Pharmacodynamics of mivacurium chloride in 13- to 18-yr-old adolescents with thermal injury

J. A. J. Martyn*,1, Y. Chang1, N. G. Goudsouzian1 and S. S. Patel2

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


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Burned patients demonstrate resistance to the effects of non-depolarizing blocking drugs as a result of acetylcholine receptor changes. They also have decreased activity of plasma cholinesterase (PCHE), which metabolizes mivacurium. We hypothesized that decreased PCHE activity would decrease metabolism of mivacurium, and counteract the receptor-related resistance following burns.

Methods. Thirteen burned patients and six controls, aged 13–18 yr were followed in 27 studies. The burned patients were sub-classified as having 10–30% or >30% body surface area burn and were studied whenever possible at <=6 days, and at 1–12 weeks after the burn. Mivacurium pharmacodynamics were examined following a bolus (0.15 mg kg–1) 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 10–30% burn group at 1–12 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: 580–5

Keywords: complications, burn injury; enzymes, plasma cholinesterase; neuromuscular block, mivacurium


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Typically, burned patients exhibit resistance to the effects of non-depolarizing neuromuscular blocking drugs.1 2 This resistance is usually seen in patients with >=25–30% total body surface area (TBSA) burn, and it takes approximately 1 week to develop. The resistance to non-depolarizing neuromuscular blocking drugs is mostly related to qualitative changes (mature to immature receptor isoform conversion), and quantitative increases in the numbers of receptors.1 2 Mivacurium is a short-acting non-depolarizing neuromuscular blocking drug, which undergoes hydrolysis by the enzyme plasma cholinesterase (PCHE). Burned patients have decreased PCHE activity.3 This decreased enzyme activity is dependent on the magnitude of, and time after, burn injury.3 4 We have recently found a lack of resistance to mivacurium chloride in 2- to 12-yr-old patients with burn injury, when recommended doses of the drug were administered.5 A comparison of PCHE activity vs recovery from neuromuscular block indicated an inverse relationship between the two variables. An important variable affecting the response to drugs is age, and in addition to others, we have shown neuromuscular responses to be different between children and adolescents.6 Therefore, as an extension of the study in children, we present data relating to the neuromuscular effects of mivacurium in 13- to 18-yr-old adolescents. In the present study in adolescents with burn injury, the pharmacodynamics of mivacurium were examined in relation to the size of burn, time after burn, PCHE activity, and dibucaine number.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patients and study procedure
This study was approved by the Sub-committee on Human Studies, Committee on Research of the Massachusetts General Hospital, Boston, Massachusetts. Written informed consent was obtained from the patient and/or from the parent or guardian of all patients and controls included in the study. Twenty-one adolescent burned patients aged 13–18 yr, ASA physical status I–III, undergoing surgery consequent to thermal burn injury, were enrolled. The control group consisted of an additional six patients who had been burned more than 3 yr before the study. This control group was used, based on previous and current clinical observations that neuromuscular responses to relaxants are normal by 3 yr after burn injury, provided other confounding factors are absent.2 The acutely burned patients were sub-classified according to burn size as having 10–30% or >30% TBSA burn. Each of these (10–30% or >30% TBSA) burn groups was divided into sub-groups according to the time of the study: <=6 days, or 1–12 weeks after burn injury. For each subject who was studied at <=6 days after burn injury, every attempt was made to re-enroll that subject for a subsequent study at 1–12 weeks after the injury. The four burn groups in this study, based on burn size and time after burn injury, are summarized in Table 1. Two subjects, each with 10–30% and >30% TBSA burn, were not studied initially at <=6 days after burn because of delayed transfer to the burn unit, but were studied at 1–12 weeks after injury. One subject with 10–30% burns did not participate in the second study at 1–12 weeks.


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Table 1 Design of data collection from burn patient
 
Patients who were obese or had evidence of clinically significant asthma, renal, hepatic, psychiatric, neurological, neuromuscular, or cardiovascular disease were excluded from the study. Patients were also excluded if medications known to influence neuromuscular transmission were administered, or if clinically significant abnormalities in haematology (haemoglobin and platelet and white blood cell counts), and clinical chemistry tests (creatinine, alkaline phosphatase, or liver transaminases) were present. Venous blood was sampled at the time of the study to determine PCHE activity and dibucaine number.

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 (0.25–3% end-tidal concentration) in oxygen by a mask; supplemental bolus doses of fentanyl were administered as necessary during induction. Anaesthesia was maintained with halothane (0.5–1.0% end-tidal), nitrous oxide, and oxygen. During maintenance of anaesthesia, propofol (1 mg kg–1 i.v. bolus doses) along with narcotic agents (fentanyl 1–2 µg kg–1 or morphine 0.1–0.2 mg kg–1) 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 kg–1) 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 2–5 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 kg–1 min–1 and adjusted every 3 min, if necessary, in increments or decrements of 1–2 µg kg–1 min–1 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.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Two patients received gentamicin during the bolus-dose part of the study and their data, including physical characteristics, are not reported (Table 1). Three patients received i.v. gentamicin after the initial bolus dose of mivacurium had been given, and after 25% recovery of the single twitch response. This neuromuscular data was used for analysis of the bolus studies, but not of the infusion studies. Only patients whose data were usable are reported in Tables 25. Thus, the physical characteristics and neuromuscular data of 13 burned (total of 19 studies) and six controls (total six studies) are reported.


