Regelkreisgesteuerte Muskelrelaxation mit einem modifizierten Zweipunktregler mit Cisatracurium

ZusammenfassungFragestellung Eine konstante neuromuskuläre Blockade kann unter klinischen Bedingungen auch mit einfachen Regelungssystemen aufrechterhalten werden. Hierbei stellen der verzögerte Wirkungseintritt, die Nichtlinearität der Dosis-Wirkungs-Beziehung und die individuelle Empfindlichkeit des einzelnen Patienten gegenüber Muskelrelaxanzien limitierende Faktoren dar.Methodik Bei 20 Patienten, die sich elektiven chirurgischen Eingriffen unterziehen mussten, wurde unter kontinuierlicher Propofol-Alfentanil-Anästhesie zur Aufrecherhaltung eines elektromyographisch ermittelten 90%igen neuromuskulären Blocks (T₁=10%) unter Cisatracurium ein modifizierter Zweipunktregler (On-off-Regler) verwendet. Mit diesem von uns entwickelten computergestützten Messarbeitsplatz wurde der Verlauf der neuromuskulären Blockade registriert, und die zeitlichen Abläufe und Abweichungen vom angestrebten Blockadeniveau wurden ermittelt.Ergebnisse Die neuromuskuläre Blockade wurde durchschnittlich 64,2±14,0 min auf einem T₁-Niveau von 10% geregelt. Der mittlere Fehler als Abweichung des erreichten Blockadeniveaus vom Sollwert betrug durchschnittlich –1,6±0,9%. Zur Aufrechterhaltung wurden 1,4±0,9 µg*kg KG^–1*min^–1 Cisatracurium benötigt.Schlussfolgerungen Es kann festgestellt werden, dass ein einfaches Regelungssystem eine sichere Anwendung des mittellang wirksamen Muskelrelaxans Cisatracurium für die Durchführung chirurgischer Eingriffe ermöglicht.     

顺式阿曲库铵的临床应用

顺式阿曲库铵(cisatracurium,代号51W89,其苯磺酸盐的商品名为Nimbex),具有阿曲库铵相似的肌松效应和代谢方式,不释放组胺,对心血管影响轻微,已成为目前较理想肌松药,安全用于肝肾功能受损、严重心血管疾病、老人、小儿及ICU患者.     

顺式阿曲库铵实用性研究进展

本文对近年来顺式阿曲库铵在临床应用中，如加快起效时间、给药方式、在肝肾功能障碍病人、老年和儿科病人、用于心血管手术等5方面的研究进展进行综述。     

Die klinische Pharmakologie von Cisatracurium

Cisatracurium (51W89) is one of the ten stereoisomers of atracurium, accounting for about 15% of the racemate. The ED₉₅ of cisatracurium was determined to be about 50?μg/kg (cation, molecular weight 929), while the ED₉₅ of atracurium (besylate salt, molecular weight 1245) was 250?μg/kg. Thus, on a molar basis in adult patients, cisatracurium is about 3.5 times as potent as the racemic atracurium mixture. We compared atracurium with cisatracurium in healthy adult patients and found an almost identical pharmacodynamic profile. In children, an ED₉₅ of about 40?μg/kg was determined, while a 1-min-longer onset of cisatracurium was found in geriatric than in young adult patients. The presence of chronic renal failure did not prolong the duration of action of cisatracurium. The recovery of neuromuscular transmission from a cisatracurium infusion of up to 145?h was investigated in intensive care unit patients. Their time from the end of infusion to a train-of-four ratio >0.7 (68±18?min) was on average only some 70% longer than after an infusion of cisatracurium for 2?h in normal surgical patients. In another study, no signs of histamine release nor any clinically relevant cardiovascular effects of cisatracurium were found in doses up to eight times ED₉₅.     

