1 Department of Anesthesiology and Critical Care, Harvard Medical School, Massachusetts General Hospital and Shriners Hospital for Children, Boston, MA 02114, USA. 2 Anaesthesia Clinical Research, GlaxoWellcome, Research Triangle Park, NC 27709, USA*Corresponding author
Accepted for publication: June 10, 2002
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Abstract |
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Methods. Thirteen burned patients and six controls, aged 1318 yr were followed in 27 studies. The burned patients were sub-classified as having 1030% or >30% body surface area burn and were studied whenever possible at 6 days, and at 112 weeks after the burn. Mivacurium pharmacodynamics were examined following a bolus (0.15 mg kg1) dose, and during and after a continuous infusion.
Results. Following a bolus, the onset time and the maximal effect were similar to controls. Recovery was prolonged in the 1030% burn group at 112 weeks (P<0.008), with a similar trend in the >30% burn group at 6 days (P<0.082) compared with controls. The infusion requirements for mivacurium were not increased in the burned groups. The PCHE activity was decreased in all burn groups and was inversely related to recovery following the bolus (r=0.73, P<0.001) and the infusion (r=0.69, P<0.001).
Conclusion. In contrast to previous studies with non-depolarizers in burned patients, normal mivacurium doses can produce paralysis, at least as rapidly as in controls, but with a possibility of a prolonged recovery from block. The standard dose of mivacurium in the presence of decreased PCHE activity is in effect, a relative overdose that explains the above findings. Mivacurium is an effective drug for use in burns, irrespective of time after, or magnitude of burn injury.
Br J Anaesth 2002; 89: 5805
Keywords: complications, burn injury; enzymes, plasma cholinesterase; neuromuscular block, mivacurium
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Introduction |
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Methods |
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Anaesthesia
Preoperative medication consisted of a benzodiazepine and/or narcotic, administered orally or i.v. depending on the presence or absence of an i.v. line. Monitoring consisted of electrocardiography, non-invasive arterial pressure (except in those patients who had an indwelling arterial cannula), pulse oximetry, end-tidal carbon dioxide, and temperature continuously. Anaesthesia was induced with propofol, or halothane (0.253% end-tidal concentration) in oxygen by a mask; supplemental bolus doses of fentanyl were administered as necessary during induction. Anaesthesia was maintained with halothane (0.51.0% end-tidal), nitrous oxide, and oxygen. During maintenance of anaesthesia, propofol (1 mg kg1 i.v. bolus doses) along with narcotic agents (fentanyl 12 µg kg1 or morphine 0.10.2 mg kg1) were administered as anaesthetic supplements. Ventilation was controlled to maintain normocapnia.
Pharmacodynamics
After induction of anaesthesia, the ulnar nerve was stimulated with a Grass S48 stimulator through 25-gauge needles inserted into a forearm, immobilized on a padded board. The thumb was linked to a Grass FT03 force transducer, and the evoked twitch tension of the adductor pollicis was recorded as twitch height on a Grass strip-chart recorder. Single square-wave stimuli of 0.2 ms duration were administered at 0.15 Hz. An initial tetanus of 30 s duration was administered to recruit all muscle fibres. Control twitch height was obtained from a stable baseline recording of at least 5 min before the administration of mivacurium. Initially, mivacurium was administered as a bolus (0.15 mg kg1) and later as an infusion. Towards the end of the surgical procedure, the continuous infusion of mivacurium was stopped. Following termination of the infusion, the stimulation mode was changed to supramaximal train-of-four stimuli (0.2 ms square waves), administered at 2 Hz. End-control twitch height was determined after at least 3 min recording a stable height of the first twitch of the train-of-four, and the train-of-four ratio (T4:T1) of 75%.
Intubation proceeded 25 min after the initial dose of mivacurium, when maximal twitch suppression was reached. The recovery of the twitch to 25% of baseline (control) height was monitored. The second part of the study consisted of a continuous infusion of mivacurium. Following recovery of the twitch after the bolus dose to 25%, additional mivacurium bolus doses were administered, followed by a continuous infusion to maintain neuromuscular suppression at 95 (SD 4)% (i.e. 5 (4)% initial twitch height). The continuous infusion rate was started at 20 µg kg1 min1 and adjusted every 3 min, if necessary, in increments or decrements of 12 µg kg1 min1 to maintain neuromuscular block within the range of 95 (4)%.
The following variables were determined: following bolus doses, the maximum twitch suppression, onset time (from completion of mivacurium injection to maximum twitch suppression), and clinically effective duration time (from completion of injection of the bolus dose to 25% twitch recovery). Times were also noted after stopping the continuous infusion to 25, 75, and 95% recovery of the first twitch of the train-of-four relative to end-control, and to T4:T1 75%. Average infusion rates for each patient who received a continuous infusion for a minimum of 30 min were also recorded.
