Conditions to optimise the reversal action of neostigmine upon a vecuronium-induced neuromuscular block

Background: Since neostigmine was introduced for reversal of neuromuscular block, there has been controversy about the optimum dose for antagonizing neuromuscular block. The purpose of this study was to characterise recovery of neuromuscular transmission following a vecuronium-induced block 15 min after neostigmine administration using different stimulation patterns, and to determine the effects of different doses of neostigmine given at various pre-reversal twitch heights. Methods: Adductor pollicis (AP) mechanical activity in response to low (0.1 and 2 Hz) and high (50 and 100 Hz) frequency stimulation, was recorded 15 min after 20, 40 and 80 μg/kg neostigmine, given to reverse a vecuronium-induced block at 10, 25 and 50% pre-reversal twitch height (TH). Fifty four ASA class I and II anaesthetised (methohexital, fentanyl, N₂O/O₂) young adult patients were studied and randomly allocated into 9 groups of 6 patients each. Results: In contrast to twitch height (TH) and residual force after 50 Hz, 5 s tetanic stimulation (RF50_Hz), the greater sensitivity of train-of-four (TOF) ratio and residual force after 100 Hz, 5 s tetanic stimulation (RF100_Hz) points out the best reversal conditions (prereversal TH and the optimal neostigmine dose) (P<0.001, two-way analysis of variance). The highest reversal scores (about 0.9 TOF ratio and RF100_Hz) were obtained when 40 μg/ kg of neostigmine was given at 25 and 50% TH. A 0.9 TOF ratio was also observed when 40 μg/kg of neostigmine was given at 10% TH, but, under these conditions, RF100_Hz was only 0.6 (P<0.05, Duncan test). Conclusion: To optimise the reversal action of neostigmine in order to obtain the highest neuromuscular transmission recovery (0.9 TOF ratio and RF100_Hz) during a vecuronium-induced neuromuscular block, the 40 μg/kg dose has to be given at 25 to 50% recovery of TH.     

Antagonism of atracurium with neostigmine

In 36 patients in whom anaesthesia was maintained with nitrous oxide and 0.5% isoflurane an atracurium-induced neuromuscular block was either allowed to recover spontaneously or antagonised with one of four doses of neostigmine (15 micrograms/kg, 35 micrograms/kg, 55 micrograms/kg or 75 micrograms/kg). The recovery times to a train-of-four ratio of 0.5, 0.75 and 0.9 were recorded. In patients given neostigmine, antagonism was at an average T1 of between 8.8% and 14.9%. There was no difference in the recovery times between the patients given neostigmine 35 micrograms/kg, 55 micrograms/kg or 75 micrograms/kg. Recovery after neostigmine 15 micrograms/kg was significantly slower than after the higher doses. One patient given neostigmine 75 micrograms/kg showed an unusual bimodal pattern of recovery. There appears to be no benefit in giving a larger dose than 35 micrograms/kg of neostogmine as a single bolus.     

Cardiovascular changes at antagonism of atracurium

The cardiovascular changes in the 10 minutes following antagonism of an atracurium-induced block were studied in 32 patients. A 5:1 ratio combination of either 15, 35, 55 or 75 micrograms/kg neostigmine, with a corresponding dose of 3, 7, 11, or 15 micrograms/kg of glycopyrronium was used for antagonism. The least change in heart rate was with neostigmine 15 micrograms/kg with an increase of more than 15 beats/minute found in only one patient. Antagonism with 35, 55 and 75 micrograms/kg neostigmine mixture produced the greatest increase in heart rate at one minute and this was significantly different from the effect of the 15 micrograms/kg dose. Twenty out of 24 patients given the larger doses had heart rate increases in excess of 15 beats/minute and in nine patients this ranged from 30 to 52 beats/minute, representing increases of 46-80% above baseline values. Arterial pressure increases after antagonism were statistically significant in all four groups, with no between-group difference; these were clinically unimportant. When antagonising an atracurium-induced block with clinically useful doses of neostigmine, the standard 5 : 1 ratio combination with glycopyrronium will result in an initial tachycardia.     