Intubationsbedingungen nach Gabe von Atracurium und Vecuronium Bolusmethode vs. Primingtechnik

Prompted by the ongoing discussion of the pros and cons of using succinylcholine, this study was conducted to compare the responses to bolus injections of atracurium or vecuronium with those after sequential injection of these drugs (priming principle). We evaluated the earliest possible intubation times, intubating conditions, and the onset times (i.e. times from the end of injection to the maximum blockade) under conditions approaching real use as closely as possible. Methods. The randomized and double-blind study was carried out with 80 ASA risk class 1 and 2 patients. Approval of the institutional ethics committee was obtained, and each patient gave informed consent. Patients were randomly allocated to four study groups of 20 patients each. Isotonic saline was administered to those patients assigned to the atracurium or vecuronium bolus groups, whereas the patients assigned to the other two groups received a priming injection of either atracurium (0.05 mg/kg) or vecuronium (0.01 mg/kg). We observed the patients for signs of incipient muscular weakness before the induction of anaesthesia. Anaesthesia was induced with thiopental 3.5 min after the first injection (5 mg/kg and 50–100?mg before intubation). After a further 1 min during which adequate mask ventilatin with oxygen was assured, corresponding to a priming interval of 4.5?min, 0.5 mg/kg of atracurium or 0.1 mg/kg of vecuronium was administered to the patients in the bolus groups and 0.45 mg/kg of atracurium or 0.09 mg/kg of vecuronium as intubating doses to those in the priming groups. Intubation was attempted at 90, 120, 150 and 180?s thereafter. Intubating conditions were evaluated on the basis of laryngoscopy, vocal cord movement and coughing or bucking of the patients. Neuromuscular function was monitored via accelerometry at the adductor pollicis muscle (TOF stimulation of the ulnar nerve every 15?s). Results. The priming doses did not diminish the elicited twitches of the adductor pollicis muscle, but led to heavy eyelids and double vision in 35% of the atracurium patients and 47% of the vecuronium patients; these symptoms were well tolerated by the patients. At the time of intubation the adductor pollicis muscle was relaxed to approximately the same degree in all groups (mean±SD for the TOF ratios in the bolus groups was 0.46±0.37 for atracurium, 0.45±0.4 for vecuronium; in the priming groups 0.52±0.39 for atracurium, 0.53±0.36 for vecuronium). The administration of the relaxants in divided doses significantly shortened the intubating time after atracurium (100 vs 124?s) and improved the intubating conditions of vecuronium (good vs tolerable), but had no effect on the time course of the neuromuscular blockade (onset times in the bolus groups 224±84?s for atracurium and 209±64 s for vecuronium; in the priming groups 249±112?s for atracurium and 205±52 s for vecuronium). Conclusions. The priming technique presented here is clinically superior to the bolus method and therefore should be preferred in all elective cases and in those patients in whom succinylcholine is contraindicated.     

Cisatracurium and atracurium as antigens.

Seventy-five consecutive patients referred to an anaesthetic allergy clinic were intradermally tested with atracurium and cisatracurium. With the exception of one patient the results were identical, suggesting that allergy to either drug is associated with allergy to the stereoisomer. For skin testing for allergy to neuromuscular blocking drugs it is only necessary to use either atracurium or cisatracurium and cisatracurium is the preferred drug.     

Cisatracurium or rocuronium versus rocuronium-cisatracurium combination

The present report evaluates the incidence of pain on intravenous injection and the condition of tracheal intubation at one minute following the administration of cisatracurium or rocuronium versus rocuronium-cisatracurium combination. We studied 60 patients, ASA 1, aged 18-60 years, undergoing elective surgical procedures. The patients were randomly assigned to 3 groups who received intravenously either 0.15 mg/kg cisatracurium [2ED95], 0,6 mg rocuronium [2ED95] or a combination of 0.075 mg/kg cisatracurium [1ED95], plus 0.3 mg rocuronium [1ED95]. In the awake patients, the pain on injection of muscle relaxant was assessed on a four point scale (none, mild, moderate, severe). Administration of the relaxant was followed by 1-2 mg/kg of lidocaine and 2 mg/kg propofol. Orotracheal intubation was performed 60 seconds following the administration of the relaxant. The intubating conditions were assessed and rated as excellent, good, fair or poor. The administration of 2ED95 cisatracurium resulted in poor intubating conditions at 60s, without pain on injection. In contrast, the administration of 2ED95 rocuronium resulted in excellent or good intubating conditions at 60s associated with high incidence of pain on injection in most of the patients. However, the combination of 1ED95 cisatracurium with 1ED95 rocuronium provided similar intubating conditions to the 2ED95 rocuronium alone, associated with a significantly less pain on injection.     

