Anesth Analg 2006;103:103-109
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000221439.87488.08
ANESTHETIC PHARMACOLOGY
Development of Bronchoconstriction After Administration of Muscle Relaxants in Rabbits with Normal or Hyperreactive Airways
Ferenc Peták, PhD*,
Zoltán Hantos, PhD, DSc*,
Ágnes Adamicza, PhD
,
Hristifor Gálity*, and
Walid Habre, MD, PhD
From the *Department of Medical Informatics and Institute of Surgical Research, University of Szeged, Hungary; and Pediatric Anesthesia Unit, Geneva Children's Hospital, Switzerland.
Address correspondence and reprint requests to Walid Habre, MD, PhD, Pediatric Anesthesia Unit, Geneva Children's Hospital, 6, rue Willy Donze, CH-1205 Geneva, Switzerland. Address e-mail to Walid.Habre{at}hcuge.ch.
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Abstract
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Neuromuscular blocking drugs can induce intraoperative bronchospasm. We characterized the magnitude and the temporal profile of the constriction in normal or in hyperresponsive airways after injections of neuromuscular blocking drugs. Respiratory system impedance (Zrs) was measured continuously over a 90-s apneic period in naïve and rabbits sensitized to allergens by ovalbumin. Fifteen s after the start of Zrs recordings, succinylcholine, mivacurium, or pipecuronium was administered in random order. Zrs was then also recorded during the administration of increasing doses of exogenous histamine. To monitor the changes in the airway mechanics during these maneuvers, Zrs was averaged for 2-s time windows, and the airway resistance (Raw) was determined by model fitting. The increases in Raw were significantly larger in the sensitized rabbits than in the naïve animals. The largest increases in Raw and the maximum rate of change in Raw were obtained for succinylcholine (146% ± 29% and 0.80 ± 0.12 cm H2O/L, respectively) and mivacurium (80% ± 25% and 0.71 ± 0.13 cm H2O/L) and the smallest were obtained for pipecuronium (40% ± 12% and 0.41 ± 0.04 cm H2O/L). Allergic sensitization leads to severe and rapidly developing bronchospasm after administrations of mivacurium or succinylcholine. These deleterious side effects should be considered when succinylcholine or mivacurium is administered in the presence of bronchial hyperreactivity.
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Introduction
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Anesthesia for patients with bronchial hyperreactivity (BHR) is associated with an increased risk of respiratory complications, bronchospasm being the most frequent life-threatening event (1–4). Neuromuscular blocking drugs (NMBDs) are the drugs most frequently incriminated in the occurrence of severe bronchospasm (5) because of the release of endogenous histamine and/or their involvement in an immunoglobulin (Ig)E-mediated immune response (6).
Because of its rapid and short-acting properties, succinylcholine is the drug of choice for rapid sequence induction, even though it is the NMBD most often reported to induce allergic reactions (7). Mivacurium is commonly used for short surgical procedures although it is associated with a medium risk of anaphylaxis (5,7). Although these two NMBDs are risk factors for the rapid development of bronchospasm, their effects in normal and in hyperreactive airways have not been systematically investigated.
Accordingly, the present study was designed to characterize how BHR influences the airway constrictor response to NMBDs with a potential for endogenous histamine release. A forced oscillation technique provides an accurate estimate of the airway and tissue variables and has been used to characterize the effects of endogenous histamine release (8). Nevertheless, this technique allows the estimation of lung mechanics only at a particular time point without giving information about continuous changes in airway function. During anaphylactic reactions, both the magnitude and the time course of bronchoconstriction furnish important information to the anesthesiologist in control of the adverse event. Thus, we used modification of the low-frequency forced oscillation technique that permits continuous measurement of airway function (9) after bronchoconstriction by exogenously administered or endogenously liberated constrictor mediators.
