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Anesth Analg 2000;91:1243-1249
© 2000 International Anesthesia Research Society

GENERAL ARTICLES

Thermal Injury Induces Greater Resistance to d-Tubocurarine in Local Rather than in Distant Muscles in the Rat

Chikwendu Ibebunjo, DVM, PhD, and J. A. Jeevendra Martyn, MD

Department of Anesthesiology and Critical Care, Harvard Medical School, Massachusetts General Hospital and Shriners Burns Hospital, Boston, Massachusetts

Address correspondence and reprint requests to J. A. J. Martyn, MD, Department of Anesthesia and Critical Care, Massachusetts General Hospital, 32 Fruit St., Boston, MA 02114. Address e-mail to martyn{at}etherdome.mgh.harvard.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We tested the hypothesis that resistance to d-tubocurarine (dTC) is more intense in muscles closer to, than distant from, burn, and is related to the expression of immature and total acetylcholine receptors (AChRs). Anesthetized rats received approximately 4% surface area burn over the tibialis muscle of one leg with the contralateral leg serving as control, or approximately 45% of the flank burn, with sham-burned pair fed controls. At 1, 4, 7, or 14 days later, the 50% effective dose of dTC, membrane AChRs, and messenger ribonucleic acid (mRNA) that encode the AChR {gamma}-subunit (AChR{gamma}-mRNA) were quantified in the tibialis. After the local leg burn, AChRs increased at Days 4, 7, and 14, and AChR{gamma}-mRNA at Days 4 and 7 after burn. The increased AChR{gamma}-mRNA correlated with total AChRs (r = 0.82), suggesting that the up-regulated AChRs may contain the immature isoform. The 50% effective dose of dTC after the local leg burn increased 1.2- to 1.5-fold at all periods and correlated significantly with AChRs (r = 0.54) and AChR{gamma}-mRNA (r = 0.57). After the flank burn, resistance was seen at Day 14 in association with muscle atrophy; AChRs and AChR{gamma}-mRNA were unaltered. The resistance to dTC after a local burn occurs sooner, is more marked, and is probably related to both increases and isoform changes in AChRs. The resistance at distant muscles appears unrelated to AChR changes.

Implications: The resistance to d-tubocurarine after a burn differs between muscles near and distant from the burn and seems to depend on quantitative and qualitative changes in acetylcholine receptors and muscle atrophy associated with the insult.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Aberrant responses to depolarizing and nondepolarizing muscle relaxants (NDMR) are often associated with burns, immobilization, and denervation. After immobilization or denervation, resistance (hyposensitivity) to NDMRs occurs together with muscle atrophy and up-regulated acetylcholine receptors (AChRs) on the muscle membrane (1–5). The up-regulated AChRs, after immobilization or denervation, express both mature and immature isoforms of the AChR, evidenced as increases of the messenger ribonucleic acid (mRNA) of all its subunits, including the {gamma}-subunit (1,6). The immature isoform of the AChR protein is composed of {alpha}-, ß-, {delta}-, and {gamma}-subunits. In the mature isoform, the {epsilon}-subunit replaces the {gamma}-subunit to form the receptor.