Kardiovaskuläre Effekte nach Bolusapplikation von Cisatracurium

Cisatracurium – one of the ten stereoisomers of atracurium – is an intermediate long-acting non-depolarizing neuromuscular blocking agent. Cardiovascular reactions have been described after administration of cisatracurium or vecuronium in surgical patients. Methods. After approval by our institutional review board, 62 patients (ASA I–II) were randomly assigned to three groups to either receive 3×ED₉₅ or 5×ED₉₅ of cisatracurium or 3×ED₉₀ of vecuronium prior to intubation as a bolus. After oral premedication with 2?mg lormetazepam anaesthesia was induced with thiopental (4–12?mg/kg) and maintained with O₂/N₂O and isoflurane (1.5%–2%). Six minutes after administration of thiopental, patients received the muscle relaxant. Six minutes later 0.1–0.2?mg fentanyl was given and the trachea was intubated. Heart rate (HR) and blood pressure (BP) were monitored every minute. Changes of heart rate or blood pressure?>20% compared to baseline were defined as clinically significant. Results. After application of the study drug, median values of blood pressure and heart rate were stable. For each muscle relaxant, there were several patients who had statistically significant cardiovascular changes. After 3×ED₉₅ cisatracurium, 3 of 21 patients exhibited haemodynamic changes?>20% (2 exhibited hypotension and 1 tachycardia), while in the high-dose cisatracurium group 2 of 21 patients demonstrated a tachycardia that was predetermined to be statistically but not clinically significant. In the vecuronium group, 2 of 20 patients sustained statistically significant hypotension and 1 patient had statistically significant tachycardia. The frequency of all individual cardiovascular changes after the application of the muscle relaxant was not dose-dependent. Conclusion. After the administration of cisatracurium in two different doses (3×ED₉₅ and 5×ED₉₅) or vecuronium (3×ED₉₀) only minor cardiovascular changes were observed. Both drugs proved to be safe for use during induction of anaesthesia in patients ASA I–II. With regard to its cardiovascular effects, cisatracurium shares with vecuronium the requirements of an ideal muscle relaxant.     

Cisatracurium during halothane and balanced anaesthesia in children

Cisatracurium, 51W89, is one of the ten stereoisomers of Tracrium^® which, unlike atracurium, has been reported to have a lack of histamine mediated cardiovascular effects at doses as high as 8×ED₉₅ in adults. We compared the time-course of neuromuscular effects of 80 μg·kg⁻¹ or 100 μg·kg⁻¹ cisatracurium during N₂O-O₂-halothane or N₂O-O₂-opioid anaesthesia, respectively, in 32 children 2–12 years old. Neuromuscular function was monitored by evoked adductor pollicis EMG. Even-numbered patients ( n =16) were allowed to obtain full spontaneous recovery of neuromuscular function and odd-numbered patients ( n =16) received neostigmine 45 μg·kg⁻¹ together with glycopyrrolate at the time of 25% EMG recovery. Data are expressed as median with 10th to 90th percentile range. Cisatracurium had an onset time (time from administration to maximal effect) of 2.2 (1.7–3.8) or 2.3 (1.8–4.9) min, a clinical duration (time to 25% EMG recovery) of 34 (22–40) or 27 (24–33) min, and a spontaneous 25–75% recovery time (time from 25 to 75% EMG recovery) of 11 (9–13) or 11 (7–12) min during halothane or balanced anaesthesia, respectively (NS). Train-of-four ratio recovered to 0.70 in 2.5 (1.8–3.0) or 3.2 (2.1–4.3) min following neostigmine during halothane or balanced anaesthesia, respectively (NS). Changes in blood pressure or heart rate following cisatracurium were negligible. We regard cisatracurium as a safe and promising intermediate duration muscle relaxant the effects of which can easily be reversed with neostigmine.     

Cisatracurium pharmacodynamics in patients with oculopharyngeal muscular dystrophy

The pharmacodynamics of muscle relaxants in patients with oculopharyngeal muscular dystrophy (OPMD) have never been studied. We designed this study to compare the pharmacodynamics of cisatracurium in OPMD patients versus a control group. Forty patients were enrolled: 20 OPMD patients requiring general anesthesia for cricopharyngeal myotomy and 20 age-matched controls undergoing an operation of similar duration and expected blood loss. Anesthesia was standardized, and both groups received a bolus of cisatracurium 0.1 mg/kg. Onset time, time to 10% T1 recovery, and the intervals 10%-25% and 25%-75% were calculated for both groups. A subgroup analysis was performed in patients with a more severe form of OPMD. Demographic and intraoperative data were similar. Onset time was significantly longer in OPMD patients compared with the control group (4.6 +/- 1.5 min versus 3.4 +/- 1.0 min; P = 0.001). There was no difference in recovery times or indices between groups, regardless of the severity of the disease. In conclusion, there was no difference in the duration of a cisatracurium-induced neuromuscular block between OPMD patients and a control group. A delayed onset of action of the drug may occur.     

