Nondepolarizing neuromuscular blocking drugs and train-of-four fade

The aim of this study was to examine differences in prejunctional effects of different relaxants by measuring the train-offour (TOF) fade during the onset and recovery of neuromuscular block. The relaxants studied were atracurium (225 μg · kg^?1), mivacurium (65 μg · kg^?1) rocuronium (300 μg · kg^?1)) and vecuronium (40 μg · kg^?1)). The TOF ratios were measured at approximate heights of T₁) (first response in the TOF) of 90, 75, 50, and 25%. The TOF fade (as shown by lower TOF ratios) increased with a decrease in the T₁) during onset of neuromuscular block. Although there was a slightly greater fade with atracurium and rocuronium during the onset of block, the differences among the relaxants were insignificant. It is concluded that the relative prejunctional effects of these relaxants are similar.     

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.     

Twitch tension and train-of-four ratio during prolonged neuromuscular monitoring at different peripheral temperatures

In eight healthy patients, the influence of the train-of-four (TOF) response of prolonged neuromuscular monitoring and of different peripheral temperatures was studied during normal core temperature. Anaesthesia was induced and maintained with midazolam-fentanyl and a 70/30% mixture of nitrous oxide and oxygen. The mechanical TOF response of the adductor pollicis muscle (twitch tension and TOF ratio), was recorded simultaneously in both hands using supramaximal TOF stimulation of the ulnar nerve at the wrist. One arm was kept normothermic. The other arm was cooled using cold infusions and cold packings. Skin, muscle and core temperatures were continuously measured. In the normothermic arm (skin temperature greater than 32.0 degrees C), the twitch tension and TOF ratio were unchanged following 130-230 min of continuous nerve stimulation. In the hypothermic arm the twitch tension and TOF ratio showed only minor variations above a skin temperature of 32.0 degrees C (corresponding to a mean muscle temperature of 34.5 +/- 0.3 degrees C). Below a skin temperature of 32.0 degrees C a progressive decrease in TOF response was recorded. A linear relationship was found between skin temperature and TOF response as well as between muscle temperature and TOF response. At a skin temperature of 27.0 degrees C (corresponding to a mean muscle temperature of 30.8 +/- 0.4 degrees C), an approximate 20% reduction in twitch tension and a 10% decrease in TOF ratio were recorded with a considerable interindividual variation. We conclude that prolonged TOF nerve stimulation does not change the mechanical twitch response in patients with a normal central and peripheral temperature. A peripheral skin temperature below 32.0 degrees C with sustained and normal body temperature is, however, associated with changes in both twitch tension and TOF ratio that may be a source of error when evaluating neuromuscular function.     

Time course and train-of-four fade of mivacurium block during sevoflurane and intravenous anaesthesia

BACKGROUND AND OBJECTIVE: Volatile anaesthetics inhibit nicotinic acetylcholine receptors at clinically relevant concentrations with higher affinity for the neuronal nicotinic receptor. The inhibitory effects of propofol on nicotinic receptors have only been documented at supraclinical concentrations. The aim of this study was to determine recovery properties and train-of-four (TOF) fade of mivacurium during sevoflurane and propofol anaesthesia, in order to examine any differences both in the enhancement of the neuromuscular block (postjunctional effects) and in TOF fade (prejunctional effects). METHODS: Twenty ASA I-II adult patients were randomly allocated to maintenance of anaesthesia with sevoflurane (end-tidal concentration 2%) or propofol. Neuromuscular block was assessed by acceleromyography and a single dose of mivacurium (0.15 mg kg(-1)) was administered (in the sevoflurane group after 30 min of exposure to sevoflurane). We measured time for recovery of the first twitch of the TOF (T1) from 25-75%, time from 25% recovery of T1 to achieving a TOF ratio (TOFR) of 0.8, TOFR at 50%, 75% and 90% recovery of T1, and height of T1 at TOFR of 0.7 and 0.9. Data were tested using t-test for independent samples. RESULTS: Recovery times (mean (95% confidence interval, CI)) of mivacurium in the sevoflurane group (T1 25-75%, 11.3 (8.1-14.5) min; T1 25%-TOFR0.8, 19.1 (15.7-22.5) min) were significantly longer (P < 0.05) than in the propofol group (T1 25-75%, 6.5 (5.2-7.7) min; T1 25%-TOFR0.8, 11.3 (7.8-10.3) min). No differences were found in the relations between TOFR and T1 or vice versa, between the groups. CONCLUSIONS: Recovery times after a single dose of mivacurium were prolonged by sevoflurane compared with propofol but no differences in TOF fade were observed between the two anaesthetics.     