Hyposensitivity to NDMRs was seen after immobilization even in the absence of overt muscle atrophy (7), and also later when AChRs had returned to normal levels but the muscle was still atrophic (1). Reports of resistance after burns have also been conflicting. Decreased sensitivity to NDMRs has been reported in rats with (8) and without (9) up-regulation of AChRs. Conversely, a 50% flank burn that caused AChR up-regulation was not associated with resistance to d-tubocurarine (dTC) in the gastrocnemius of the rat (10). The up-regulation of AChRs in muscles distant from the burn may not be transcriptionally (gene) mediated (11,12). The sensitivity to NDMRs of the skeletal muscles directly under the burn, and its relationship to qualitative and quantitative changes in AChRs, have not been studied. Thus, the hypothesis tested in this study was that muscles closer to the burn would show greater resistance to NDMRs according to the level of expression of total and immature AChRs, and muscle atrophy. This hypothesis was tested by examining the relationship of pharmacodynamics of dTC in muscles near and distant from burn to muscle mass, the expression of total AChRs, and of the AChR {gamma}-subunit. Physiologically oriented functional studies, concomitantly performed in most of the animals reported herein, will be presented as a separate report.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The Institutional Subcommittee on Animal Research approved the study. Male Sprague Dawley rats (200–250 g) were allocated randomly to groups. The rats were weighed daily for 2 wk before and after burn, until the end of the study. After 2 wk of acclimatization, rats were anesthetized with pentobarbital, 60–70 mg/kg IP. To determine the local and distant effects of burns, the sensitivity of the tibialis muscle to dTC was measured after burn injury to one hind limb or to the trunk of rats, respectively. To produce local leg burn, both hind legs were shaved, and a hot brass block at 95°C was applied for 12 s on the skin over the tibialis muscle of one of the hind legs. A hot brass block, instead of scald injury, was purposely used to prevent the burn from extending over the knee or ankle joints, because this would immobilize the joints. A brass block at room temperature, applied to the contralateral leg, served as control. The burned and sham-burned legs were chosen at random. For body burn, the trunk of the anesthetized rat was shaved and a third degree burn, with sharp margins and anesthetic, of approximately 45% of total body surface area was produced, as described previously (13). Rats immersed in lukewarm water served as controls. All rats were fluid resuscitated with 10 mL of saline intraperitoneally, and kept warm with a heat lamp until recovery from anesthesia. Because burn injury causes significant lack of weight gain at Day 7 relative to sham burn, an additional food-restricted, sham-burned group was studied to quantify the neuromuscular effects of weight loss alone. The burn and sham-burn areas were dressed with 1% silver sulfadiazine cream.

At 1, 7, or 14 days after body burn, and at 1, 4, 7, or 14 days after the local leg burn, the potency of dTC in the tibialis muscles was measured simultaneously in both hind legs in vivo (1). Pentobarbital anesthetized rats were intubated and mechanically ventilated with air at 70 to 80 breaths/min and a tidal volume of 10 mL/kg (model 683; Harvard Apparatus Inc., South Natick, MA). The jugular vein was cannulated for fluid, and drug administration and anesthesia were maintained by intermittent doses of pentobarbital. The rectal temperature was maintained at 37° to 38°C by using a heat lamp.

The knees were fixed with clamps, and the tendons of the right and left tibialis muscles were attached to an FT-03 force transducer (Grass Instruments Co., Quincy, MA). A baseline tension of approximately 50 g, yielding optimal evoked tension, was applied to each muscle. Supramaximal stimuli of 0.2-ms duration, 2 Hz for 2 s every 12 s (train-of-four pattern) were applied to the sciatic nerves via a Grass SIU5 isolation unit, and the evoked tension was recorded (Western Graphtec, Irvine, CA). After stabilization for at least 15 min, the cumulative dose-response curves of dTC were determined simultaneously in both legs (1). Thus, it can be assumed that the blood concentration of dTC would be the same in both legs. IV dTC (20 µg/kg increments) was administered until the first twitch, T1, decreased to approximately 5% of baseline tension (95% depression) in both muscles. Attainment of peak effect for each dose was judged by three equal consecutive or increasing T1 responses. The times for twitch recovery to 50% of baseline levels were also noted. The entire tibialis muscle on both sides was then dissected out, weighed, wet-weight measured, and frozen in isopentane precooled in liquid nitrogen and stored at -70°C for later assay.

