Neuromuscular interaction between cisatracurium and mivacurium, atracurium, vecuronium or rocuronium administered in combination

We compared the dose–response relationships of cisatracurium, mivacurium, atracurium, vecuronium and rocuronium and examined the interactions of cisatracurium with mivacurium, atracurium, vecuronium and rocuronium in humans by isobolographic and fractional analyses. We studied 180 adult patients during nitrous oxide–fentanyl–propofol anaesthesia. Neuromuscular block was monitored using mechanomyography to detect the twitch response of the ulnar nerve at the wrist. The dose–response curves were determined by probit analysis. The calculated ED₅₀ values and their 95% confidence intervals were 40.9 (38.1–43.7), 49.8 (47.0–52.6), 187.2 (175.1–199.3), 36.6 (34.7–38.5) and 136.4 (129.2–143.6) μg.kg⁻¹ for cisatracurium, mivacurium, atracurium, vecuronium and rocuronium, respectively. Corresponding ED₉₅ values were 57.6 (53.5–61.7), 91.8 (88.1–95.5), 253.1 (238.9–267.3), 52.9 (49.1–56.7) and 288.7 (276.2–301.2) μg.kg⁻¹, respectively. The interaction between cisatracurium and mivacurium, vecuronium or rocuronium was found to be synergistic, but the interaction between cisatracurium and atracurium was found to be additive. Synergy between cisatracurium and vecuronium or rocuronium was greater than between cisatracurium and mivacurium.     

A comparison of the neuromuscular blocking effects and reversibility of cisatracurium and atracurium

The neuromuscular blocking effects and the reversibility of cisatracurium 0.1 or 0.15 mgkg⁻¹ were compared with those of atracurium 0.5 mgkg⁻¹ during anaesthesia with propofol, nitrous oxide and isoflurane. Neuromuscular block was monitored using train-of-four stimulation while recording the mechanomyographic response of the adductor pollicis muscle. The block was either allowed to recover spontaneously or was antagonised with neostigmine 50 μgkg⁻¹ at 10% or 25% recovery of the first twitch of the train-of-four. The median times to maximum block were 2.7, 2.2 and 1.5 min following cisatracurium 0.1 and 0.15 mgkg⁻¹ and atracurium 0.5 mgkg⁻¹, respectively. After cisatracurium 0.1 mgkg⁻¹ had been given, the median time to recovery of the train-of-four ratio to 0.8 ('adequate recovery') was 74 min during spontaneous recovery, 48 min after reversal with neostigmine when the first twitch of the train-of-four had returned to 10% of control and 50 min after reversal when the first twitch of the train-of-four had returned to 25% of control. These times for cisatracurium 0.15 mgkg⁻¹ and atracurium 0.5 mgkg⁻¹ were 90, 66 and 57 min and 75, 56 and 54 min, respectively. Administration of neostigmine significantly shortened the time to adequate recovery for both drugs but there were no significant differences in the case of either neuromuscular blocking drug between the groups of patients given neostigmine at 10 or 25% recovery of the first twitch of the train-of-four.     

Train–of–four fade during onset of neuromuscular block with nondepolarising neuromuscular blocking agents

Fade in the train-of-four (TOF) responses during onset of neuromuscular block was studied following administration of atracurium (225 or 450 micrograms/kg), vecuronium (40 or 80 micrograms/kg), pancuronium (60 or 120 micrograms/kg) and tubocurarine (450 micrograms/kg). TOF ratios were measured at approximate heights of T1 (first response in the TOF) of 75, 50 and 25%. Fade in TOF increased as the height of T1 decreased, with maximum fade being observed at T1 of 25%. The greatest difference between relaxants was observed at T1 of 25%, vecuronium showing the least fade and pancuronium, atracurium and tubocurarine showing increasing fade, in that order. The difference between atracurium and tubocurarine or between vecuronium and pancuronium was not significant, but the degree of TOF fade was significantly greater with atracurium and tubocurarine in comparison to vecuronium or pancuronium.     

Neuromuscular transmission and its blockade

The role of two recently introduced muscle relaxants--atracurium and vecuronium--in contemporary anaesthetic practice is assessed. Recent advances in the physiology of neuromuscular transmission, particularly the roles of calcium and calmodulin, are reviewed, and new ideas concerning the reversal and monitoring of neuromuscular blockade are discussed.     

Neuromuscular and cardiovascular advantages of combinations of mivacurium and rocuronium over either drug alone

We Investigated isobolic mixtures of mivacurium and rocuronium to determine if the combination offered any advantages over either drug alone. We used five dose regimens to achieve ED₉₅× 2: {(1.5 × ED₉₅ mivacurium) + (0.5 × ED₉₅ rocuronium); (I × ED₉₅ mivacurium) + (1 × ED₉₅ rocuronium); (0.5 × ED₉₅ mivacurium) + (1.5 × ED₉₅ rocuronium); (2 × ED₉₅ mivacurium); (2 × ED₉₅ rocuronium)}. We studied onset time, duration of block, recovery of block, arterial blood pressure and heart rate. Mivacurium alone produced the block of shortest duration (p < 0.001). Onset time was shortest in the rocuronium alone group and was significantly faster in all the rocuronium treated groups compared to mivacurium alone (p < 0.001). Arterial blood pressure and heart rate decreased transiently in the mivacurium alone group but not in the other groups. These results demonstrate increased cardiovascular stability and more rapid onset of block with combinations of mivacurium and rocuronium without significant prolongation of the block.     

