Cisatracurium and rocuronium are nondepolarizing neuromuscular blocking drugs of intermediate duration that have been widely used in the anesthetic management of pediatric patients for many years. These drugs can facilitate tracheal intubation and optimize surgical conditions. Nondepolarizing neuromuscular blockers have, however, been associated with the potentially serious complication of bronchoconstriction and even cardiac arrest. In particular, rapacuronium, an ultra-short-acting nondepolarizing muscle relaxant that was withdrawn from clinical use in 2001 due to unacceptably high incidents of bronchoconstriction, is an extreme example of the potentially dangerous association of neuromuscular blockers with bronchoconstriction.1,2 Rapacuronium, however, is not the only neuromuscular blocker associated with bronchoconstrictive events. Both cisatracurium and rocuronium have also been implicated in bronchoconstrictive episodes, especially in northern Europe and Australia, although much milder and mostly without serious clinical consequences.3–7
The cause of bronchoconstriction associated with neuromuscular blockers has been related to either the activation or blockade of muscarinic receptors or histamine release. Both cisatracurium and rocuronium have little tendency to release histamine in laboratory settings.8,9 However, they have the potential to produce anaphylactoid reactions.3,7,10–12 It should be noted that, even though histamine may be implicated in some cases, the severity of bronchospasm far exceeds the magnitude of histamine release.10
The definite diagnosis of bronchoconstriction in the awake patient can be made most objectively through pulmonary function tests (PFTs) performed at pulmonary function laboratories by means of spirometry. Maximum expiratory flow-volume (MEFV) curve analysis with bronchodilator or bronchoconstrictor challenges requires cooperative patients old enough to understand and follow instructions from pulmonology technicians. The forced lung deflation technique is an unique PFT method specifically developed to evaluate pulmonary function in anesthetized or heavily sedated and paralyzed infants and children through the cuffed endotracheal (ET) tube or tracheostomy tube in the operating room or the intensive care unit.2,13 This technique produces MEFV curves from which maximum expiratory flow rates (MEFs) at low lung volumes (25%, 10%) can be measured. These indices are highly specific in diagnosing bronchoconstriction, especially involving relatively smaller airways.13–15
Using this technique, Fine et al.2 observed that even though MEFs at low lung volumes decreased dramatically after a single IV dose of rapacuronium in 5 anesthetized children, changes in compliance or resistance were barely detectable during manual ventilation. As evidenced by drastic reductions in MEFs in low lung volumes, rapacuronium appeared to preferentially constrict relatively small airways, and wheezing was not detected in these patients, even with the presence of severe lower airway obstruction. It is therefore probable that the incidence and severity of bronchoconstriction after the administration of neuromuscular blocking drugs could be much more frequent than previously reported in the literature.
The specific aims of the present study were to examine the effect of 2 commonly used nondepolarizing neuromuscular blockers, cisatracurium and rocuronium, on lung mechanics in clinically relevant doses to examine whether these neuromuscular blockers affect lower airway function, since such studies have not been reported. More specifically, we hypothesized that both cisatracurium and rocuronium would affect lower airway function as evidenced by a significant decrease in MEF10. We further hypothesized that bronchodilator administration would not only reverse the bronchoconstriction brought about by the test drugs but also dilate the airways beyond baseline values by reversing the intrinsic bronchomotor tone, which exists in children even under general anesthesia.
We studied 25 children between the ages of 9 months and 9.9 years (median 5.25 years). All patients were ASA physical status I or II and scheduled for elective dental or genitourinary surgery, requiring tracheal intubation. The protocol was approved by the IRB at Children’s Hospital of Pittsburgh of University of Pittsburgh Medical Center, and written informed consent was obtained from 1 or both parents of all children. In addition, informed assent was obtained from most children older than 7 years of age. Patients with cardiopulmonary disease, bronchial asthma requiring bronchodilator treatment within the past 6 months, abnormalities of the musculoskeletal system, history of malignant hyperthermia, known pseudocholinesterase deficiency, history of egg anaphylaxis, symptomatic, or with a recent history of upper respiratory tract infection were excluded from the study. Two patients, each with a history of asthma and previously treated with a bronchodilator (but not within the past 6 months), were included, 1 in each treatment group.