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METHODS
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After approval from the Institutional Ethics Committee, 14 adult rabbits of either sex (2.3–3.0 kg) were studied. Seven animals were actively sensitized by IP injections of 0.1 mg ovalbumin (OVA) and 10 mg aluminum hydroxide (Sigma-Aldrich Ltd, Budapest, Hungary) on days 0 and 13. These rabbits were then exposed to aerosolized (Voyage Mefar jet nebulizer, Italy) OVA (10 mg/mL) for a 20-min period daily from day 25 to day 29. Experiments were performed on day 30. This sensitization induces OVA-specific IgE antibodies. When exposing the sensitized animals to the specific allergen by inhalation before the experiments, the antibody-antigen reaction lead to an accumulation of inflammatory cells including mast cells in the bronchial lumen resulting in the development of airway hyperresponsiveness (10). Seven control (group C) animals were exposed to an aerosol of saline. There was no significant difference in age or weight between the animals involved in the protocol groups.
Anesthesia was induced by an IM injection of xylazine (5 mg/kg), followed by the injection of pentobarbital sodium (30 mg/kg) via an ear vein. The rabbits were then tracheotomized with a 3.5-mm inner diameter polyethylene cannula and their lungs were mechanically ventilated with room air (Model 683; Harvard Apparatus, South Natick, MA) while a tidal volume of 7–9 mL/kg, a frequency of 30/min and positive end-expiratory pressure of 4 cm H2O were maintained. A carotid artery was cannulated for continuous arterial blood pressure monitoring (model 156 PC 06-GW2; Honeywell, Zürich, Switzerland). A femoral vein was also cannulated for drug delivery. Maintenance doses of anesthetic (pentobarbital sodium 5 mg/kg) were administered IV every 30–40 min. Analgesia was provided by the regular administration (every 20–30 min) of IV boluses of fentanyl (3 µg/kg).
The measurement system for the collection of input impedance spectra of the rabbit respiratory system (Zrs) was similar to that used previously (8). The tracheal cannula was attached to a T-piece that allowed the animal to be switched either to the ventilator or to a loudspeaker-in-box system. The loudspeaker delivered computer-generated pseudorandom forced oscillations of 2-s periods in the frequency range 1–11 Hz into the trachea. The loudspeaker chamber was pressurized to maintain the same transrespiratory pressure during the tracking maneuvers. The oscillatory signal was led through a screen pneumotachograph (11-mm inner diameter), which was used to measure the tracheal flow. The pressure decrease across the screen was measured with a differential pressure transducer (model 33NA002D; ICSensors, Malpitas, CA). An identical pressure transducer was applied to measure the tracheal pressure (Ptr) during oscillations via a side port of the endotracheal tube.
The signals tracheal pressure and tracheal flow were low-pass filtered at 25 Hz and sampled with a microcomputer at a rate of 128 Hz. The time window of the Zrs calculation by fast Fourier transformation was 2 s, and the spectra estimated by moving sample-by-sample along the recording were averaged for 2 s. Accordingly, these Zrs data represented the average impedance for a 4-s interval, and the successive overlapping estimates were obtained every 2 s, resulting in 45 Zrs estimates from a 90-s recording. The airway resistance (Raw) was then extracted from these Zrs spectra by fitting a four-parameter model incorporating an airway and constant-phase (11) tissue compartments. This approach has been shown to provide reliable estimates for Raw in rabbits (8,12) and in other mammals (9,11,13). A smoothing procedure (three-point running average) was applied to the time sequences of the Raw. The rate of change in Raw (as a measure of the rate of airway narrowing, Vo) was determined by calculating the first derivative of the Raw versus time curves. The reported Raw values were corrected for the resistance of the measurement set-up, including the tracheal cannula.