Postoperative residual block after intermediate-acting neuromuscular blocking drugs

The frequency and duration of postoperative residual neuromuscular block on arrival of 150 patients in the recovery ward following the use of vecuronium (n = 50), atracurium (n = 50) and rocuronium (n = 50) were recorded. Residual block was defined as a train-of-four ratio of <0.8. An additional group of 10 patients received no neuromuscular blocking drugs during anaesthesia. The incidence of postoperative residual neuromuscular block was 64%, 52% and 39% after the use of vecuronium, atracurium and rocuronium, respectively. Similar numbers of patients were not able to maintain a sustained head or leg lift for 5 s on arrival in the recovery ward. The mean [range] times to attaining a train-of-four ratio of > or =0.8 after arrival in the recovery ward were 9.2 [1-61], 6.9 [1-24] and 14.7 [1.5-83] min for vecuronium, atracurium and rocuronium, respectively. None of the 10 patients who did not receive neuromuscular blocking drugs had train-of-four ratios <0.8 on arrival in the recovery ward. It is concluded that a large proportion of patients arrive in the recovery ward with a train-of-four ratio <0.8, even with the use of intermediate-acting neuromuscular blocking drugs. Although the residual block is relatively short lasting, it may occasionally be prolonged, requiring close observation and monitoring of such patients in the recovery ward.     

The haemodynamic effects of rocuronium and vecuronium are different under balanced anaesthesia

Background: Rocuronium has been reported to have minimal haemodynamic effects. However, this conclusion has been drawn primarily from investigations conducted under narcotic-based anaesthesia. This study was designed to evaluate the cardiovascular effects of rocuronium under isoflurane/N20/fentanyl anaesthesia and to compare rocuronium's haemodynamic effects to those of vecuronium and pancuronium.
Methods: Anaesthesia was induced with fentanyl 2 μg/kg, thiopentone 4 mg/kg, and suxamethonium 0.5 mg/kg in 75 ASA I or II patients. After tracheal intubation, anaesthesia was maintained with isoflurane 0.5% and N₂0 50% in oxygen. Five min after intubation (baseline), patients randomly received either vecuronium 100 μg/kg, rocuronium 600 μg/kg, rocuronium 900 μg/kg, rocuronium 1200 μg/kg, or pancuronium 140 μg/kg. One min after administration of muscle relaxant, mean arterial pressure (MAP) and heart rate (HR) were recorded and were subsequently measured at 1-min intervals for the next 4 min.
Results: HR decreased significantly ( P <0.05) at all times compared to baseline in patients receiving vecuronium. HR significantly ( P < 0.05) increased in those receiving rocuronium 1200 μg/kg or pancuronium. Patients who received vecuronium had a sigruficant ( P < 0.05) decrease in MAP at all times compared to baseline. Comparing results between groups, patients who received rocuronium or pancuronium had significantly ( P < 0.05) higher MAP compared to those administered vecuronium.
Conclusion: The haemodynamic effects of rocuronium and vecuronium are different under balanced anaesthesia. Rocuronium may attenuate the fall in MAP that often occurs under balanced anaesthesia without surgical stimulation.     

Intubating conditions using cisatracurium after induction of anaesthesia with thiopentone

We studied tracheal intubation conditions produced by the muscle relaxant, cisatracurium, following induction of anaesthesia with fentanyl (2 μgkg⁻¹) and thiopentone (6 mgkg⁻¹). Sixty patients were randomly assigned to receive cisatracurium in a single bolus dose of either 0.15 or 0.20 mgkg⁻¹. Tracheal intubation was commenced 120 s after injection of the relaxant. The mean (SD) time taken to achieve intubation was significantly shorter in the 0.20 mgkg⁻¹ group (137 (16) s) than the 0.15 mgkg⁻¹ group (149 (12) s; p < 0.05). The intubating conditions were better after the larger dose. Our results suggest that when anaesthesia is induced using thiopentone, a dose of 0.20 mgkg⁻¹ of cisatracurium is recommended to ensure satisfactory intubating conditions.     

Comparison of intubating conditions with atracurium, vecuronium and pancuronium

A blind trial, comparing time of onset of satisfactory conditions for tracheal intubation with atracurium 0.6 mg/kg, vecuronium 0.1 mg/kg and pancuronium 0.1 mg/kg is described. Intubation was attempted at 30-second intervals in 60 patients, randomly allocated to receive one of the above muscle relaxants. Patients receiving atracurium 0.6 mg/kg could be intubated from 30 to 120 seconds. Patients receiving either vecuronium 0.1 mg/kg or pancuronium 0.1 mg/kg were able to be intubated between 60 and 240 seconds. The results showed a statistically significant earlier onset of satisfactory intubating conditions with atracurium than with vecuronium or pancuronium in these doses but no difference between vecuronium and pancuronium.     

