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PEDIATRIC ANESTHESIA

The Effect on Lung Mechanics in Anesthetized Children with Rapacuronium: A Comparative Study with Mivacurium

Gavin F. Fine, MB, BCh^*, Etsuro K. Motoyama, MD^*, Barbara W. Brandom, MD^*, Kathleen M. Fertal, BSN^*, Rebecca Mutich, RRT, and Peter J. Davis, MD^*

*Department of Anesthesiology and Division of Pulmonology, Children’s Hospital of Pittsburgh; and the Departments of Anesthesiology and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Address correspondence and reprint requests to Gavin F. Fine, MB, BCh, Children’s Hospital of Pittsburgh, Department of Anesthesiology, 3705 Fifth Ave., Pittsburgh, PA 15213. Address e-mail to finegf{at}anes.upmc.edu

	Abstract

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The administration of rapacuronium increases the risk of severe bronchospasm. There have been no studies of pulmonary function directly demonstrating airway constriction with rapacuronium in children. In this study, 10 ASA physical status I or II patients (aged 2–6 yr) were randomly divided into 2 equal groups, receiving either rapacuronium or mivacurium. Anesthesia was induced with sevoflurane and maintained with remifentanil (0.2–0.3 µg · kg^-1 · min^-1) and propofol (200–250 µg · kg^-1 · min^-1) infusions. We performed three sets of pulmonary function tests: baseline, after the administration of muscle relaxant, and after the administration of a ß₂ agonist. In both groups, there were no changes in static respiratory compliance. The increase in total respiratory system resistance after the administration of rapacuronium did not reach statistical significance (214.4% ± 122.65% of baseline, P 0.1), whereas maximal expiratory flow at 10% of forced vital capacity (MEF)₁₀ and MEF_{functional residual capacity} on partial flow-volume curves by the forced deflation technique decreased markedly (53.4% ± 18.49%, P < 0.01 and 41.3% ± 27.42%, P < 0.001, respectively). With the administration of mivacurium, no changes were observed in respiratory system resistance (109.5% ± 30.28%). MEF₁₀ decreased slightly (77.0% ± 9.03%, P < 0.005) whereas MEF_FRC did not (81.2% ± 29.85%, not significant). After the administration of a ß₂ agonist, all measurements returned to baseline. Thus, the administration of rapacuronium consistently results in lower airway obstruction with minimal changes in static respiratory compliance when compared with mivacurium.

IMPLICATIONS: Pulmonary function tests in the present study showed that rapacuronium consistently causes severe bronchoconstriction, confirming clinical case reports of bronchospasm. The bronchoconstriction is reversible with albuterol. Mivacurium also causes very mild subclinical bronchoconstriction.

	Introduction

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The use of neuromuscular blockers to facilitate intubation is routine for many surgical procedures. For pediatric ambulatory surgical patients, the ideal muscle relaxant should be of rapid onset and short duration and have minimal side effects. Rapacuronium and mivacurium are two neuromuscular blocking drugs of short duration (1–5). Large doses of mivacurium have been associated with histamine release (6) whereas rapacuronium administration has been associated with bronchospasm (as evidenced by decreases in dynamic compliance and difficulty in patient ventilation) (7–10). Bronchospasm associated with rapacuronium administration was initially (in phase III studies) thought to occur only at larger doses, to be clinically insignificant, and to be related to inadequate (light) anesthesia (1,3). However, recent case reports suggest that bronchospasm after rapacuronium administration can be severe and possibly life threatening (7–9).

We hypothesize that the incidence and severity of lower airway obstruction with rapacuronium is more than that seen with the administration of mivacurium as a control drug. The present study was undertaken to find whether rapacuronium indeed causes bronchospasm and to quantify the effects of rapacuronium in comparison with those of mivacurium on respiratory mechanics in well-anesthetized children using pulmonary function tests (PFTs) highly sensitive to lower airway function, which have been specifically developed for intubated infants and children (11).