The AChRs on the muscle membrane were quantified by 125I-{alpha}-bungarotoxin (125I-{alpha}BTX), as described in detail previously (10). Briefly, the frozen muscle was thawed, homogenized in 0.01 M potassium phosphate buffer, pH 7.4, and centrifuged at 4°C. The precipitates were resuspended, homogenized, and AChRs extracted in 2% (v/v) Triton X-100 by shaking overnight at 4°C. Triplicate samples of the muscle extract were incubated with 2.5 nM 125I-{alpha}BTX (specific activity approximately 16.8 µCi/µg; DuPont NEN®, Wilmington, DE) in the 2% Triton X-100 buffer for 90 min. In parallel triplicate incubations, specific binding of 125I-{alpha}BTX was blocked using excess (1 µM) unlabelled {alpha}BTX. Whatman (Clifton, NJ) GF/B glassfiber filters, pretreated with polyethylenimine, were used to separate unbound toxin from receptor-toxin complexes. The {gamma}-radioactivity of each filter was counted (Tracor Analytic, Elk Grove Village, IL). The protein concentration of the muscle extract was assayed (BioRad Laboratories, Hercules, CA), and the AChRs were expressed as femtomoles per milligram of protein (fmol mg protein-1).

Total RNA was isolated from the muscle samples by the acid guanidinium isothiocyanate-phenol-chloroform method (14) and purified by using ribonuclease-free deoxyribonuclease (Boehringer-Mannheim, Indianapolis, IN) (15). The concentration and purity of the RNA were determined by spectrophotometric absorbance at 260 and 280 nm. A ratio of 1.7 to 2.0 was considered acceptable. The integrity of the RNA was verified by electrophoretic separation on 2% agarose gels and staining with ethidium bromide to visualize 18S and 28S ribosomal RNA. The expression of the mRNA that encodes the AChR{epsilon}- (AChR{epsilon}-mRNA) and {gamma}-subunits (AChR{gamma}-mRNA) was quantified by reverse transcriptase-polymerase chain reaction (RT-PCR). The primer sequences, amplification cycles, and the method of quantitation of PCR products have been described previously (1). The expression of ß-actin mRNA was used to control for intersample variations in the amount of RNA loaded for the RT-PCR reactions (6).

Thirty-six rats were used for the leg-burn study with 8, 10, 8, and 10 rats at Days 1, 4, 7, and 14, respectively. One rat in the Day-4 group died prematurely during the muscle function studies. Muscle samples from half of the rats at each time point were analyzed for membrane AChRs (n = 4–5), and the other half for gene expression (n = 4–5). A total of 36 rats was used for the body-burn study. The sample sizes were 4:3, 6:4, and 9:4 (burned/sham burned) at Days 1, 7, and 14, respectively, and six rats for the food-restriction groups. Three rats in the Day-14 group were excluded from the study because scab formation compromised full range movement in the hind leg. Muscles from 4 burned, 3–4 sham-burned, and 5 food-restricted rats were analyzed for AChR protein (right leg) and gene expression (left leg), respectively.

Dose-response curves to dTC were constructed on log-probit coordinates and the 50% effective dose (ED50) of dTC (µg/kg) was calculated. The paired t-test was used to compare the burned limb to the contralateral unburned limb. For the flank-burn study, analysis of variance and the Scheffé post hoc tests were used to compare the burned, sham-burned, and food-restricted groups at Day 7, whereas the unpaired t-test was used to compare the burn and sham groups at Day 1 or 14 posttreatment. The relationship of ED50 or the duration of action of dTC to muscle weight, membrane AChRs, and AChR{gamma}-mRNA expression was investigated by linear regression analyses. Results were expressed as mean ± SEM with P < 0.05 considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Hyperemia and edema were evident immediately after leg burn. Edema and hyperemia were less marked by Day 4, and by Day 7, the wound appeared dry and had shrunken to approximately 75% of its original size. By Day 14, the wound had healed and was nearly undetectable in the leg burn. The injured area after body burn decreased in size from approximately 45% to 38% and 31% by Days 7 and 14, respectively. At Day 14, the hard scab in three rats, as indicated previously, limited extension and flexion of the hip joint. Because of the potential confounding effects of limb immobilization on neuromuscular pharmacodynamics, these three rats were excluded from the study.

After local leg burn, the weight of the tibialis muscles was comparable among groups at Days 1, 4, and 7 postburn. However, at Day 14, the tibialis muscle on the burned side was significantly smaller than the contralateral side (Table 1).