Attenuated ventilatory response to hypoxaemia at vecuronium-induced partial neuromuscular block

The effect of a partial neuromuscular block on the ventilatory response to hypercarbia and to hypoxaemia was studied in 11 non-anaesthetized male subjects. Respiratory frequency, tidal volume, minute volume, respiratory timing and drive were measured during air breathing and during stimulation by hypercarbia and hypoxaemia. The ventilatory response was defined as the ratio between, respectively, tidal volume and minute volume during ventilation stimulated by hypercarbia and hypoxaemia compared to measurements during air breathing. The ventilatory measurements were repeated on three separate occasions: before neuromuscular block was established, during an infusion of vecuronium aiming at a mechanical adductor pollicis train-of-four (TOF) ratio of 0.70, and after the infusion had been stopped and the neuromuscular block had spontaneously recovered to a TOF ratio of > 0.90. Resting ventilation during air breathing remained with minor variations throughout the experiment. The ventilatory response to hypercarbia was not affected at a TOF ratio of 0.70 as compared to measurements before vecuronium and at a TOF ratio of > 0.90. In contrast, the ventilatory response to hypoxaemia was markedly reduced at a TOF ratio of 0.70. We conclude that a mechanical TOF ratio of 0.70 following vecuronium may be associated with an inadequate ventilatory response to hypoxaemia.     

The effect of peripheral hypothermia on a vecuronium-induced neuromuscular block

Seven healthy patients were investigated during midazolam-fentanyl nitrous oxide-oxygen anaesthesia. The mechanical twitch response of the adductor pollicis muscle was recorded simultaneously during bilateral supramaximal train-of-four (TOF) stimulation of the ulnar nerves at the wrist. Intense neuromuscular block was evaluated using the post-tetanic count (PTC) method. Core temperature and the peripheral skin temperature of one arm were kept normal and stable. Following cooling of the other arm to a peripheral hand skin temperature of 27 degrees C, vecuronium was administered in a bolus dose of 0.05 mg.kg-1 followed by maintenance doses of 0.02 mg.kg-1. In the hypothermic and the normothermic arm the onset time following the bolus dose was 180 +/- 40 (mean +/- s.d.) seconds and 140 +/- 30 s, respectively, the duration of action was 26.4 +/- 4.5 and 16.5 +/- 4.0 min and the recovery time was 265 +/- 90 and 130 +/- 60 s (P less than 0.01). The time course of action following maintenance doses showed a similar marked difference between the hypothermic and the normothermic arm. In the normothermic arm a close correlation was found between the number of post-tetanic twitches and the time to first response to TOF stimulation. In contrast, in the hypothermic arm the number of post-tetanic twitches showed great variation with a poor correlation to the duration of intense neuromuscular block. It is concluded that the time course of action of a vecuronium-induced neuromuscular block is markedly prolonged during peripheral hypothermia and intense neuromuscular block cannot reliably be assessed using the PTC method at low peripheral temperature.(ABSTRACT TRUNCATED AT 250 WORDS)     

Profound atracurium induced neuromuscular blockade

Speed of reversal of profound atracurium induced neuromuscular blockade following edrophonium (0.5 or 1.0 mg/kg) or neostigmine (0.04 or 0.08 mg/kg) was measured using the train-of-four pattern of nerve stimulation. In all patients adequate clinical reversal was present when the ratio of the strength of the fourth to the first twitch (T4 ratio) was 0.5. Both doses of edrophonium were associated with a significantly faster speed of reversal than the smaller dose of neostigmine (p less than 0.05 in both cases). However, the larger dose of neostigmine was associated with a reversal time approaching that of edrophonium. Possible explanations for these findings are discussed in terms of contemporary theories of neuromuscular pharmacology.     