Figure 1 depicts the time course of the experimental protocol. An IV bolus of fentanyl (5 µg/kg) was administered to suppress spontaneous breathing efforts during the first phase of the impedance recording. The tracheal cannula was next detached from the respirator and connected to the pressurized loudspeaker chamber for 90 s. The Zrs measurement was started with a 15-s baseline recording, after which a muscle relaxant (randomly selected pipecuronium 0.3 mg/kg, mivacurium 2 mg/kg, or succinylcholine 2 mg/kg) was injected into the femoral vein. Larger doses were used here than in clinical practice because of the substantially larger clearance and enhanced metabolism of anesthetic drugs in rabbits. As a result of the hyperinflation, the rabbits remained apneic for the first 15 s of the recording, while the muscle relaxant prevented spontaneous chest movements during the remainder of the maneuver. The rabbit's lungs were subsequently mechanically ventilated for at least 15 min, and the control Zrs was then recorded in the same manner as above, except that no drug was administered. The Zrs recording was repeated the same way while either of the other two muscle relaxants was administered in random sequence. Another control Zrs recording was made thereafter, which was followed by impedance measurements during the administration of IV boluses of histamine (2.5, 5, 10, or 20 µg/kg) with the same timing as the muscle relaxants. Finally, a bolus of OVA (1 mg) was injected IV when the changes in Zrs were recorded. The animal was allowed a period of mechanical ventilation of at least 15 min between the maneuvers.
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Figure 1. Flow chart of the study protocol. Neuromuscular blocking drug (NMBD)-1 to NMBD-3 refer to the randomized administration of NMBDs pipecuronium, mivacurium, and succinylcholine. CTRL = control measurements without drug administrations; H2.5 to H20 = IV administrations of exogenous histamine between doses of 2.5 and 20 µg/kg. Zrs = respiratory system impedance; OVA = ovalbumin.
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The largest value of Raw (Rawmax) and its time (TRawmax) were estimated from the Raw versus time curves. The relative change in Raw at this time point was calculated by relating Rawmax to the Raw found in a control impedance recording at the corresponding time point (dCRawmax). The maximum rate of change in Raw (Vomax) and its time (TVomax) were obtained by considering the peak values of Vo during the tracking maneuvers after drug administration.
Data are reported as mean ± se values. Two-way repeated measures analysis of variances, with sensitization and the drug administrations (histamine or muscle relaxants) as variables, were used to estimate the effects of sensitization on the development and the magnitude of the lung responses. Pairwise comparisons were performed by using Student-Newman-Keuls multiple comparison procedures. Statistical tests were conducted with the significance level set at P < 0.05.
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RESULTS
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All sensitized rabbits responded to 1 mg OVA (152% ± 23% peak increase in Raw at 205 ± 39 s), whereas the mechanical variables remained at the baseline level in the group C animals.
The time course of the changes in Raw and Vo in a control recording and after administration of increasing doses of histamine in a representative sensitized rabbit are demonstrated in Figure 2. Although no temporal changes in Raw or Vo were obvious in the control tracking maneuver, exogenous histamine induced an immediate bronchoconstriction with rapid development and slower subsequent phases. The increasing doses of exogenous histamine enhanced the magnitude and the velocity of airway narrowing without affecting the time required to reach the maximal response.
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Figure 2. Time course of airway resistance (Raw) and its first derivative (rate of airway narrowing, Vo) in a control recording and after administration of increasing doses of histamine, obtained in a representative sensitized animal.
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Figure 3 illustrates the progression of airway constriction after the injection of different NMBDs in a representative sensitized rabbit. The administration of pipecuronium caused only mild increases in Raw and Vo. A more apparent airway response was observed after mivacurium administration. Succinylcholine led to immediate, marked increases in Raw and Vo. The peak responses of Raw and Vo generally occurred later, and the increases in these variables lasted longer than those after the administration of exogenous histamine.
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Figure 3. Time course of airway resistance (Raw) and its first derivative (rate of airway narrowing, Vo) in a control recording and after administration of muscle relaxants in a representative sensitized animal.
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The characteristic variables relating to the bronchoconstriction that developed after histamine administration to the normal and the sensitized rabbits are depicted in Figure 4. Allergic sensitization caused marked, statistically significant increases in the histamine-induced responses in Raw and in the rate of development of bronchoconstriction. The time of the peak Raw or Vo was unaffected by the dose of the constrictor agonist or the presence of sensitization.