Relationship between single twitch depression and train-of-four fade: influence of relaxant dose during onset and spontaneous offset of neuromuscular blockade

The characteristics of the train-of-four (TOF) response were studied electromyographically during onset and spontaneous offset of neuromuscular blockade with bolus doses of vecuronium (ED95, and ED95 X 2). During onset of blockade there was less fade with the larger than the smaller dose of vecuronium, demonstrating a variable and dose-related relationship between the ratio of height of the initial twitch, T1, and fourth twitch, T4. With both doses TOF fade was more pronounced during recovery than during onset of block, but at the same T1 values during offset, both doses were associated with similar degrees of fade during recovery. Thus with bolus doses of vecuronium the T4 ratio during recovery bears a fixed relationship to initial T1 depression that is independent of dose.     

The pattern of train-of-four fade after atracurium: influence of different priming doses

This study was designed to investigate the effect of three different priming doses of atracurium--0.06, 0.07, and 0.08 mg/kg--followed 3 min later by the remainder of a 0.5 mg/kg dose on the relationship between the depression in the first twitch of the train-of-four (T1) and train-of-four (TOF) fade. This relationship was studied after the administration of the full dose of the relaxant in all groups. Of all the priming doses, 0.08 mg/kg atracurium, when followed 3 min later by 0.42 mg/kg atracurium, had a significantly greater fade in the TOF ratio at any given T1 value. This may indicate significant prejunctional activity. Acceleration of the onset of neuromuscular blockade was, however, evident in all groups that received atracurium in divided doses. The implication is, therefore, that prejunctional activity may not contribute significantly to the acceleration of onset of neuromuscular blockade after administration of atracurium in divided doses, as described in this study.     

Posttetanic potentiation and fade in the response to tetanic and train-of-four stimulation during succinylcholine-induced block

We designed this study to confirm anecdotal observations that neuromuscular block after a single administration of succinylcholine is characterized by fade to train-of-four (TOF) or tetanic stimulation, as well as posttetanic potentiation. This prospective, randomized, 2-center observational study involved 100 patients. Patients were allocated to 1 of 5 groups and received 0.1, 0.3, 0.5, 0.75, or 1.0 mg/kg succinylcholine during propofol/fentanyl/nitrous oxide anesthesia. Neuromuscular function was monitored by TOF using mechanomyography. At 10%-20% spontaneous recovery of the first twitch of TOF, the mode of stimulation was changed from TOF to 1-Hz single-twitch stimulation followed by a tetanic stimulus (50 Hz) for 5 s. Three seconds later, the single twitch (1 Hz) was applied again for approximately 30 s followed by TOF stimulation until full recovery of the TOF response. Succinylcholine-induced neuromuscular block had the following characteristics: 1) twitch augmentation before twitch depression, which was seen more frequently in patients given smaller doses (0.1 and 0.3 mg/kg) than in those given larger doses (0.5-1.0 mg/kg); 2) TOF fade during onset and recovery of the block; 3) tetanic fade; and 4) and posttetanic potentiation. Posttetanic potentiation was related to the pretetanic twitch height but was not related to the dose of succinylcholine administered. Some characteristics of Phase II block were detectable during onset and recovery from doses of succinylcholine as small as 0.30 mg/kg. Posttetanic potentiation and fade in response to train-of-four and tetanic stimuli are characteristics of neuromuscular block after bolus administration of different doses of succinylcholine. IMPLICATIONS: Posttetanic potentiation and fade in response to train-of-four and tetanic stimuli are characteristics of neuromuscular block after bolus administration of different doses of succinylcholine. We also conclude that some characteristics of a Phase II block are evident from an initial dose (i.e., as small as 0.3 mg/kg) of succinylcholine.     