Relationship between posttetanic count and response to carinal stimulation during vecuronium-induced neuromuscular blockade

The correlation between degree of peripheral neuromuscular blockade and response to carinal stimulation was evaluated in two groups of 25 patients: one group was anaesthetized with thiopental, N2O and halothane, and the other group received thiopental, N2O and fentanyl. The degree of peripheral blockade was evaluated using train-of-four (TOF) and posttetanic twitch (PTC) stimulation of the ulnar nerve. The degree of diaphragmatic paralysis was evaluated indirectly by stimulating the carina and observing the corresponding muscular response, which was graded as severe, mild or absent. During halothane anaesthesia a PTC of 0 always indicated that no response to carinal stimulation could be elicited. On the appearance of the first response to posttetanic twitch stimulation (PTC = 1), 2% of the patients showed a mild response to carinal stimulation. At the first response to TOF stimulation, 48% of the patients reacted with a mild response. During thiopental, N2O, fentanyl anaesthesia one of 25 patients showed a mild response to carinal stimulation at a PTC of 0. When PTC was 1, 20% of the patients reacted mildly to the stimulation. At the first response to TOF stimulation, 92% showed a response to carinal stimulation; 24% of these responses were severe, necessitating intervention. It is concluded that the TOF response elicited peripherally is a late sign of neuromuscular recovery of the diaphragm, and that the method of counting posttetanic twitches is superior to the TOF response in evaluating early recovery of this muscle. Further, to ensure total diaphragmatic paralysis, the neuromuscular blockade of the peripheral muscles should be so intense that no response to posttetanic twitch stimulation (PTC = 0) can be elicited.     

Priming with anticholinesterases — the effect of different combinations of anticholinesterases and different priming intervals

This study was designed to investigate the effect of different combinations of neostigmine and edrophonium when administered in divided doses and the effect of different intervals (priming intervals) between the doses. Seventy-two patients divided into 12 groups (n = 6 in each) were included in the study. An initial dose of neostigmine 0.012 mg.kg-1 or edrophonium 0.2 mg.kg-1 was administered, followed at different priming intervals (1, 2 or 3 min) by either edrophonium 0.8 mg.kg-1 or neostigmine 0.048 mg.kg-1 for antagonism of atracurium-induced neuromuscular blockade. Reversal was attempted at 10 per cent spontaneous recovery of twitch height. Adequate reversal of neuromuscular block (train-of-four ratio of 0.75) was achieved in all patients. Significant (p less than 0.05) acceleration of the recovery index (time taken for the twitch height to recover from 25 to 75 per cent of control) and reversal time (time taken from the end of injection of the priming dose until TOF ratio value had reached 0.75) was obtained in groups which received edrophonium-edrophonium combination. Recovery indices and reversal times were found to be significantly shorter (p less than 0.05) with a 1 min priming interval. In two additional groups of patients premedicated and anaesthetized as the others equipotent mixtures of the antagonists were administered as a single bolus dose. Reversal times were significantly longer (p less than 0.05) when compared to those given the same amounts of the combination but in divided doses with a 1 min priming interval.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of neostigmine at different levels of mivacurium-induced neuromuscular blockade

The effectiveness of neostigmine 40 μg/kg for antagonism of two different levels of neuromuscular blockade, induced by a bolus dose of mivacurium 0.15 mg/kg, was studied in 45 patients. The patients were anaesthetized with thiopentone, fentanyl, nitrous oxide in oxygen, and enflurane. Neostigmine was administered at either 10% recovery of the twitch height (TH10) at the adductor pollicis muscle ( n =14) or upon reappearance of the first response at the orbicularis oculi muscle (OO1) after train-of-four (TOF) stimulation ( n = 16), the latter representing a deeper degree of neuromuscular blockade. Fifteen of the 45 patients did not receive neostigmine (control group). Neostigmine administration at OO1 rather than at TH10 at the adductor pollicis muscle caused reversal of neuromuscular blockade to occur 8 min earlier and shortened the time to reach 25% recovery of the twitch height (TH25) at the adductor pollicis muscle by about 5 min, compared with the control group. However, the time needed to reach a T4/T1 ratio ≥0.8 was similar in both the early and late neostigmine administration groups, being 9 min faster than in the control group. It can be concluded that there is no advantage in administering neostigmine at profound neuromuscular blockade to achieve clinically adequate recovery (T4/T1 ratio ≥0.8). However, the time between injection of mivacurium and TH25 may be shortened by using neostigmine at profound neuromuscular blockade, a procedure which may be useful in case of unpredictably difficult intubation, since diaphragmatic movements usually reappear at TH25.     