All patients underwent induction of anesthesia with inhalation of sevoflurane combined with nitrous oxide and oxygen in a 2:1 mixture, followed by the insertion of an IV catheter. No anticholinergic drugs (atropine or glycopyrrolate) were given. Tracheal intubation was performed during deep sevoflurane anesthesia with an appropriate sized cuffed ET tube, preceded by 0.5 to 2 mL of 1% topical lidocaine in a 3-mL syringe sprayed through a 20-gauge IV catheter directly to the glottis under direct vision with a laryngoscope and/or with IV propofol (2–3 mg/kg). Once the proper ET tube position was confirmed by auscultation of the chest, it was secured by adhesive tape. Sevoflurane and nitrous oxide were then discontinued (since sevoflurane and all other inhaled anesthetics are potent bronchodilators), and anesthesia was maintained thereafter with continuous IV infusions of propofol (200 to 300 μg/kg/min) and remifentanil (0.2 to 0.5 μg/kg/min). Propofol may have a much milder bronchodilatory effect than volatile anesthetics, but it does not interfere with the effect of bronchodilator challenge. Both during and after the experimental period, all patients received standard monitoring for perianesthetic care, which included continual auscultation of the chest with a precordial stethoscope, electrocardiograph, pulse oximeter, capnograph and anesthetic gas monitors, axillary temperature readings, and noninvasive measurements of systemic blood pressure repeated every 3 to 5 minutes.
The first (baseline) set of PFTs (see below) was performed at least 5 minutes after beginning the propofol infusion and when the end-tidal sevoflurane concentration had decreased below 0.2%. Immediately after the initial PFTs, either cisatracurium (0.2 mg/kg) or rocuronium (1.0 mg/kg), as selected by randomization, was infused IV by push through a 3-way stopcock in the infusion set up, usually 12 to 24 inches away from the IV catheter. One investigator, blinded to the selection of the test drugs or the PFT results displayed on the monitor screen, manually ventilated the patients’ lungs in an effort to identify any clinical suggestion of increases in airway pressure, which might suggest increases in airway resistance or decreases in compliance. Five to 8 minutes after the administration of the study drug, when neuromuscular monitoring confirmed complete neuromuscular blockade, the second set of PFTs was obtained. To determine whether bronchoconstriction caused by the neuromuscular blocking drugs could be reversed by a bronchodilator, a PFT was repeated after the administration of 2 puffs of albuterol in a metered dose inhaler via a nebulization chamber (Aerochamber®) inserted between the ET tube and the anesthesia circuit. The third set of PFTs was obtained after waiting 8 to 10 minutes to insure maximal bronchodilation after albuterol administration. The PFT techniques in anesthetized infants and children have been described in detail elsewhere,2,13–15 and the application of these techniques in the present study is briefly described below.
An MEFV curve was produced as follows. First, lungs were inflated slowly from the end-tidal volume (functional residual capacity) to the peak airway pressures of 40 cm H20 to reach total lung capacity (TLC) 3 times. This TLC maneuver eliminates preexisting airway closure or atelectasis, which are recruitable, as well as standardizes the “volume history” of the respiratory system.16,17 At the fourth inflation to TLC, lungs were rapidly deflated from TLC to residual volume (RV) by pushing a slide bar of a 3-way valve in 1 quick stroke, which occluded the inflow gas and immediately opened the airways to a large (> 60 L) negative pressure reservoir kept at −40 cm H2O, producing a rapid lung deflation to RV in <1 to 2 seconds. The expiratory flow during rapid lung deflation was recorded with a pneumotachograph until the expiratory flow ceased at RV or for up to 3 seconds. The expiratory flow and integrated volume signals were instantaneously displayed on an X-Y plotter, and the resultant MEFV curve was saved for later analysis. After each MEFV curve maneuver, the lungs were reinflated to TLC several times to prevent airway closure. With this maneuver, consecutive MEFV curves are nearly or completely identical, and 2 to 3 MEFV curves were obtained to insure reproducibility.2,13 From the MEFV curves, forced vital capacity (FVC) and maximum expiratory flow rates at 25% and 10% of FVC above RV (MEF25 and MEF10), respectively, were measured and recorded. In this study, only MEF10 of FVC was used in the measurements of MEFs rather than more conventional MEF25 of FVC because larger volume portions of MEFV curves are often affected by the presence of an ET tube, and MEF25 values were not available in a number of subjects. However, MEFs below 15% to 20% of FVC toward RV on the MEFV curve were intact in all patients and were independent of the presence of an ET tube.16
Theoretically, MEF in this “flow limited segment” of MEFV curves (MEFX) are determined not by the degree of the patient’s effort (or, in this case, the level of negative pressure applied) to produce MEF but by the elastic recoil pressure of the lung (PL) and the resistance of lower airways more peripheral to the equal pressure point, EPP (upstream segment, Rus). The EPP is the point in the lower airways where the pressure gradient across the airway wall is zero during forced expiration and subjected to dynamic compression, as indicated by the equation:
In healthy young adults and children, EPP is located in the intrathoracic airways, between the fifth and eighth generations of the tracheobronchial tree.16,17 In patients with small airway obstruction, EPP moves further upstream toward the segment of obstruction where the dynamic compression takes place during forced exhalation.13,16 MEF, therefore, is independent of events in the upper (extrathoracic) and large intrathoracic airways, including ET tubes. The measurement of MEFs at low lung volumes (such as MEF10) is an index highly specific for assessing the conductance or patency of relatively small airways.16,17
Although not included for the final data analysis for this manuscript, static compliance of the respiratory system (Crs, mL/cm H2O) and total respiratory system resistance (Rrs, cm H2O/mL/s) were also obtained during the passive expiratory maneuver from the end-inspiratory pause at 10 cm H2O. Analyses of PFT were made by the same member of the group, who was blinded to the choice of the test drug. Differences between the baseline and postneuromuscular blocker values of >10% for FVC and >30% of MEF10 were considered clinically significant.2
Fractional changes from the baseline values from each intervention were used to compare subjects. This was necessary to assign equal importance to individual results for our subject population that included different ages and different body sizes and therefore different predictive values. Shapiro-Wilk test was used to assess for the normal distribution (all P > 0.07). Normal distributed data were analyzed with a paired t test method. The Wilcoxon rank sum test was used to analyze the nonnormally distributed data; this involved only the rocuronium-treated FVC group. STATA 9 program by Stata Corp LP (College Station, TX) was used to analyze the data. A probability of <0.05 was considered statistically significant. From preliminary data, a change of MEF10 by 15% predicted a SD of 0.05 and a 0.8 power with a sample size of 12. This is generally consistent with a similar study with a nearly identical experimental design.2
During and immediately after the PFTs, oxygen saturation by means of pulse oximetry (SpO2) remained 100% in all children studied. There was no appreciable change in the vital signs. The axillary temperature was within the physiological range in all patients in both groups (35.9°C ± 0.61°C vs 35.5°C ± 0.53°C).
Fourteen boys and 11 girls comprised the total study cohort of 25 children. There were no statistical differences in age or gender distributions between the 2 groups of children. In each group, there was 1 subject with a history of asthma but no use of a bronchodilator in the preceding 6 months; no subjects had symptoms or a recent history of upper respiratory infection. Demographic data are shown in Table 1.
The investigator blinded to the medication given and to the PFT display, who manually ventilated all the children’s lungs in the present study, did not detect any changes in the “compliance” or “resistance” of the respiratory system before versus after the administration of the test drugs. Furthermore, he did not detect any wheezing with a precordial stethoscope during the forced deflation. The MEF rate in healthy patients is normally above 0.5 L/s and at above this flow rate, a clinician should be able to detect wheezing by auscultation, as in the case of asthma involving large intrathoracic airways.
The mean baseline FVC was 106.7 ± 25.1 (SD) (% predicted value). Three children had baseline FVC values below the predicted value based on height. Figure 1 represents a typical example of MEFV curves from 1 subject at baseline and after neuromuscular blockade with cisatracurium. There is a mild decrease in MEF10, but the shape of the MEFV curve and the slope of the descending limb of MEFV curves are similar.
Table 2 shows the mean values of the cisatracurium group of 12 patients of FVC and MEF10 after cisatracurium infusion, in fractions of the baseline values and after a bronchodilator nebulization, again in fractions of the baseline values. There were no statistical differences in FVC before and after the administration of cisatracurium. However, MEF10 showed a mild but significant decrease (0.80 ± 0.18, P = 0.002) from baseline values. After bronchodilation, there was a small but significant increase in FVC (1.02 ± 0.02, P = 0.005) and a noticeable increase in MEF10 (1.24 ± 0.43, P = 0.04) beyond the baseline values.
Figure 2 shows the individual plot of MEF10 at baseline (1.0), after cisatracurium and after bronchodilator administrations, in fractions of baseline values, connected with dotted lines for each subject. The solid line connecting 3 measuring points represents the mean values for postcisatracurium and postbronchodilator administration. After cisatracurium injection, there was no significant change in FVC but a significant decrease in the mean MEF10 (P = 0.002); after bronchodilation, there was a small but significant increase of FVC (P = 0.005) and a sizable increase in MEF10 (P = 0.04, Table 2) above baseline values.