Barrier pressure and muscle relaxants

The effects of pancuronium and vecuronium on the lower oesophageal sphincter pressure were studied in 24 healthy patients anaesthetised with 0.5% halothane in nitrous oxide and oxygen. Following pancuronium 0.1 mg/kg intravenously, there was a significant increase in barrier pressure from a control value of 2.0 (SEM 0.14) kPa to 3.0 (SEM 0.27) kPa 1 minute after injection (p less than 0.05). This increase was sustained throughout the 15 minute period of recording and was accompanied by a significant increase in heart rate (p less than 0.001). Following administration of vecuronium 0.1 mg/kg intravenously there was an initial modest, though not significant increase in barrier pressure. This increase was significant (p less than 0.05) at 15 minutes. There were no cardiovascular changes following vecuronium.     

A comparison of the pharmacodynamics of rocuronium and vecuronium during halothane anaesthesia

Thirty healthy patients were randomised to receive either a single bolus dose of rocuronium 0.6 mg.kg-1 or vecuronium 0.1 mg.kg-1 during halothane anaesthesia. Onset time, duration 25, duration 75 and train-of-four 70 were measured. The onset of neuromuscular blockade following rocuronium was more rapid than vecuronium (p = 0.0001). All other pharmacodynamic parameters were similar. During the first minute following injection of the neuromuscular blocking agent, the heart rate increased by 36% in the rocuronium group but remained stable in those patients who received vecuronium (p = 0.0008). No adverse effects were noted in either group.     

Quantification of train-of-four responses during recovery of block from non-depolarising muscle relaxants

Train-of-four (TOF) responses were assessed in 70 patients (seven groups of ten patients each) during recovery of neuromuscular block from atracurium (226 or 452 μg/kg), vecuronium (40 or 80 μg/kg), pancuronium (60 or 120 μg/kg) and tubocurarine (450 μg/kg) in order to quantify the height of T₁ (first response in the TOF sequence) at which T₂, T₃ and T₄ (2nd, 3rd and 4th response in TOF sequence) reappear. Patients were anaesthetised with thiopentone, nitrous oxide in oxygen and fentanyl. There were small but significant differences between relaxants. The clinically useful parameter, i.e. the 4th response in the TOF sequence, appeared at approximately 30% height of the first response (T₁) rather than at 25% as generally believed. It is suggested that the third response in the TOF sequence, which reappeared at an average height of T₁ of about 25%, be used for administration of further supplements of muscle relaxants since abdominal muscle relaxation becomes inadequate at this stage.     

Tracheal intubation conditions after one minute: rocuronium and vecuronium, alone and in combination

Rocuronium is a recently introduced nondepolarising neuromuscular blocking agent with a rapid onset and intermediate duration of action. Experimental observations have suggested that during onset it acts synergistically with other nondepolarising agents, but that at a steady state the combined action is additive. In order to investigate whether synergism during onset produces a clinical benefit we performed the following study of tracheal intubation conditions. Consenting patients presenting for elective surgery which required tracheal intubation were randomly allocated to receive a standard anaesthetic and either a twice ED₉₅ dose of rocuronium, or vecuronium, or an equipotent mixture of both drugs. Tracheal intubation conditions were assessed after 60 s and scored as excellent, good, poor or impossible. The conditions produced in the rocuronium and the mixture groups were similar and both were significantly better than those of vecuronium. Excellent intubation conditions were achieved in 57% of the rocuronium group, 70% of the mixture group and 27% of the vecuronium group. We conclude that a mixture of rocuronium and vecuronium acts synergistically during the early part of their action and a mixture containing one ED₉₅ of both agents provides comparable conditions for tracheal intubation as an equipotent dose of rocuronium.     

Muscle relaxants and histamine release

Many anaesthetic drugs and adjuvants can cause the release of histamine by chemical (anaphylactoid) or immunologic (anaphylactic) mechanisms. While both types of reactions can be clinically indistinguishable, they are mechanistically different. In anaphylactoid reactions, only preformed mediators are released, of which histamine may be the most clinically important. In true immunologic reactions, mast cell degranulation occurs, and many vasoactive substances (including histamine) are released. Clinical signs and symptoms of both classes of reactions include hypotension (most common), tachycardia, bronchospasm, or cutaneous manifestations. Anaphylactoid reactions may occur commonly under anaesthesia in response to many drugs, including induction agents, some opiates, plasma expanders, and curariform relaxants. Anaphylactic reactions are far less common than anaphylactoid reactions, but they nevertheless represent more than half of the life-threatening reactions that occur in anaesthetic practice. Muscle relaxants are the most frequently implicated class of drugs; suxamethonium is the most common agent implicated in anaphylactic reactions during anaesthesia, but even drugs without apparent chemical histamine release (i. e., vecuronium) are frequently implicated in anaphylactic reactions.