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Figure 4. Variables characterizing the magnitude and the progression of bronchoconstriction evoked by increasing IV doses of histamine (H2.5–H20) in normal (closed circles) and in sensitized rabbits (open circles). Rawmax = peak response in airway resistance after histamine boluses; Vomax = maximal rate of airway narrowing after histamine injections; dCRawmax = relative change in airway resistance at peak bronchoconstriction. *P < 0.05 between normal and sensitized animals.
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Figure 5 presents the variables relating to the magnitude and the progression of bronchoconstriction after injection of the muscle relaxants to rabbits with normal or allergic sensitized airways. Independent of the sensitization, the magnitude and the velocity of the development of bronchoconstriction were the greatest after succinylcholine administration and less pronounced after mivacurium injection, whereas pipecuronium resulted in the smallest changes in airway mechanics. Allergic sensitization caused marked, statistically significant increases in both the degree and the rate of bronchoconstriction after the administration of each of the NMBDs; the responses after pipecuronium injections were markedly less than those after mivacurium or succinylcholine. Although the peaks in Raw and Vo occurred significantly later than those observed after constrictor administration, the time profile of the bronchoconstriction was essentially unaffected by the sensitization.
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Figure 5. Variables relating to the magnitude and the progression of bronchoconstriction after injection of mivacurium (MIV), succinylcholine (SUC), and pipecuronium (PIP) in rabbits with normal (open bars) or allergic sensitized airways (filled bars). *P < 0.05, **P < 001, ***P < 0.005 between normal and sensitized animals. #P < 0.05, ##P < 001, ###P < 0.005 versus succinylcholine in the corresponding variable.
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DISCUSSION
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The present study details the progression of bronchoconstriction after the administration of NMBDs that have a potential to induce anaphylaxis in rabbits with normal or sensitized airways. Furthermore, the magnitude and the temporal profile of the airway narrowing were characterized after exogenous administration of histamine. We demonstrated that administration of succinylcholine and mivacurium, muscle relaxants commonly used in clinical practice, lead to an instantaneous airway narrowing, the peak response being observed later for endogenous release than exogenous administration of histamine. These responses were significantly exaggerated in the presence of BHR: both the level of the maximal bronchospasm and the velocity of the airway smooth muscle shortening were markedly greater in allergically sensitized animals.
Because perioperative complications during anesthetic management often affect the airway, the use of a technique with which the airway and tissue properties may be determined separately provides anesthesiologists with a valuable tool allowing a better understanding of the changes in the lungs. Thus, low-frequency forced oscillations were used in the present study, as these have been shown to supply airway and tissue variables reliably both in rabbits (8,12) and in other mammals (9,11,13). Furthermore, for a precise characterization not only of the magnitude, but also of the time course of the developing bronchoconstriction, an advanced, low-frequency forced oscillation technique was adopted that permits continuous measurement of the airway function over a period of time (9). Although this approach also provides information on the altered dissipative and elastic properties of the respiratory tissues, the behavior of the airway was the focus of interest in the present study because both IV administered constrictor agonists and the anaphylaxis induced by the IV administration of the allergen primarily affect the airways (13).
Our aim was to compare the effects of different constrictor stimuli on the airways within the same animal, as this approach furnishes a possibility for the direct assessment of the association between the airway responses induced by the various pathways. Thus, the study protocol was designed to measure Zrs data after repeated administration of the three NMBDs in random sequence. To avoid possible interactions, great attention was paid to the drug clearance time among the consecutive measurements. Accordingly, the lack of any systematic difference in the profile of the lung responses to the different NMBDs when they were administered in different sequence suggests that the effects of the possibly remaining drug did not influence our findings. The relatively large doses used in the present study were selected because of the substantially higher clearance and enhanced metabolism of anesthetic drugs in rabbits (14). With the same dose of mivacurium in our previous study, we obtained increases in plasma histamine levels that were comparable to those observed earlier in humans after a smaller dose of NMBD (8).