Data analysis
Analysis of variance techniques were used to compare outcomes between groups. As a result of the small sample size of the study, statistical tests were restricted to comparisons between each burn group and controls. That is, no intra-burn group comparisons were made. Adjusted P values were reported from Dunnett multiple comparisons procedure. Pearson correlation coefficient (r) was used to summarize the relationship between PCHE activity and recovery time. A P<0.05 was considered statistically significant.
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Results |
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Discussion |
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The salient findings in this study of mivacurium pharmacodynamics in burned and control adolescent patients were: (1) a trend to a faster onset time in burn patients compared with controls (Table 3), with maximal effect similar in all groups; (2) the profiles of neuromuscular recovery being similar to, or prolonged in burned patients relative to controls after bolus doses and continuous infusions (Table 4); (3) with the exception of >30% burn at 112 weeks, the mean infusion rates were decreased in the burn groups compared with controls (Table 4); and (4) PCHE levels, but not dibucaine levels, were decreased in burned patients (Table 4) with an inverse relationship between PCHE activity and the recovery profile (Fig. 1).
Burned patients have resistance to both benzylisoquinoline and steroidal neuromuscular blocking drugs,712 demonstrated as inadequate paralysis from an ED95 dose, a requirement for higher doses for a given effect, prolonged onset of effect, faster recovery, more frequent dosing intervals, and/or higher infusion rates. The present results with mivacurium fulfil none of these criteria for resistance. The onset was similar to or faster than controls, maximal effects were the same, recovery rates were the same or prolonged, and infusion rates were similar or lower in burned patients compared to controls. This study shows evidence of prolonged recovery, which suggests that burned adolescents may demonstrate increased sensitivity to mivacurium. This study is therefore, consistent with previous studies of mivacurium in children5 and adults,13 showing that burned patients do not exhibit resistance to mivacurium. The adult study, however, did not discriminate between the effects of burn size and time after burn on pharmacodynamics or PCHE activity.
Causes for the resistance to non-depolarizers following burns include: increased protein binding;14 enhanced clearance kinetics;15 16 and most importantly, upregulation of acetylcholine receptors.17 18 Although acetylcholine receptor changes were not quantified in this study, one can assume, based on previous animal1 17 18 and human studies,19 that qualitative and quantitative changes were present at the muscle membrane, especially in patients with the bigger burns at 112 weeks after injury. One may be surprised, therefore, that our burned patients did not demonstrate resistance to the competitive neuromuscular blockers, mivacurium.
The rationale for sub-classification of our burn groups was to quantify the effect of time after burn, and magnitude of burn on mivacurium pharmacodynamics. The PCHE activity was decreased in all burn groups. In 1030% TBSA burned patients, resistance will not be seen at any time, as clinically significant receptor changes usually do not occur with minor burns. Even in patients with >30% burn at 6 days, receptor changes are not expected. Thus, the lower mivacurium infusion rates relative to controls, observed in the 1030% burn group at 112 weeks, and >30% group at
6 days, may be related to a lower PCHE activity in the absence of upregulation of acetylcholine receptors. In contrast, in patients with >30% burns studied at 112 weeks after the insult, resistance to non-depolarizing neuromuscular blockers usually occurs because of receptor changes. In the present study, receptor changes were probably present in these patients, as the infusion requirement of mivacurium was similar to that of controls, despite the lower PCHE activity. This suggests that resistance had developed to mivacurium at the receptor level, but the kinetic effect of lowered metabolism counteracted this resistance, resulting in an infusion rate similar to controls. In other words, the receptor-related (dynamic) resistance was counterbalanced by the kinetic component, decreased metabolism of mivacurium because of depressed PCHE activity.
The dibucaine numbers were not different between groups, and therefore one can rule out hereditary factors or qualitative changes in PCHE activity, causing prolonged recovery from mivacurium in the burned patients. The PCHE activities, however, were lower in all burned patients (Table 5 and Fig. 1). Thus, the usual bolus dose of mivacurium 0.15 mg kg1 in the presence of decreased PCHE activity is a relative overdose. This explanation is consistent with findings in other diseases associated with acquired decreases in PCHE activity. The onset of effect with mivacurium can be similar or faster but recovery is prolonged.20 21 Our study also confirms an inverse relationship between PCHE activity and recovery from paralysis following a bolus dose or infusion. These findings are consistent with other observations of the importance of PCHE in the recovery from mivacurium.22
A good substitute for succinylcholine for use in burned patients is currently not available. Rapid onset of paralysis for intubation of burned patients with a full stomach, or for the treatment of laryngospasm requires higher than normal doses of non-depolarizing relaxants.2 24 The prolonged onset of effect is a serious disadvantage when treating laryngospasm in burned patients, who can desaturate rapidly because of the hypermetabolic state and poor lung function.25 This study documents that normal (ED95) doses of mivacurium, can produce effective paralysis, at least as rapidly as in normal patients.
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Acknowledgements |
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References |
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