vecuronium. Rocuronium is five times less potent than vecuronium. Twice the ED95 of rocuronium provides good or excellent intubating conditions within 60 to 90 s. Slight vagolytic effects were reported following injection of 0.6 mg/kg rocuronium, while histamine release was not observed. Cisatracurium is one of the ten steroisomers of atracurium. It is five times as potent as the chiral mixture while having a similar pharmacodynamic and -kinetic profile. Up to eight times the ED95 did not cause significant histamine release or clinically relevant cardiovascular effects. Mivacurium is a short-acting nondepolarizing benzylisoquinoline muscle relaxant that undergoes rapid breakdown by plasma cholinesterase (PChE). Its duration of action is about one-half as long as that of equipotent doses of atracurium and vecuronium and three times as long as succinylcholine. Mivacurium has a moderate histamine-releasing potential. In patients with atypical or reduced PChE activity, the duration of action of mivacurium is prolonged.

The pharmacodynamics of cisatracurium in healthy adults

Cisatracurium is an intermediate-duration, non-depolarizing neuromuscular-blocking agent, the purified form of one of the 10 stereoisomers of atracurium which is cleared primarily by Hofmann elimination. It produces minimal cardiovascular changes and does not release histamine even at up to eight times the dose that produced 95% of the maximum response (ED95) for neuromuscular block. At twice the ED95, the pharmacodynamic profile of cisatracurium is similar to that of an equipotent dose of atracurium apart from a slightly slower onset of action. A more rapid onset is produced when the dose is increased. The clinically effective duration of action, as assessed by the twitch response of the adductor policis muscle to a train of four stimulations, increases with increasing doses; however, doubling the dose only adds approximately 23 min to the duration of clinically effective block. The clinically effective duration of action ranges from 45 min after twice the ED95 (0.1 mg/kg) to approximately 90 min after eight times the ED95 (0.4 mg/kg). Neuromuscular block can be maintained with incremental or repeat bolus doses or continuous infusions of cisatracurium without any cumulative neuromuscular-blocking effect. Neuromuscular block induced with cisatracurium can be readily reversed using anticholinesterase agents. Cisatracurium has a predictable and rapid rate of spontaneous recovery (5-95% recovery about 30 min) irrespective of the initial dose administered or the duration of maintenance dosing.

Variability of pipecuronium neuromuscular blockade

The dose‐response relationship and the variability of the time variables in pipecuronium neuromuscular blockade were studied in 29 patients (ASA physical status 3) during halothane anaesthesia. The ED95 (twitch tension) was determined in 9 patients using the cumulative dose response technique. Another 20 patients received the resulting ED95 as a single bolus. The mean ED95 was 35 μg‐kg‐1 (95% confidence interval: 29–41 μg.kg‐1). Following bolus injection of 1. ED95, an 80–100% twitch depression was achieved within 4.6±1.3 min (mean ± s.d.). The duration from end of injection of pipecuronium to 25% twitch recovery, the time from 25% to 75% twitch recovery, and the time from 25% twitch recovery to the train‐of‐four ratio (TOF) returning to 0.7 was 35 ± 14, 37 ± 26, and 63 ± 27 min, respectively. The time from end of injection to TOF = 0.7 varied within a 2‐h range (54–160 min). Thus, the time variables in pipecuronium neuromuscular blockade were as poorly predictable as those reported in the literature on pancuronium, alcuronium and doxacurium.

Lactated Ringer’s Solution versus Hydroxyethyl Starch for Volume Replacement in Autologous Blood Donors with Cardiovascular Disease: A Controlled, Randomized Trial

Background and Objectives: The study was designed to evaluate whether volume replacement following blood donation can prevent arterial hypotension in autologous blood donors with cardiovascular disease. Materials and Methods: One hundred nineteen autologous blood donors with known cardiovascular disease were randomly allocated to receive, following withdrawal of 500 ml of blood, either no infusion (control group) or a 25 ml/min intravenous infusion of either 1,500 ml of lactated Ringer’s solution (LRS) or 500 ml of 6% hydroxyethyl starch (HES). Starting before phlebotomy, arterial blood pressure was measured oscillometrically every 5 min until 90 min after donation. Results: Group means showed little difference between the groups in blood pressure throughout the monitoring period. The proportion of patients who at least once had a ≥ 20% decrease from baseline in systolic blood pressure was 3–5 times greater in the control group than in the LRS and the HES group (50 vs. 10 and 15%, respectively; p < 0.001 on χ2 analysis for a 2 × 3 table). Systolic hypertensive episodes (≥ 20% increase over baseline) were observed more frequently in the LRS group than in the control and the HES group (41 vs. 10 and 18%, respectively; p = 0.003). Conclusion: Both LRS and HES, administered at a volume ratio to blood loss of 3:1 and 1:1, respectively, significantly reduced the incidence of systolic hypotensive episodes in autologous blood donors with cardiovascular disease. LRS at a 3:1 volume ratio to blood loss was associated with a high rate of systolic hypertension.