Pharmacodynamics and Pharmacokinetics of Cisatracurium in Geriatric Surgical Patients

Background: Cisatracurium, one of ten stereoisomers that comprise atracurium, is more potent than atracurium and has less propensity to release histamine. This study compares the pharmacokinetics and pharmacodynamics of cisatracurium in elderly and young patients.

Methods: Twelve elderly (aged 65-82 yr) and 12 younger patients (aged 30-49 yr) were anesthetized with nitrous oxide, fentanyl, and isoflurane (0.7%, end-tidal). The mechanomyographic response to train-of-four stimulation was assessed every 15 s after the administration of cisatracurium (0.1 mg/kg). Arterial samples were obtained over 6 h. Plasma cisatracurium concentration versus time data were fit to compartmental models. Pharmacokinetic parameters were determined assuming that elimination occurred from the central compartment only. This provides accurate clearance and half-life estimates but underestimates Vss (reported herein as Vss '). The pharmacodynamic response was described by the neuromuscular blocking profile.

Results: Onset to 90% paralysis (mean+/-SD) was delayed in the elderly (3.4+/-1.0 vs. 2.5+/-0.6 min). Recovery profiles were the same for both groups. Elimination half-life was minimally prolonged in the elderly (25.5+/-3.7 vs. 21.5 +/-2.4 min). The Vss ' was larger in the elderly (126 +/-16 vs. 108+/-13 ml/kg), although the clearances were the same for the two groups (5.0+/-0.9 vs. 4.6+/-0.8 ml *symbol* kg sup -1 *symbol* min sup -1).     

顺式阿曲库铵应用于肾功能不全患者麻醉的临床研究进展

本文综述了顺式阿曲库铵的理化特性、代谢途径及其应用于肾功能不全患者的药效学观察等研究的现状和进展。顺式阿曲库铵作为一种新型的中时效非去极化肌松药．不释放组胺．不依赖肝肾代谢．且无蓄积作用．恢复较快．安全治疗窗宽．是目前较为理想的可以用于肾功能不全患者的麻醉肌松药。     

Cisatracurium in cardiac surgery--continuous infusion vs. bolus administration

The aim of this study was the comparison of infusion vs. intermittent bolus administration of cisatracurium (CA) following cardiac surgery with regard to total intraoperative dose and time of recovery from neuromuscular blockade. From June 2005 to April 2006 sixty ASA II-III patients who were undergoing coronary bypass graft and valve replacement surgery, were equally divided and randomized to receive either intermittent bolus (Group A, n = 30) or continuous infusion (Group B, n = 30) of CA in Madani Heart Center in the Tabriz (Iran). Total intraoperative dose of CA and time to TOF ratio = 0.8 after operation were measured. Anesthesia technique in two groups was the same. All of the patients underwent cardiopulmonary bypass. Intensity of neuromuscular blockade maintained on one train-of-four (TOF) twitch response of adductor pollicis during operation. Mean received dose of CA was 32.8 +/- 20.6 micro/kg/hr in Group A and 89.7 +/- 39.4 micro/kg/hr in Group B (p = 0.003). Total intraoperative dose of CA was 23.6 +/- 4.9 mg in Group A and 39.2 +/- 10.1 mg in Group B (p = 0.001). Spontaneous recovery from neuromuscular blockade in ICU (TOF ratio = 0.8) was reached in 43.8 +/- 9.2 min in Group A, and 64.2 +/- 15.1 min in Group B (p = 0.0001). Intubation time in ICU was not significantly different (Group A = 8.3 +/- 5.1 hrs vs. Group B = 10.2 +/- 6.2 hrs, p = 0.256). These results support the intermittent bolus administration of cisatracurium in cardiac surgery following cardiopulmonary bypass.     