Twitch, tetanus and train-of-four as indices of recovery from nondepolarizing neuromuscular blockade

This study was undertaken to compare the sensitivities of the train-of-four response (2 Hz for 2 s), the single twitch (0.15 Hz), and the tetanic response (50 Hz for 5 s) as indices of residual nondepolarizing block. Spontaneous or induced recovery of evoked thumb adduction in response to ulnar nerve stimulation was studied. One hundred and seven adult surgical patients were divided according to the relaxant used, into six groups. We found that when the single twitch recovered to control height, the train-of-four ratio was well below 1.0. This ratio was significantly lower during spontaneous recovery than following neostigmine antagonism of the block (P less than 0.01). The tetanic response was fully sustained when the train-of-four ratio was above 0.7. When the ratio was less than 0.7, variable degrees of fade of tetanus were evident. Analysis of variance indicated similar train-of-four ratios among the six groups at complete recovery of the single twitch irrespective of the relaxant technique used (P less than 0.1). It is concluded that a train-of-four ratio of 0.7 or higher reliably indicates the recovery of the single twitch to control height and a sustained response to tetanic stimulation at 50 Hz for 5 s. The clinical significance of this study is as follows: the train-of-four response provides the same indication of clinical recovery from nondepolarizing block as obtained from tetanic stimulation at a physiological frequency; and reliance on the recovery of the single twitch to control height as a criterion of spontaneous return to normal clinical neuromuscular function may be misleading.     

Post-tetanic count and train-of-four responses during neuromuscular block produced by vecuronium and infusion of nicardipine

We have examined onset and recovery of neuromuscular block produced by vecuronium using either post-tetanic count (PTC), or the first twitch of the train-of-four (TOF) (T1/T0) and TOF ratio (T4/T1) during continuous infusion of nicardipine. Sixty adult patients were allocated to one of four groups of 15 patients each: nicardipine-PTC, nicardipine- TOF, control-PTC and control-TOF. In the nicardipine-PTC and nicardipine-TOF groups, nicardipine 0.03 mg kg-1 was given before vecuronium 0.1 mg kg-1 and a continuous infusion of nicardipine was started immediately at a rate of 2 micrograms kg-1 min-1. Mean time from administration of vecuronium to onset of neuromuscular block in the nicardipine-PTC and nicardipine-TOF groups was significantly shorter than in the control-PTC and control-TOF groups (166 (SD 39) vs 220 (28) s; P < 0.05). There was no significant difference in recovery of PTC between the nicardipine-PTC and control-PTC groups or in recovery of TOF ratio in the nicardipine-TOF and control-TOF groups. However, during recovery, T1/T0 in the nicardipine-TOF group was significantly less than that in the control-TOF group, 60-100 min after administration of vecuronium.      

Intubating conditions and onset of neuromuscular block of rocuronium (Org 9426); a comparison with suxamethonium

The intubating conditions and neuromuscular blocking profile following 600 micrograms.kg-1 rocuronium (Org 9426) have been investigated in patients under various experimental conditions. They were compared with conditions following 1.5 mg.kg-1 suxamethonium, preceded by a precurarising dose (10 mg) of gallamine, and with those in a control group in the absence of a muscle relaxant. Rocuronium produced good to excellent intubating conditions at 60 as well as at 90 s after administration, even though there was only a partial blockade of the adductor pollicis muscle. Intubating conditions following suxamethonium were comparable with those after rocuronium. Half of the control patients could be intubated. The clinical duration and the recovery time of 600 micrograms.kg-1 of rocuronium were 24(4) and 9(3) min (mean(s.d.)), respectively. Rocuronium may have a major advantage over existing non-depolarising muscle relaxants due to the early presence of excellent intubating conditions. The results indicate that rocuronium may replace suxamethonium in procedures in which rapid sequence induction is required.     

Onset of neuromuscular block after tourniquet inflation: comparison of suxamethonium with vecuronium

To determine the influence of circulatory factors on onset of neuromuscular block, we have measured twitch height in an arm with a tourniquet inflated during onset and compared this with data from a control arm in 20 patients under fentanyl-thiopentone-nitrous oxide- isoflurane anaesthesia. Patients were allocated randomly to receive either vecuronium 0.1 mg kg-1 (n = 10) or suxamethonium 1 mg kg-1 (n = 10). The EMG response of the first dorsal interosseous to single twitch stimulation of the ulnar nerve every 10 s was recorded in both arms. When neuromuscular block was 20% (i.e. twitch height was 80% of control), the tourniquet was inflated to a pressure of 250 mm Hg. It was deflated 5 min later. In the vecuronium group, the rate of onset did not differ in both arms and mean maximum block was 95 (SD 4)% in the tourniquet arm, which was not different from 99 (2)% in the perfused arm. In the suxamethonium group, the presence of a tourniquet decreased the rate of onset by 66%. Maximum block was only 74 (20)% in the tourniquet arm compared with 97 (5)% in the perfused arm (P < 0.05). The difference in maximum neuromuscular block between arms was 4 (3)% in the vecuronium group and 22 (17)% in the suxamethonium group (P < 0.01). We conclude that during onset, neuromuscular block continued to increase in spite of interruption of blood flow, and this increase was greater with vecuronium than with suxamethonium. These results suggest that redistribution of free molecules of drug from extra-junctional to junctional areas is one of the factors governing onset of action of neuromuscular blocking drugs.      