	Methods

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After approval of the IRB for human experimentation and informed parental consent were obtained, 10 patients between the ages of 2 and 6 yr were enrolled in the study. All patients were ASA physical status I or II and were scheduled to undergo dental or genitourinary surgery, which required tracheal intubation. Excluded from the study were patients with cardiopulmonary disease, reactive airway disease requiring bronchodilator treatment within the past 6 mo, abnormalities of the musculoskeletal system, known pseudocholinesterase deficiency, or a history of egg allergy. Consistent with the daily practice of pediatric anesthesia in the spring season, many children had a history of recent upper respiratory infection (URI) whereas others had a history of asthma or wheezing, although none of them were symptomatic at the time of the study. There were patients with a history of URI and reactive airway disease in both treatment groups.

All patients underwent induction of anesthesia with sevoflurane combined with nitrous oxide and oxygen in a 2:1 mixture. After induction, an IV catheter was inserted, sevoflurane discontinued, and a continuous IV infusion of propofol (200 to 250 µg · kg^-1 · min^-1) and remifentanil (0.2 to 0.3 µg · kg^-1 · min^-1) was begun. With adequate anesthesia (no significant changes in hemodynamic variables and no patient movement with laryngoscopy) and an application of 1 to 2 mL of 1% lidocaine (depending on the patient’s size) to the larynx, the patient’s trachea was intubated with an appropriately sized cuffed endotracheal tube. At least 5 min after beginning the infusions and when the end-tidal sevoflurane concentration was <0.2%, the first (baseline) set of PFTs was performed. Then, either rapacuronium (1.5 mg/kg) or mivacurium (0.3 mg/kg) was given, as selected by randomization. The investigators were blinded to the selection of the test drugs.

The patients were manually ventilated by one investigator, who was unaware of the muscle relaxant given or the PFT results displayed on the oscillograph, to determine whether changes in resistance or dynamic compliance could be detected. Two to 3 min after the administration of the study drug, when neuromuscular monitoring confirmed complete neuromuscular blockade, the second set of PFTs was obtained. If oscillographic tracings of PFTs were suggestive of bronchoconstriction, 2 puffs of albuterol in a metered dose inhaler were administered via a nebulization chamber and the third set of PFTs was obtained 8 min after albuterol administration.

All patients were monitored during and after the experimental period with standard monitoring for perianesthetic care, which included continuous auscultation of the chest by means of a precordial stethoscope, electrocardiograph, pulse oximeter, respiratory and anesthetic gas monitors, axillary or esophageal temperature readings, and noninvasive measurements of systemic blood pressure repeated every 3 to 5 min.

The techniques of PFTs in anesthetized children have previously been described by Motoyama et al. (11) and LeSouëf et al. (12). The application of these techniques in this study is briefly described herein. The maximal expiratory flow-volume (MEFV) curve was produced by 3 slow deep inspirations of the lungs to the peak airway pressure of +40 cm H₂O. The maneuver standardized the volume history of total lung capacity (TLC). The lungs were then rapidly deflated from TLC to residual volume by pushing a slide bar of a 3-way valve in one stroke, which occluded the inflow gas and quickly opened the airways to a large (60 L) negative pressure reservoir (-40 cm H₂O). The lungs were rapidly deflated through a pneumotachograph until the expiratory flow ceased at residual volume or up to 3 s. The expiratory flow and integrated volume signals were instantaneously displayed on an X-Y storage oscillograph and the resultant MEFV curve was photographed for inspection and later analysis. After each MEFV curve maneuver, the lungs were reinflated to TLC. With this maneuver, consecutive MEFV curves are completely or nearly identical (11); two to three MEFV curves were obtained. From the MEFV curve, forced vital capacity (FVC) and a maximal expiratory flow rate at 10% of FVC (MEF₁₀) were measured. Maximal expiratory flow rates (MEFs) toward the lower end of MEFV curves are effort independent (or, in this case of artificially produced effort, independent of the applied expiratory negative pressure) (13). According to the equal pressure point theory of Mead et al. (13), MEF at the flow limited segment of MEFV curves are determined, not by the degree of effort (or, in this case, expiratory pressures applied to the airway opening by the forced expiratory maneuvers), but by the elastic recoil pressure of the lung (P_stl) and the resistance of airways upstream (peripheral) to the airways that are subjected to dynamic compression (upstream segment, R_us) as indicated by the following equation, MEF = P_stl/R_us.