Die Wirkung unterschiedlicher Primingdosierungen auf die Pharmakodynamik von Cisatracurium

OBJECTIVE: The aim of the study was to evaluate the effect of two different priming regimen on the onset time of 100 micrograms/kg cisatracurium, when compared to bolus administration. METHODS: 51 patients were randomly assigned and received either a bolus of 100 micrograms/kg cisatracurium, or a priming dose of 10 micrograms/kg cisatracurium followed after 4 min by 90 micrograms/kg cisatracurium, or a priming dose of 15 micrograms/kg cisatracurium followed after 4 min by 85 micrograms/kg cisatracurium. The neuromuscular monitoring was performed using a mechanomyograph (Groningen II Monitor). Anaesthesia was induced with propofol and fentanyl and maintained by continuous infusion of propofol. RESULTS: The priming combination of 15 micrograms/kg cisatracurium followed after 4 min by 85 micrograms/kg cisatracurium produced a statistically significant reduction in the onset time (95% block) (180 +/- 60 s) and time to complete block (210 +/- 48 s), when compared to the bolus group (240 +/- 60 s and 288 +/- 66 s) (p < 0.05). CONCLUSION: Our data indicate that the "priming principle" is an appropriate technique to shorten the onset time of cisatracurium. To achieve a maximum effect the priming combination of 15 micrograms/kg cisatracurium followed after 4 min by 85 micrograms/kg cisatracurium is recommended.     

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.     

Comparative Clinical Pharmacology of Rocuronium, Cisatracurium, and Their Combination

Background: The comparative clinical pharmacology of cisatracurium and rocuronium and their combinations has not been reported. In this study, the authors compared the relative potency and the clinical profile and characterized the interaction of both drugs.

Methods: Two hundred twenty adults classified as American Society of Anesthesiologists physical status I and anesthetized with propofol-fentanyl-nitrous oxide were studied. In part 1, the neuromuscular-blocking effects of cisatracurium and rocuronium were assessed after administration of bolus doses of 20-50 [micro sign]g/kg and 100-300 [micro sign]g/kg, respectively. In part 2, we compared the time course of 1xED50, 1, 1.5, and 2xED95 doses of both drugs (where ED50 and ED95 are, respectively, the doses producing 50% and 95% depression of the first twitch height [T1]). In part 3, equieffective combinations of both drugs were studied to characterize their interaction.

Results: The calculated ED50 values and their 95% confidence intervals were 111 (107-115) and 215 (207-226) [micro sign]g/kg for rocuronium and cisatracurium, respectively. Compared with equipotent doses of cisatracurium, rocuronium had a faster onset, and a faster spontaneous T1 and train-of-four recovery times that were significant except at maximum recovery with the 2xED95 dose. The interaction between rocuronium and cisatracurium was synergistic, and the time profile of the combination group was different from that of the single-dose groups.     

Pharmacokinetics and Pharmacodynamics of Cisatracurium in Young and Elderly Adult Patients

Background: The effects of a muscle relaxant may differ in elderly compared with young adult patients for a variety of reasons. The authors compared the effects of a new muscle relaxant (cisatracurium) in young and elderly adults and used pharmacokinetic/pharmacodynamic modeling to identify factors explaining differences in time course of effect.

Methods: Thirty-one young (18-50 yr) and 33 elderly (> 65 yr) patients anesthetized with nitrous oxide, isoflurane, and fentanyl were studied. Cisatracurium (0.1 mg/kg) was given after induction of anesthesia and later additional boluses of 0.025 mg/kg or an infusion of cisatracurium was given. Neuromuscular transmission was measured using the first twitch of the train-of-four response at the adductor pollicis after supramaximal stimulation of the ulnar nerve at 2 Hz every 15 s. Five venous blood samples were obtained for plasma drug concentration at intervals ranging from 2 to 120 min from every patient. Three additional samples were obtained from those who received an infusion. A population pharmacokinetic/pharmacodynamic model was fitted to the plasma concentration and effect data. The parameters of the model were permitted to vary with age to identify where differences existed between young and elderly adults.

Results: Onset of block was delayed in the elderly; values being mean 3.0 (95% confidence interval 1.75-11.4) min and 4.0 (2.4-6.5) min in the young and elderly, respectively (P < 0.01). Duration of action was similar in the two groups. Plasma clearance was 319 (293-345) ml/min in the study population and did not differ between young and elderly patients. Apparent volume of distribution was 13.28 (9.9-16.7) l and 9.6 (7.6-11.7) l in the elderly and young adults, respectively (P < 0.05). There also were differences in pharmacodynamic parameters between the young and elderly; the predominant change being a slower rate of biophase equilibration (k sub e0) in the elderly (0.060 [0.052-0.068])/min compared with the young (0.071 [0.065-0.077]/min; P < 0.05).