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Table 2 Physical characteristics of patients. Mean (SD); TBSA=total body surface area
 

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Table 5 Mean PCHE activity and dibucaine number. *Mean [SEM]; number of studies in parenthesis; +range; **P<0.001 compared with controls
 
The study population was comparable between groups (Table 2). At the recommended dose of mivacurium 0.15 mg kg–1, profound neuromuscular block was achieved in all patients (Table 3). Both groups of burned patients studied after 1–12 weeks achieved more rapid relaxation than the other sub-groups, although this effect was not statistically significant (P=0.092 for 10–30% burn and P=0.066 for >30% burn compared with controls). The trend for a faster onset of effect at <=6 days for both burn groups also did not attain statistical significance (Table 3). For patients with small (10–30%) burns, studied 1–12 weeks after injury, recovery of the single twitch height to 25% following the bolus dose of mivacurium was longer than that of patients in the control group (Table 3, P=0.008). In patients with >30% burns studied <=6 days after injury, this difference did not reach statistical significance (P=0.082).


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Table 3 Pharmacodynamics of mivacurium after bolus dose. Values are mean [SEM]; number of patients is in parentheses. *P<0.05 compared with controls, **0.05<P<0.10 compared with controls
 
With the exception of the small (10–30%) burn group studied <=6 days after injury, the average duration of continuous infusion was comparable between groups (Table 4). Mean infusion rate for patients with small burns (10–30%) studied at 1–12 weeks, and those with >30% burns studied at <=6 days after injury, were significantly lower than controls. The recovery profiles following termination of the infusion for all groups of burned patients, particularly in patients with >30% TBSA burns studied <=6 days after injury, showed slower rate of recovery compared with controls (P=0.05, 0.028, and 0.004 for time to T4:T1 ratio >=75%, time to 95% recovery of T1 in train-of-four, and time from 25 to 75% of T1 in train-of-four, respectively).


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Table 4 Mivacurium pharmacodynamics during and after continuous infusion. Values are mean [SEM]; number of patients in parenthesis. *P<0.05 compared with controls
 
The dibucaine numbers of patients with burn injury were comparable with those for the control group, irrespective of the time after burn or the size of burn injury (Table 5). Mean PCHE activity following burn injury was significantly suppressed compared with that of the control group (all P=0.001). There was no observable difference in the PCHE activity when related to time after, or magnitude of, burn injury. Regression analysis of pooled data from controls and burns indicated that recovery from mivacurium block was inversely related to PCHE activity; the lower the PCHE activity the longer the recovery. This relationship was observed both after the bolus (r=–0.73, P<0.001), and the infusion (r=–0.69, P<0.001) (Fig. 1). A curvilinear plot did not significantly improve the regression line.



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Fig 1 Correlation of PCHE activity to recovery from block, following infusion (upper figure) and bolus (lower figure). There was a significant inverse relationship between PCHE and recovery, following the infusion (R2=0.49, r=–0.7, P<0.001) and the bolus (R2=0.53, r=–0.73, P<0.001).

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The purpose of these studies was to examine the effects of burn size and time after burn on the neuromuscular effects of mivacurium. If all patients had received gentamicin at the same time, it would have been appropriate to include all of them and study the neuromuscular effects of mivacurium when combined with gentamicin. Because of the confounding pharmacodynamic effects of gentamicin when co-administered with neuromuscular blocking drugs, it was justifiable that patients receiving gentamicin be excluded. This resulted in a decrease in number per group, with the potential for type II error in the data. Despite the paucity of numbers, a major weakness of this study, statistical significance was still observed, and therefore certain definitive conclusions can be made.

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 1–12 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 1–12 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 10–30% 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 10–30% burn group at 1–12 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 1–12 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 kg–1 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.


    Acknowledgements
 
Supported in part by grants (to J.A.J.M.) from GlaxoWellcome, Shriners Hospitals for Children and from National Institutes of Health, GM31569-20, GM55082-6, and GM61411-4.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Ibebunjo C, Martyn JAJ. Thermal injury induces greater resistance to d-tubocurarine in local than in distant muscles in the rat. Anesth Analg 2000; 91: 1243–9[Abstract/Free Full Text]

2 Martyn JAJ, White DA, Gronert GH, Jaffe RS, Ward J. Up- and down-regulation of skeletal muscle acetylcholine receptors. Effects on neuromuscular blockers. Anesthesiology 1992; 76: 822–43[ISI][Medline]

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6 Goudsouzian NG, Martyn JAJ. Potentiation of mivacurium by rocuronium is age- and time dependent: a study in children, adolescents and young and elderly adults. J Clin Pharmacol 1997; 37: 649–55[Abstract/Free Full Text]

7 Mills AK, Martyn JAJ. Evaluation of atracurium neuromuscular blockade in paediatric patients with burn injury. Br J Anaesth 1988; 60: 450–5[Abstract]

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11 Martyn JAJ, Goudsouzian NG, Matteo RS, Liu LMP, Szyfelbein SK, Kaplan RF. Metocurine requirements and plasma concentrations in burned paediatric patients. Br J Anaesth 1983; 55: 263–8[Abstract]

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16 Martyn JAJ. Clinical pharmacology and drug therapy in the burned patient. Anesthesiology 1986; 65: 67–75[ISI][Medline]

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24 Hagen J, Martyn JAJ, Szyfelbein SKS, Goudsouzian NG. Cardiovascular and neuromuscular responses to high-dose pancuronium-metocurine in pediatric burned and reconstructive patients. Anesth Analg 1986; 65: 1340–5[Abstract]

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