In healthy adults and children, the equal pressure point is located in the intrathoracic (central) airways (13,14). MEF, therefore, is independent of the events in the upper (extrathoracic) and large intrathoracic airways, including the endotracheal tubes. MEFs on MEFV curves, therefore, are a very sensitive index of the patency of relatively small airways (13,14).

The partial expiratory flow-volume (PEFV) curve was produced in a similar manner, except that the negative airway pressure (-40 cm H₂O) was applied after a partial inflation of the lungs to a tidal end-inspiratory level (10 cm H₂O). From a PEFV curve, MEF at functional residual capacity (FRC) (MEF_FRC) was obtained.

Static compliance and resistance of the respiratory system (C_rs [mL/cm H₂O] and R_rs [cm H₂O · mL^-1 · s^-1], respectively) were obtained during the passive expiratory maneuver from the end-inspiratory pause at 10 cm H₂O. C_rs is tidal volume/10/cm H₂O, whereas R_aw is the estimated expiratory flow (_E) at time zero (₀) (by extrapolating backwards the linear portion of the declining passive expiratory flow curve with time) divided by the airway opening pressure (R_aw = 10/₀) (15).

The order of measurements was: 1) C_rs/R_rs maneuver (passive expiration from end-inspiratory hold at 10 cm H₂O) x 2, 2) PEFV curves x 3, 3) MEFV curves x 3, and 4) C_rs/R_rs maneuver x 2.

The analyses of PFTs were performed by an investigator who was blinded for the choice of the test drug. A difference between the baseline and postmuscle relaxant values of >10% of C_rs and >30% of flow functions were considered clinically significant (16). Paired t-tests were used for each index of lung and airway function. A probability of <5% was considered significant.

	Results

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The study was prematurely terminated after 10 patients had been enrolled (5 patients were exposed to each neuromuscular blocker) because rapacuronium was voluntarily withdrawn from clinical use by the manufacturer. Six boys and 4 girls between the ages of 2.5 and 5.8 yr (body weight, 11.0–22.7 kg) were studied. There were neither differences in demographics nor any hemodynamic differences between the two groups (Table 1). Of the 5 children in the Mivacurium group, 3 had a recent history (within 3 wk) of URI and 1 a history of reactive airway disease (asymptomatic >6 mo); in the Rapacuronium group, 2 children were healthy, whereas 2 others had a history of asthma (asymptomatic), and the remaining child had a recent URI.

View larger version (14K): [in this window] [in a new window]   Figure 1. A typical example of the effect of rapacuronium on partial expiratory flow-volume curves, as obtained by the forced deflation technique (11), from a 3-year-old child under total IV (propofol/remifentanil) anesthesia. 1 = The baseline flow-volume curve, 2 = a flow-volume curve, executed under the same volume and pressure settings as 1, but obtained after a single-dose infusion of rapacuronium. There is a severe decrease in peak expiratory flow, a flattening of the forced expiratory flow-volume curve, and a decreased forced expiratory volume. The severe decrease in maximal expiratory flow at functional residual capacity (MEFFRC) form the baseline value together with the concavity of the curve toward the volume axis indicate the involvement of relatively small airways (see text).