Impaired neuromuscular transmission after recovery of the train-of-four ratio

BACKGROUND: Residual neuromuscular blockade may increase the risk of development of post-operative pulmonary complications, but is difficult to detect clinically. It was speculated that patients may have impaired neuromuscular transmission after surgery of long duration, despite the recovery of the train-of-four (TOF) ratio. METHODS: The muscle force (mechanomyography), motor compound muscle action potential amplitude and fatigue of the adductor pollicis (AP) muscle were assessed after recovery of the TOF ratio to 0.9. Thirteen patients receiving repetitive administration of neuromuscular blocking agents (NMBAs) during surgery (median, 5.3 h; interquartile range, 3.4-6 h) were studied post-operatively in the intensive care unit. At the time of the measurements, patients were scheduled for extubation and the AP TOF ratio amounted to a mean (standard deviation, SD) of 0.94 (0.05). Six healthy volunteers of similar age, weight and gender were studied for comparison. Force-frequency curves were generated by stimulation (10-80 Hz) of the ulnar nerve, and the AP electromyogram (EMG) amplitude was measured, in parallel, before and after evoked muscle fatigue. RESULTS: The maximum AP force at a stimulation frequency of 20-80 Hz was significantly lower in patients than in controls [40 N (16 N) vs. 65 N (18 N) at 80 Hz]. In patients, but not in controls, the EMG amplitude decreased with increasing nerve stimulation frequency, and a tetanic fade of both force and EMG, amounting to 0.41 (0.33) (EMG) and 0.61 (0.35) (mechanomyography) at 80 Hz, was observed. Force after fatiguing contractions did not differ between the groups. CONCLUSION: After repetitive administration of NMBAs during surgery, even with recovery of the TOF ratio to 0.9 or more, muscle weakness from impaired neuromuscular transmission can occur. The clinician should consider that post-operative recovery of the TOF ratio to 0.9 does not exclude an impairment of neuromuscular transmission.     

Epidurally administered mepivacaine delays recovery of train-of-four ratio from vecuronium-induced neuromuscular block

BACKGROUND: The aim of this study was to examine the efficacy of epidurally administered mepivacaine on recovery from vecuronium-induced neuromuscular block. METHODS: Eighty patients were randomly assigned to one of two study groups. They were either given epidurally a bolus of 0.15 ml kg(-1) of mepivacaine 2%, followed by repetitive injections of 0.1 ml kg(-1) h(-1) throughout the study, or were not given epidurally. General anaesthesia was induced and maintained with fentanyl, propofol and nitrous oxide. Neuromuscular block was induced with vecuronium 0.1 mg kg(-1) and monitored using acceleromyographic train-of-four (TOF) at the adductor pollicis. Patients in each treatment group were randomized to receive neostigmine 0.04 mg kg(-1) at 25% recovery of the first twitch of TOF or to recover spontaneously to a TOF ratio of 0.9. The effect of epidural mepivacaine on speed of spontaneous and facilitated recovery of neuromuscular function was evaluated. RESULTS: The time from administration of vecuronium to spontaneous recovery to a TOF ratio of 0.9 was significantly longer in the epidural mepivacaine group [105.4 (14.2) min] as compared with the control group [78.5 (9.1) min, P < 0.01]. Neostigmine administered at 25% of control in T1 shortened recovery from neuromuscular block, however the time required for facilitated recovery to a TOF ratio of 0.9 in the epidural group was significantly longer than that in the control group [7.6 (1.6) min vs 5.8 (2.1) min, P < 0.01]. CONCLUSIONS: In clinical anaesthesia, it should be recognized that epidurally administered mepivacaine delays considerably the TOF recovery from neuromuscular block.     