There have been a number of case reports and clinical observations of bronchospasm development after administration of NMBDs (15–17). Nevertheless, there have been only a few studies in which the changes in normal lung function were assessed systematically at a particular time point after NMBD administration (8,18,19), and there has been only one study in which the experimental setting allowed a systematic and reproducible assessment of altered airway function after the injection of a NMBD (8). Accordingly, there are two major methodological advances in the present experiments: this is the first systematic study on the effects of NMBDs in a valid animal model of BHR, and it is also the first work to report the time course of airway constriction induced by NMBDs.
Use of this technique reveals substantial differences in the airway responses developed after administering exogenous constrictor agonists and NMBDs. The time course to the maximum Raw was almost twice as long in the latter case. This delay may reflect the time needed for the immune system to activate an anaphylactic IgE-mediated reaction and/or the time necessary for the mast cells to release bronchoactive mediators via degranulation. Because TRawmax was similar in the control and in the sensitized rabbits, the delayed and longer lasting airway constriction after administration of NMBDs was most likely attributable to the time necessary to obtain a prolonged mast cell degranulation rather than an anaphylactic reaction.
In agreement with our previous findings (8), the administration of mivacurium in the present study was followed by a mild bronchospasm in normal rabbits. However, drastic increases in the magnitude and the rate of airway constriction were observed in the allergic animals, whereas the time of the peak response was not influenced by allergic sensitization. The latter suggests that the mechanism responsible for airway constriction was similar in the two groups and is unlikely to be related to an IgE-mediated allergic response because the immune response is expected to be delayed with respect to direct histamine release. Indeed, the peak of the Raw response resulting from the immune response occurred 3–4 minutes after OVA administration in the sensitized rabbits. The primary involvement of histamine release may be suspected from the ability of antihistamine pretreatment to protect the development of an airway narrowing after mivacurium administration (8).
Succinylcholine has a risk of inducing anaphylactic and/or anaphylactoid reactions (5–7). In the present study, it induced significantly greater airway responses than those observed for the other two drugs, both in the control and in sensitized animals. Besides the potent histamine release (20,21), succinylcholine may also contract the airway smooth muscle via stimulation of muscarinic receptors (22,23). The latter mechanism may be related to chemical structural similarities between succinylcholine and acetylcholine and hence to the ability of succinylcholine to mimic the effects of acetylcholine on the muscarinic receptors. The presence of this superimposed mechanism may be substantiated by the significantly shorter time required to reach the maximal velocity of airway smooth muscle shortening with this drug than the times for the other muscle relaxants used in the present study.
Unlike the other NMBDs, pipecuronium possesses only a mild potential to alter airway tone (24). Our results in control animals demonstrated only a slight relative change in Raw (10%). Sensitization led to increased responsiveness of the airway to the constrictor stimuli induced by pipecuronium, although the degree and the velocity of airway smooth muscle contraction were markedly less than those observed with the other two NMBDs. This finding confirms the results of previous studies that there is a less pronounced, but still definite, stimulation of histaminic receptors by pipecuronium (23,25).
The present study has established the time course of airway constriction after the administration of mivacurium, succinylcholine, or pipecuronium, and demonstrated the potential of these drugs to induce bronchoconstriction. The magnitude and the velocity of airway constriction depend on the particular NMBD, succinylcholine having the greatest bronchoconstrictor effect. Allergic sensitization leads to marked increases in the magnitude and the rate of the airway reaction that develop after all of these NMBDs and results in severe bronchospasms after succinylcholine or mivacurium injections. These findings emphasize that, in the presence of bronchial hyperresponsiveness, succinylcholine and mivacurium may induce a severe, rapidly developing airway narrowing that may lead to acute lung function deterioration. Anesthesiologists should be alert when considering these drugs in the presence of airway hyperresponsiveness.
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Footnotes
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Accepted for publication March 16, 2006.
Supported, in part, by Hungarian Scientific Research Grant OTKA F038340, and Swiss National Science Foundation Grant 3200-105828/1.
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Abstract
Introduction