View larger version (17K): [in this window] [in a new window]   Figure 2. A typical example of the effect of mivacurium on partial flow-volume curves, as obtained by the forced deflation technique (11), from a 3-year-old child under total IV (propofol/remifentanil) anesthesia. 1 = The baseline flow-volume curve, 2 = a flow-volume curve, executed under the same volume and pressure settings as 1, but obtained after a single-dose infusion of mivacurium. In this case, there is a mild-to-moderate decrease in maximal expiratory flow at functional residual capacity (MEFFRC), whereas peak expiratory flow and expiratory volume are unchanged (see text).

A reduction in "dynamic compliance" (or increase in stiffness of the lung) after the administration of a muscle relaxant while manually ventilating the patient was clinically noticeable by a blinded investigator in only one of five patients in the Rapacuronium group, whereas no reduction in "dynamic compliance" was noted in any of the patients in the Mivacurium group. There were no episodes of desaturation or hemodynamic changes associated with the administration of rapacuronium or mivacurium while the patients were ventilated with 60% N₂O in O₂.

In 1 patient receiving rapacuronium and not given albuterol initially, the third set of PFTs, obtained 1 h after the initial postrelaxant PFTs, still showed the same degree of bronchoconstriction as the second PFT set (shortly after the administration of the relaxant), even though the neuromuscular blockade had long been gone. In contrast, in the remaining four patients, in whom bronchoconstriction was judged severe enough to warrant the administration of a bronchodilator (albuterol), bronchoconstriction was immediately and completely reversed.

	Discussion

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There have been several case reports of patients with severe bronchospasm related to the administration of rapacuronium, as evidenced by marked decreases in dynamic compliance, great difficulty in manual ventilation of the patient, and oxygen desaturation (17). When this study was designed, the physiologic characteristics and potential incidence of purported bronchoconstriction in patients after rapacuronium administration were unknown. We therefore planned a pilot study to examine the effect of rapacuronium on lung mechanics, as compared with that of mivacurium as a control, using the pulmonary function techniques that are the most sensitive measurements for assessing changes in lower airway function (11,12).

Although the sample size was small because of the drug company’s voluntary withdrawal of the rapacuronium from clinical use (thus prematurely terminating the study), the study’s results clearly demonstrated adverse effects of rapacuronium on decreased airway function. In all five children studied, the administration of even the smallest recommended dose of rapacuronium consistently produced marked bronchoconstriction. This was evidenced by the severe decrease in the MEF rates on both the MEFV and PEFV curves produced by the forced deflation technique (11). This bronchoconstriction occurred in healthy children as well as those with a recent URI or a history of asthma. Together with changes in flow-volume curves, R_rs also increased in most patients, although it did not reach statistical significance (P 0.1) because of large variations in R_rs changes (i.e., large SD), whereas C_rs was unchanged. These findings indicate that the decreased dynamic compliance reported in the literature was apparently caused by increased airway resistance, but not by parenchymal changes in the lungs, such as atelectasis or interstitial pulmonary edema. Tobias et al. (10) recently reported quantitative data that demonstrated decreases in dynamic compliance along with decreases in peak inspiratory/expiratory flows in adult patients after the administration of rapacuronium. The present findings confirm their assertion that rapacuronium causes bronchoconstriction.

MEF rates at low lung volumes, as measured by MEF_FRC or MEF₁₀, are extremely sensitive indices of lower airway dynamics, independent of the upper- and large intrathoracic airways or the presence of an endotracheal tube (13,14,18). PEFV curves are more sensitive than MEFV curves because the maximal lung inflation to TLC partially reverses bronchoconstriction (19). In the current study, MEF₁₀ on MEFV curves and MEF_FRC on PEFV curves showed similar degrees of reduction after rapacuronium administration. Observed marked reductions in MEF₁₀ and MEF_FRC, together with the concavity of flow-volume curves toward the volume axis, indicate the constriction of relatively small (parenchymal) airways (13,18). A lack of wheezing in children in the current study, as well as in the published case reports, is also consistent with the involvement of smaller, parenchymal airways constriction, because wheezing usually arises from tracheobronchial constriction, as with allergic asthma, rather than from the constriction of relatively small airways, as with the ex-premature infants with bronchopulmonary dysplasia (18).