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  		Table 1. Tibialis Muscle Weight (mg) After Local Leg Burn, Body Burn, or Food Restriction
 
Relative to pretreatment weights, flank sham burn caused weight loss at Day 1, followed by progressive weight gain. Body (flank) burn caused weight loss at Days 1 and 7, followed by a reduced rate of body weight gain at Day 14. Food restriction for 7 days also caused a decline in rate of body weight gain relative to prefood restriction rates. The tibialis muscle mass was similar among the groups at Day 1, but was significantly less at Days 7 and 14 after body burn compared with sham, and also relative to food restriction (at Day 7) (Table 1).

Total (mature and immature) AChR protein on the tibialis after leg burn was 0.57- (P > 0.05), 3.9-, 5.4-, and 3.0-fold (P < 0.05) the contralateral sham at Days 1, 4, 7, and 14 postburn, respectively (Table 2). Membrane AChRs in the tibialis muscles were comparable at all periods after flank burn, flank sham burn, and food restriction.


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  		Table 2. Expression of Membrane Acetylcholine Receptors (fmol mg protein-1) in the Tibialis Muscle After Localized Leg Burn, Body Burn, Sham Burn, or Food-Restricted Sham Burn
 
Expression of the AChR{gamma}-mRNA was nearly undetectable in tibialis muscles from the sham-burned limb after 25 PCR amplifications. Compared with the sham-burned limb, the AChR{gamma}-mRNA increased 1.6-, 2.7-, 3.4-, and 1.9-fold at Days 1, 4, 7, and 14, respectively, after the leg burn (Figure 1a). There was a significant positive correlation between AChR{gamma}-mRNA and total AChRs (r = 0.82, P = 0.0001) (Figure 2). The expression of the AChR{epsilon}-mRNA did not differ between burned and contralateral leg at any time (Figure 1b).



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  		Figure 1. The expression of transcripts of acetylcholine receptor (AChR){gamma} and AChR{epsilon} after burns. The expression of AChR{gamma}-messenger ribonucleic acid (mRNA), but not of AChR{epsilon}-mRNA, in the tibialis muscle increased at Days 4 and 7 after the local leg burn relative to sham burn (A and B). Flank burn did not alter the expression of AChR{gamma}-mRNA or AChR{epsilon}-mRNA in the tibialis muscle (C and D). *P < 0.05 between burned and sham-burned control.

 


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  		Figure 2. Correlation of acetylcholine receptor (AChR){gamma}-messenger ribonucleic acid (mRNA) to total membrane AChRs. The low levels of expression of AChR{gamma}-mRNA and membrane AChRs after sham burn (open symbols), and the increased levels of expression after burns (closed symbols), resulted in a positive correlation between the expression of AChR{gamma}-mRNA and total membrane AChRs (r = 0.82).

 
No differences were observed in the expression of AChR{epsilon}-mRNA, or AChR{gamma}-mRNA in the tibialis muscles between the flank-burned, sham-burned, and food-restricted rats (Figure 1, c and d).

The ED50 of dTC after leg burn was 1.2- to 1.5-fold greater compared with the contralateral side (Figure 3a). The time for spontaneous recovery of T1, to 50% of baseline tension, was also shorter on the burned leg at Days 4, 7, and 14 (Figure 3b). The ED50 of dTC correlated positively with the expression of AChR{gamma}-mRNA (r = 0.57, P = 0.0002) and total membrane AChRs (r = 0.54, P = 0.0015) in the tibialis after the local leg burn (Figure 4).



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  		Figure 3. The effects of a local leg burn or distant flank burn on the 50% effective dose (ED50) and duration of action of d-tubocurarine (dTC) in the tibialis muscle. There was an increase in the ED50 of dTC at all periods (A) and a decrease in the duration of action of dTC at Days 4, 7, and 14 (B) in tibialis muscles of the burned relative to sham-burned leg. After flank burn, the ED50 was increased at Day 14 (C), but the duration of action of dTC in the tibialis muscle remained unchanged relative to respective controls at all periods (D). Food restriction for 7 days did not alter the response of the tibialis muscle to dTC. *P < 0.05 between the burned and sham-burned control.