Figure 3 represents an example of MEFV curves from 1 subject at baseline and after neuromuscular blockade with rocuronium. There is a marked decrease in MEF10, and, as compared with Figure 1 with cisatracurium, the shape of the MEFV curve and the slope of the descending limb of MEFV curve changed considerably downward from the baseline MEFV curve after rocuronium administration. MEF10 decreased >50% from the control curve in this particular case.
Table 3 shows the mean values of the rocuronium group of 13 patients of FVC and MEF10 after rocuronium infusion and after bronchodilator nebulization respectively; data are shown as fractional change of the baseline values. After rocuronium administration, FVC decreased slightly (0.99 [first quartile 0.97, third quartile 1] P = 0.02) but was statistically significant. MEF10 decreased significantly from baseline values (0.78 ± 0.26, P = 0.008).
Figure 4 shows plots of MEF10 of FVC at baseline (1.0) after rocuronium and albuterol administration in fractions of baseline values and are connected with dotted lines for each subject. The solid line connecting 3 measurement points represents the mean values for postrocuronium and post bronchodilator administration. There was a significant decrease in the mean MEF10 after rocuronium (P = 0.008); after bronchodilation, there was a significant increase of MEF10 above the baseline values (P = 0.01, Table 3).
Both cisatracurium and rocuronium have been implicated in causing bronchoconstrictive episodes, but PFTs have not been used to substantiate these clinical impressions in children. We now have demonstrated that both drugs in clinical doses cause mild but statistically significant decreases in MEF10: on average 20% with cisatracurium and 21.9% with rocuronium. Since there was a 1% decrease in FVC, measurements of MEF10 after rocuronium administration were made at a lung volume slightly higher than the volume at which the initial MEF10 measurements were made (i.e., the second measurements were not made at the “isovolume points” on MEFV curve). This volume discrepancy slightly underestimates the degree of reductions in MEF. In other words, the actual decrease in MEF10 was even >21.9%. Furthermore, in contrast to the effect of cisatracurium, in 3 of 13 patients in the rocuronium group, MEF10 decreased markedly (50% or more of the individual baseline values or at or outside of 2 SD of the mean value), indicating possibly clinically relevant increases in resistance of the relatively small airways. One of these 3 children had a history of asthma.
As mentioned previously, MEF at low lung volumes, expressed as MEF10 or MEF25 in this and the previous report,2 are a highly specific index of lower airway dynamics, independent of the upper and large intrathoracic airways or the presence of an ET tube.2,13–17 Bronchoconstriction, associated with the use of neuromuscular blocking drugs, can be related to their effects on either muscarinic receptors or histamine release, although the latter is far less likely. Two types of muscarinic receptors are important in airway tone. M2 muscarinic receptors are auto feedback receptors on the presynaptic postganglionic vagal nerve junction and function to inhibit further release of acetylcholine, while M3 muscarinic receptors are on the airway smooth muscles and facilitate smooth muscle contractions.18,19 Conceptually, medications that either enhance M3 muscarinic receptor function or inhibit M2 muscarinic receptor function are likely to cause bronchoconstriction. Conversely, medications that block M3 muscarinic receptor function are likely to be protective.
Another potential but less likely mechanism of neuromuscular blocker-induced bronchoconstriction is immune or nonimmune system-induced histamine release. Histamine release is reported with the use of several nondepolarizing neuromuscular blocking drugs, including curare, atracurium, and mivacurium.8,20–22 However, as noted earlier, even though histamine may have been implicated in some cases, the severity of bronchospasm is far in excess of the magnitude of histamine release.10
In the present study, it is unlikely that histamine release was the cause of the observed changes in airway dynamics. In patients who developed significant decreases in MEF10 with the use of cisatracurium or rocuronium, there were no other signs of histamine release, such as skin rash or decrease in arterial blood pressure. In an in vitro guinea pig trachea model, when rocuronium was dosed alone and even in dosages above normal clinical use, there were no airway effects seen, implying that it alone, at least in the guinea pig, does not cause histamine release.23 In human studies, when rocuronium was dosed ≤1.2 mg/kg, there was no evidence of measurable histamine.8,9
Muscarinic receptors are most likely to be the cause of observed decrease in MEF10. As mentioned above, rocuronium has been shown to have both M2 and M3 muscarinic receptor blocking effects within clinically used concentrations. Its M3 blocking effects at a given concentration are weaker than at the M2 muscarinic receptor, therefore providing a mechanism for causing bronchoconstriction at a time of enhanced vagal stimulation, such as tracheal intubation. Furthermore, just like rapacuronium, rocuronium has some positive allosteric effects at the M3 muscarinic receptor, which would further enhance any present bronchoconstriction. These effects only occurred at concentrations higher than used in clinical practice in in vitro studies,23,24 but it might well be that certain patients are just more susceptible to these allosteric effects, such as those with a history of asthma or active upper respiratory tract inflammation. The current study was inconclusive since only one of the 3 patients with a noticeable decrease in MEF10 had a history of asthma.