High-dose vecuronium neuromuscular block: a comparison of arrhythmias and onset of block during sufentanil anaesthesia

This study compared the heamodynamic effects of sufentanil with those observed following concomitant sufentanil and highdose vecuronium administration to determine whether vecuronium induces bradyarrhythmias. Sixty coronary artery bypass patients were stratified into beta blocker (n = 30) or non-beta blocker (n = 30) groups and following induction with sufentanil (9 ± 3 μg · kg^?1) and midazolam (0.07 ± 0.04 mg · kg^?1), received either succinylcholine 1 mg · kg^?1 (SxCh), vecuronium 0.3 mg · kg^?1 (Vec 0.3), or vecuronium 0.5 mg · kg^?1 (Vec 0.5). Using a Holter ECG monitor, bradyarrhythmias were classified as mild (HR 46–50), moderate (HR 40–45) or severe (HR < 40). In the pre-induction period, there were no differences in the incidence of mild, moderate or severe bradyarrhythmias among the SxCh, Vec 0.3 or Vec 0.5 groups, in either the beta blocker or non-beta blocker groups. Following induction, there were similar reductions in mean heart rate and mean arterial pressure in all three muscle relaxant groups in both the beta and the non-beta blocker groups; however, there was no difference in the incidence of mild, moderate or severe bradyarrhythmias among the SxCh, Vec 0.3 or Vec 0.5 groups. The Vec 0.5 beta blocker group had a higher incidence of mild bradyarrhythmias (32 ± 36%) than the Vec 0.5 non-beta blocker group (2 ± 3% P = 0.017). Using EMG recording, the onset time of maximal neuromuscular block for the Vec 0.3 group (108 ± 17 sec) was longer (P < 0.05) than the SxCh (76 ±21 sec) and Vec 0.5 (82 ± 13 sec) groups, which were similar. We conclude: (i) vecuronium does not affect HR or the incidence of bradyarrhythmias following sufentanil administration and that the observed reduction in HR and mean arterial pressure were due to sufentanil administration, (ii) vecuronium (0.5 mg · kg^?1) provides an onset time of neuromuscular block similar to SxCh, and (iii) patients taking beta blockers preoperatively are more prone to develop bradyarrhythmias during sufentanil administration.     

Electrical and mechanical train-of-four responses during depolarizing and nondepolarizing neuromuscular blockade

Simultaneous measurements of train-of-four (TOF) responses by integrated electromyography (IEMG) and twitch force were compared for atracurium, vecuronium, and succinylcholine in 30 subjects during nitrous oxide-fentanyl anesthesia. Determinations of TOF were made during neuromuscular blockade (NMB) onset and recovery. Scattergrams and least squares regression lines were plotted, and z-tests for parallel slope and common intercept were used to compare lines. Data for atracurium and vecuronium were indistinguishable in all groups (z less than 0.05), and therefore pooled to represent nondepolarizing blockade. During onset of nondepolarizing NMB, TOF showed a linear relationship indistinguishable from the line of identity (slope 0.93, intercept -0.06, z less than 0.05). During recovery the intercept was unchanged (z greater than 0.05), but the slope was significantly changed, indicating mechanical TOF lags behind IEMG during recovery. This finding is important for interpretation of IEMG when used for clinical monitoring. Comparison of data for depolarizing NMB shows more complex relationships. Integrated electromyography is found to be convenient and reliable for monitoring nondepolarizing NMB.     

Difference of train-of-four fade induced by nondepolarizing neuromuscular blocking drugs: a theoretical consideration on the underlying mechanisms

Nondepolarizing neuromuscular blocking drugs induce train-of-four (TOF) fade, i.e., the reduction of the fourth to the first twitch height in a train under TOF stimulation. It has been observed that the degree of TOF fade varies with the drug used and is inversely correlated with the potencies of the drug. In this study, the cause of difference of TOF fade was considered using a dynamic model. The model was based on the following assumptions: (1) Twitch response is evoked by the binding of acetylcholine (ACh) molecules to the postsynaptic nicotinic receptors in a neuromuscular junction, (2) time-dependent ACh mobilization in a motor nerve terminal results in less ACh output at the fourth stimulus in a train than at the first stimulus, (3) the drugs compete with ACh for the postsynaptic receptors and inhibit the receptor-binding of ACh, and (4) the drugs have various affinities for the receptors. This study suggested that the difference of affinities of the drugs for postsynaptic ACh receptors may cause the difference of TOF fade.