 


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  		Figure 4. The regressions of the expression of (A) acetylcholine receptor (AChR){gamma}-messenger ribonucleic acid (mRNA) and (B) membrane AChRs against the 50% effective dose (ED50) of d-tubocurarine (dTC) in the tibialis muscle after the local leg burn or sham leg burn. The ED50 of dTC in the tibialis muscle increased directly as the expression of AChR{gamma}-mRNA (r = 0.57, P = 0002) or total membrane AChRs (r = 0.54, P = 0015) increased.

 
The ED50 of dTC in the tibialis muscle after flank burn was comparable at Days 1 and 7, but greater at Day 14 compared with sham burn (Figure 3c). The ED50 of dTC in the food-restricted controls also did not differ from that of Day 7 after body burn (Figure 3, c and d). The duration of dTC block did not differ between flank-burned and sham-burned groups (Figure 3d). The ED50 and duration of action of dTC correlated inversely with muscle mass (4 = 0.47, P = 0.0001), but not with AChRs after the body burn (Figure 5).



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  		Figure 5. The relationship between muscle weight and 50% effective dose (ED50) of d-tubocurarine (dTC). The regression plot shows the inverse correlation between the ED50 of dTC and tibialis muscle mass after distant flank burn, sham burn, or 7 days of food restriction (r = 0.47, P = 0.0001).

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our study indicates that the time course, magnitude, and underlying mechanisms of the resistance to dTC in the tibialis muscle vary depending on whether the muscle is near or distant from the burn. After a localized leg burn, resistance to dTC was evident by Day 1 and persisted throughout the observation period at 4, 7, and 14 days after injury. Up-regulation of membrane AChRs and/or AChR{gamma}-mRNA was observed at Days 4, 7, or 14 after the burn injury, with a positive correlation between ED50 of dTC and AChRs or AChR{gamma}-mRNA. There was also a positive correlation between expression of total AChRs and AChR{gamma}-mRNA. In contrast, the flank burn induced resistance only at Day 14, when muscle had atrophied; no changes in receptor number or its transcripts were observed. In the food restricted, sham-burned rats, despite decreased body weight gain, neither the ED50 of dTC nor AChRs or AChR{gamma}-mRNA were altered.

In humans, resistance to benzylisoquinoline and steroidal NDMRs was observed at seven or more days after greater than or equal to 30% body surface area burn (16–21). Reports in animals have been conflicting. Kim et al. (8) reported resistance to dTC in the gastrocnemius muscle at Days 7 and 14 after a 50% flank burn, with a direct association between the ED50 of dTC and AChRs in splenectomized rats. Marathe et al.(9) and Pavlin et al. (23) found resistance to atracurium only at 30 to 60 days after a 30% flank burn with no AChR changes in the rat gastrocnemius. Ward and Martyn (10) reported no change in ED50 of dTC in the rat gastrocnemius at Days 10, 14, 21, and 28 after a 20% to 50% flank burn, although the expression of AChRs was increased. The up-regulation of AChRs in the distant gastrocnemius muscle after the flank burn was probably not transcriptionally mediated, because the transcripts, including the expression of AChR{gamma}-mRNA, were not altered (11,12).

Besides differences in burn size and time after the burn, the most likely reasons for these discrepancies are probably the presence or absence of muscle disuse, and the location of muscle relative to site of injury. Although animals are allowed free movement in their cages, almost all humans are immobilized in bed after burns. Muscle disuse or immobilization by itself causes resistance to nondepolarizing neuromuscular blocking drugs (1,2), and can confound the neuromuscular pharmacodynamics. The present study specifically excluded rats in which burn scars limited limb movement. Thus, in the absence of concomitant immobilization, up-regulation of AChRs was not seen at the distant tibialis muscle after the flank burn.