Reversal of profound paralysis: use of large doses of edrophonium to antagonize vecuronium and pancuronium induced neuromuscular blockade

The ability to evoke reversal of dense vecuronium- and pancuronium-induced paralysis (T1 10% of control) with edrophonium 1.0 mg.kg-1 was studied using train-of-four nerve stimulation and electromyographic monitoring. Two different end-points, train-of-four ratios of 0.5 and 0.7, were used to define "adequate reversal", and the results for both relaxants were compared. Reversal was reliable and rapid for vecuronium if either ratio was used with times of 2.8 (1.5) and 9 (3) min required to achieve ratios of 0.5 and 0.7, respectively. However, if the block was due to pancuronium, reversal was unreliable with 2 of 9 and 4 of 9 patients not achieving ratios of 0.5 and 0.7, respectively. Reversal was also markedly prolonged in this group with a mean time of 37 (23) min to achieve a ratio of 0.7, and in almost half these patients a supplementary dose of edrophonium was required.     

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.     

Train-of-Four recovery after pharmacologic antagonism of pancuronium-, pipecuronium-, and doxacurium-induced neuromuscular block in anaesthetized humans

Previous studies have suggested that the increased duration of action of long-acting neuromuscular relaxants may make their pharmacologic antagonism more difficult and, thus, increase the likelihood of residual block. This hypothesis was tested in healthy, adult humans who received a background of isoflurane/N₂O/fentanyl anaesthesia.
Study subjects were paralyzed with either pancuronium (N=8), pipecuronium (N=8), or the longer-acting relaxant, doxacurium (N=8). Neuromuscular function was monitored, and, using a blinded, randomized study design, the relaxants were titrated to identify the ED₉₅ dose in each patient. Thereafter, spontaneous recovery was observed until there was 25% ofbaseline response to the first supramaximal twitch (Tl) in a train-of-four (TOF). At this time, the block was antagonized with neostigmine 0.07 mg/kg and glycopyrrolate 0.014 mg/kg i.v., and recovery of TOF was recorded.
Spontaneous recovery to 25% of the baseline Tl response occurred at 52± 14 min (mean±SD) following administration of either pancuronium and pipecuronium, and 85 ±33 min following doxacurium ( P <0.05 for doxacurium versus pancuronium and pipecuronium). In doxacurium-rreated patients, reversal of block with neostigmine was less predictable and less complete than with the other two relaxants. For example, the ratio of the fourth to first twitch (T4/T1) of the TOF at 10 and 15 min after reversal was significantly less with doxacurium (59 ±14% and 61±16%, respectively) than with either pancuronium (75±6% and 75±10%) or pipecuronium (76±9% for both). At 30 min post-neostigmine, the incidence of residual block (i.e. T4/T1 <0.70) was: pancuronium 2 patients, pipecuronium 1 patient, and doxacurium 5 patients.
These studies support the hypothesis that incomplete reversal of neuromuscular block is more likely with longer-acting neuromuscular relaxants.     

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.     