The cisatracurium group also had statistically significant decreases in MEF10, which were, in general, milder than those in the rocuronium group. These changes may well have been due to its M2 muscarinic receptor blocking effects24 within clinically used concentrations. Unlike rocuronium, cisatracurium was not shown to have any allosteric effects at the M3 muscarinic receptor, which might explain the difference observed in the percent change in MEF10.25 Most reports of bronchoconstriction after the administration of cisatracurium have been associated with an anaphylactoid reaction.10–12 However, in an in vitro animal model, cisatracurium, just like rocuronium, had no airway effects even when dosed in concentrations above those used clinically, implying that it alone does not cause histamine release.23 Cisatracurium produces no apparent histamine release, even at doses 8 times the 95% effective dose (ED95).26
The lungs are innervated by both parasympathetic and sympathetic nerve fibers. The parasympathetic system provides the dominant role in airway bronchoconstriction.27 In humans, the sympathetic fibers do not directly innervate the smooth muscle of the airway, though β-2 receptors are present throughout the lungs.28,29 The parasympathetic nerves maintain airway tone by releasing acetylcholine onto M3 receptors, providing baseline bronchomotor tone. These baseline bronchomotor tones were present in our subjects, despite being under general anesthesia with propofol, but became diminished by the administration of β-2 agonist. This is evident in both the cisatracurium and rocuronium groups, when MEF10 increased beyond the baseline values after patients received albuterol.
With the possible exceptions of the 3 of 13 subjects in the rocuronium group, bronchoconstriction demonstrated by the decrease in MEF10 in our study may not be clinically significant. Nevertheless, demonstration of complete reversal of this bronchoconstriction with a bronchodilator has important clinical implications. These findings now validate findings in the previous rapacuronium study, in which the PFTs in the operating room showed the most severe and clinically significant bronchoconstriction, involving smaller airways but was completely reversed with a bronchodilator.2
Prior knowledge of rapacuronium’s bronchoconstrictive potential may have prevented its devastating complications, including death. Alternatively, rapacuronium could have potentially been used safely by pretreating the patient with bronchodilators or antimuscuranic drugs such as atropine or both. Based on these findings, it is strongly recommended that all neuromuscular blocking drugs and related drugs undergo airway function testing to better demonstrate their safety profile before clinical use.
In summary, cisatracurium and rocuronium both cause bronchoconstriction at clinically relevant doses. While these changes in our study patients were not clinically significant, it appears that certain patients, with or without histories of asthma, are particularly sensitive to these effects. In light of these increases in airway tone in almost all patients receiving cisatracurium and rocuronium in our study, it is the authors’ opinion that it is beneficial to administer an antimuscarinic, an antihistamine, and/or a β-2 agonist whenever one of these neuromuscular blockers is administered, in particular for patients at higher risk of developing bronchoconstriction, such as those with a history of asthma or a recent upper respiratory tract infection.
Name: Charles I. Yang, MD.
Contribution: This author helped conduct the study and write the manuscript.
Attestation: Charles I. Yang has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Gavin F. Fine, MBChB.
Contribution: This author helped design and conduct the study.
Attestation: Gavin F. Fine has seen the original study data and approved the final manuscript.
Name: Edmund H. Jooste, MBChB, DA.
Contribution: This author helped write the manuscript.
Attestation: Edmund H. Jooste has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Rebecca Mutich, BS, RCP.
Contribution: This author helped conduct the study and analyze the data.
Attestation: Rebecca Mutich has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Stephen A. Walczak, RRT, CPFT.
Contribution: This author helped design and conduct the study.
Attestation: Stephen A. Walczak has seen the original study data and approved the final manuscript.
Name: Etsuro K. Motoyama, MD.
Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.
Attestation: Etsuro K. Motoyama has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
This manuscript was handled by: Steven L. Shafer, MD.
The authors thank Barbara W. Brandom, MD, encouraging us to conduct the study and for her helpful suggestions and review of the manuscript; Michael Young, MPH, and Joyce Chang, PhD, for their assistance in statistical analysis; Francis Schneck, MD, and Brian S. Martin, DMD, for their cooperation during our clinical studies on their Pediatric Urology and Pediatric Dental Services patients; Kathleen Fertal, RN, and Christopher Edwards for their technical assistance; and Christine Heiner and Susan M. Danfelt for their editorial assistance.
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