Potential mechanisms that might explain the hyposensitivity to NDMRs include increased junctional and extrajunctional localization of AChRs, expression of the immature isoform of the AChR, increased levels of acetylcholine, and changes that limit access of drug to AChRs. The mechanism of the resistance to dTC at Day 1, with no changes in AChR, is unclear. Subtle receptor changes, not detectable by the analytical methods that we used, might have been present at Day 1 postburn. The increased ED50 at Days 4, 7, and 14 after local burn, was paralleled by changes in AChR expression in the same muscle. These observations are consistent with the preliminary report by Pavlin et al.1 of resistance to atracurium with up-regulation of AChRs at two and four weeks after a localized leg burn. The superimposition of a 40% flank burn on the 4% leg burn accentuated the resistance and up-regulation of AchRs.1 The role of AChR up-regulation in the resistance to dTC was supported by the positive correlation between the ED50 with membrane AchRs (r = 0.54). The ED50 of dTC also correlated significantly with AChR{gamma}-mRNA (r = 0.57). Furthermore, there was good correlation between AChR{gamma}-mRNA and total AChRs (r = 0.82), suggesting that the up-regulated AChRs may have consisted of a modest number of the immature isoform of the receptor (6).

Irrespective of isoform, up-regulation of mature and/or immature AChRs at the peri-junctional area would increase the amount of the NDMRs required to competitively block acetylcholine (24). Expression of immature AChRs at the junction might also induce resistance because of the partial agonist effects of dTC at immature AchRs (25). A reduced affinity of immature AChRs for NDMRs has also been reported by some authors (26), but not by others (27). These observations together thus suggest that both qualitative and quantitative changes in AChRs are important determinants of the hyposensitivity to dTC of muscles beneath the burn. The lack of a suitable commercially available antibody to the rat AChR{gamma}-subunit protein precluded the characterization of mature versus immature protein isoform expressed peri-junctionally.

The altered neuromuscular sensitivity to dTC after the distant flank burn cannot be explained by AChR changes, as none were observed. The previous observation of resistance to dTC with increased AChRs at distant muscles (8) may have been related to the confounding effects of limb immobilization produced by the burn scab. However, the hyposensitivity observed at Day 14 after the flank burn in the present study may be related to the relative muscle atrophy that was associated with the flank burns; indeed, there was an inverse relationship between muscle mass and the ED50 of dTC. This is consistent with findings in later stages of immobilization in which resistance to dTC occurred in the absence of changes in AChRs, and correlated with muscle mass (1).

In summary, our study demonstrated that in muscles distant from a burn, resistance to dTC was slow in onset and correlated with muscle atrophy. Despite the small magnitude of local burn, resistance was rapid in onset (within 24 hours), and persisted for at least 14 days after the burn. A four-fold up-regulation of AChRs and transcript of the {gamma}-subunit were seen as early as Day 4 after the local burn, suggesting that the up-regulated receptors may have consisted of the immature isoform. Thus, the resistance to nondepolarizing NDMRs after burns differs between muscles near and distant from the burn, and depends on the level of expression of immature AChRs, mature AChRs, and muscle atrophy associated with the insult.


   Acknowledgments
 
This work was supported by National Institutes of Health RO1 Grants GM 31569-18, GM 55082-04, and GM 61411-01 to JM.


   Footnotes
 
1 Pavlin EG, Howard M, Slattery JT. Large burns magnify and prolong increases in acetylcholine receptors and resistance to non-depolarizing muscle relaxants in muscle under burned skin in rats [abstract]. Anesthesiology 1994;81:A1105. Back


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication July 10, 2000.




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J. A. J. Martyn, Y. Chang, N. G. Goudsouzian, and S. S. Patel
Pharmacodynamics of mivacurium chloride in 13- to 18-yr-old adolescents with thermal injury
Br. J. Anaesth., October 1, 2002; 89(4): 580 - 585.
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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2000 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press