The potencies of edrophonium and neostigmine as antagonists of pancuronium

Dose response curves were constructed for edrophonium and neostigmine when used to antagonise pancuronium, 0.07 mg/kg during thiopentone-nitrous oxide-halothane anaesthesia. The antagonist was given when 10% twitch height had been restored and the effect was measured 10 minutes later. Recoveries to 50% and 90% twitch height were achieved with 167 and 828 micrograms/kg of edrophonium, and 10.5 and 51 micrograms/kg of neostigmine. The dose response curves were parallel and neostigmine was 16 times more potent than edrophonium. Combinations of equipotent doses of edrophonium and neostigmine were also administered and produced additive but not synergistic effects. It is concluded that either edrophonium or neostigmine may be used for the reversal of pancuronium neuromuscular blockade, but the combination of the two offers no advantage.     

Recovery from neuromuscular blockade: residual curarisation following atracurium or vecuronium by bolus dosing or infusions

We conducted a survey of the incidence of Postoperative Residual Curarisation (PORC) in two groups of patients following the use of atracurium or vecuronium. In the first group (B) the neuromuscular blocking drugs were administered by bolus dosing, and in the second group (I) by continuous infusion. On arrival in the recovery room, neuromuscular function was assessed both by compound evoked electromyogram (EMG) in a train of four pattern and also clinically, by the ability to sustain a headlift for >5 seconds, and to cough. Results were obtained from 150 patients (100 in group B and 50 in group I). The incidence of PORC, as defined by a train of four ratio of <0.7, on arrival in the recovery room was 12% in group B, and 24% in group I. Clinical criteria of adequate neuromuscular reversal revealed different results, with the majority of patients being unable to perform either clinical test on arrival in recovery. Those patients in whom a peripheral nerve stimulator was used intra-operatively did not have a reduced incidence of PORC. We have demonstrated that PORC is still a common occurrence even with intermediate duration of action neuromuscular blocking drugs.     

Reversal of neuromuscular block

The effect on heart rate of different rates of injection (10 seconds, 1, 3 and 5 minutes) of a fixed dose (neostigmine 2.5 mg and atropine 1.2 mg) and a weight-related dose (neostigmine 50 micrograms/kg and atropine 25 micrograms/kg) of neostigmine-atropine mixture given for the reversal of residual competitive neuromuscular block was studied in 196 healthy adult patients. In both series slow injection lessened and delayed the initial rise in heart rate. The subsequent fall in heart rate was less when the drugs were injected over 3 min compared with the 10 seconds and 1 minute injection groups but when given over 5 minutes there was a steady fall in heart rate, more so with the weight-related dose. It is recommended that a neostigmine and atropine mixture should be administered over 3 min.     

The effect of ulinastatin pre-treatment on vecuronium-induced neuromuscular block in patients with hepatic cirrhosis

The aim of this study was to investigate the effect of ulinastatin, a protease inhibitor, on the neuromuscular block produced by vecuronium in patients with hepatic cirrhosis. Thirty adult patients with hepatic cirrhosis were randomly allocated to receive ulinastatin (cirrhosis/ulinastatin group, n = 15) or saline (cirrhosis/saline group, n = 15). Fifteen healthy adult patients without hepatic cirrhosis comprised a control group. Patients were given a standardised anaesthetic that included nitrous oxide and isoflurane in oxygen, and fentanyl. A bolus dose of ulinastatin 5000 unit x kg(-1) was given to members of the cirrhosis/ulinastatin group. The same volume of normal saline was given to the other two groups. Two minutes later, vecuronium 0.1 mg x kg(-1) was given. The onset of neuromuscular block was significantly slower in the cirrhosis/ulinastatin group than in the cirrhosis/saline and control groups (p < 0.05). Spontaneous recovery of neuromuscular function was significantly quicker in the cirrhosis/ulinastatin and control groups than in the cirrhosis/saline group (p < 0.05). The time course of recovery in the cirrhosis/ulinastatin and control groups was similar. We conclude that in cirrhotic patients, ulinastatin delays the onset of neuromuscular block produced by vecuronium. After pretreatment with ulinastatin, the speed of recovery from neuromuscular block in patients with cirrhosis becomes similar to that seen in healthy patients.