Many factors control airway caliber, including postganglionic muscarinic receptors, with M₂ and M₃ subtypes being the most common. M₂ receptor activation produces smooth muscle relaxation, and selective muscarinic antagonists potentiate vagally induced bronchospasm (20). M₃ receptor blockade conversely inhibits vagally induced bronchospasm, because M₃ receptor activation mediates smooth muscle contraction and hence bronchoconstriction of the airway (21). As demonstrated by Hou et al. (22) in their in vitrostudies, certain muscle relaxants function as antagonists for M₂ and M₃ muscarinic receptors. These authors noted that the activity of muscle relaxants on the pulmonary system is affected by the type of muscarinic receptors for which the drug has the higher affinity (22). If a muscle relaxant has a high affinity for the M₂ receptors, then vagally induced bronchoconstriction will be potentiated (23). The proposed mechanism of action of bronchoconstriction observed after rapacuronium is postulated to be the high affinity of rapacuronium for the M₂ muscarinic receptors (24), resulting in enhanced acetylcholine release on M₃ receptors. If rapacuronium-induced bronchoconstriction is mediated by antagonism of the M₂ muscarinic receptors, pretreatment with an anticholinergic drug, such as atropine or glycopyrrolate, may prevent it. Because of the removal of rapacuronium from the market, we were unable to test this hypothesis. Although bronchoconstriction mediated by M₂ receptor blockade is most likely, other unknown mechanisms for bronchoconstriction may also be operative for the observed bronchoconstriction with rapacuronium.

The observed marked decreases in MEF₁₀ and MEF_FRC and increases in R_rs in the present study are equivalent to a significant positive bronchoconstriction after a bronchial challenge test with carbachol or histamine. This is sufficient to cause clinically significant tightness in the chest and the sensation of dyspnea (25). Yet changes in "dynamic compliance" were noticeable during manual ventilation only in one of five patients who received rapacuronium, indicating the insensitivity or inaccuracy of clinical judgments about dynamic compliance during manual ventilation. Therefore, the reported cases in the literature of bronchospasm after the administration of rapacuronium may be just the "tip of the iceberg." When using sensitive indicators for bronchospasm, it seems that bronchospasm occurs frequently, even though it may not be clinically apparent. Furthermore, it is clinically important to note that bronchoconstriction was prolonged in one patient in this study who received rapacuronium, but did not receive albuterol treatment for bronchodilation.

Unexpectedly, we also found small but significant decreases in MEF₁₀ (but not MEF_FRC) with the administration of mivacurium, although R_rs was unchanged, again indicating the high sensitivity of flow-volume curve assessments. Although these changes are clinically insignificant, they nonetheless indicate subtle and heretofore unrecognized changes in airway dynamics. There have been reports relating histamine release to bronchospasm with mivacurium. The observed mild decreases in MEF₁₀ in the Mivacurium group, however, are unlikely to be related to histamine response, because there were no other changes in circulatory or cutaneous signs attributable to histamine release. In addition, Shorten et al. (6) have shown that significant histamine release with mivacurium is associated with doses larger than 0.3 mg/kg, which is more than the dose used in this study. Based on the present findings, it is apparent that the potential effect on airway function should be investigated for all other muscle relaxants currently in use as well as those proposed for future development.

In conclusion, rapacuronium has marked effects, whereas mivacurium seems to have subtle effects, on airway function. The present findings of severe bronchoconstriction after the administration of rapacuronium seem to be unrelated to inadequate anesthesia because the patients had already been tracheally intubated, well-anesthetized, and were stable before the administration of the drug. The bronchoconstriction induced by rapacuronium is readily reversible with the administration of a ß₂ agonist.

	Acknowledgments

 
Partial funding was provided by Abbott Laboratories, Inc.

The authors thank David Chasey for his editorial assistance.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999