Anesth Analg 2001;93:898-902
© 2001 International Anesthesia Research Society
PEDIATRIC ANESTHESIA
Salbutamol Prevents the Increase of Respiratory Resistance Caused by Tracheal Intubation During Sevoflurane Anesthesia in Asthmatic Children
Pietro Scalfaro, MD*,
Peter D. Sly, MD FRACP
,
Craig Sims, FANZCA
, and
Walid Habre, MD
*Pediatric Intensive Care Unit, Pediatric Department, CHUV University Hospital, Lausanne, Switzerland; Division of Clinical Sciences, Telethon Institute for Child Health Research, Perth, University of Western Australia; Department of Anesthesia, Princess Margaret Hospital for Children, Perth, Western Australia; and Pediatric Anesthesia Unit, Geneva Children’s Hospital, Geneva, Switzerland
Address correspondence and reprint requests to Dr. W. Habre, Division of Pediatric Anesthesia, Geneva Children’s Hospital, 6, Rue Willy Donze, 1205 Geneva, Switzerland. Address e-mail to Walid.Habre{at}hcuge.ch
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Abstract
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Asthmatic children having their tracheas intubated with sevoflurane often have an increase in respiratory system resistance (Rrs). In this randomized, placebo-controlled, double-blinded study, we investigated the protective effect of an inhaled ß2-adrenergic agonist. Either salbutamol or placebo was administered 30 to 60 min before anesthesia to 30 mildly to moderately asthmatic children scheduled for elective surgery. Induction was performed with sevoflurane in a mixture of 50% nitrous oxide in oxygen and maintained at 3%, with children breathing spontaneously via a face mask and Jackson-Rees modification of the T-piece. Airway opening pressure and flow were measured before and after insertion of an oral endotracheal tube. Rrs and respiratory system compliance were calculated with multilinear regression analysis. The groups were comparable with respect to age, weight, asthma history, and breathing pattern. Intubation induced a different Rrs response in the two groups: children treated with salbutamol showed a 6.0% (-25.2% to +13.2%) decrease (mean, 95% confidence interval), whereas in the Placebo group there was a 17.7% (+4.4% to +30.9%) increase (P = 0.04). Neither asthma history nor the serum inflammation marker eosinophilic cationic protein was predictive for this response. We conclude that when using sevoflurane in mildly to moderately asthmatic children, a preanesthetic treatment with inhaled salbutamol is protective of an increase in Rrs.
IMPLICATIONS: Tracheal intubation with sevoflurane as the sole anesthetic is now often performed in children. It can induce an increase in respiratory system resistance in children with asthma. This study shows that in children with mild to moderate asthma, a preanesthetic treatment with inhaled salbutamol can prevent the increase of respiratory system resistance.
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Introduction
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Asthma is characterized by airway inflammation, and asthmatic children are prone to broncho-spasm induced by different irritant stimuli during the perioperative period. Tracheal intubation can induce a release of acetylcholine from postganglionic cholinergic nerves, and it produces bronchospasm via vagal reflex pathways (1). Sevoflurane is now a widely used anesthetic in children (2–4). We demonstrated that asthmatic children who did not receive their routine medication before anesthesia increased their respiratory system resistance (Rrs) when endotracheal intubation was achieved with sevoflurane (5).
Eosinophilic cationic protein (ECP) is a marker of eosinophil activation, which plays a key role in the pathogenesis of asthma by stimulating respiratory epithelium and inducing factors active on bronchial smooth muscle (6,7). ECP measurements have been used in asthmatics to monitor the severity of the disease and the response to regular treatment (8,9).
This study was designed to test the hypothesis that the preanesthetic administration of inhaled salbutamol would prevent the Rrs increase after tracheal intubation under sevoflurane in asthmatic children. In addition, the marker of asthma disease activity, ECP, was measured, with the hypothesis that increased levels would correlate with Rrs increase after intubation.
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Methods
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After Institutional Ethics Committee approval and parental written consent, asthmatic children aged 2 to 13 yr, scheduled for elective surgery and requiring general anesthesia with tracheal intubation, were included. ASA physical status was I or II. All patients had a history of asthma episodes with wheezing in the last 12 mo, diagnosed clinically and treated by their physician with inhaled antiasthma medication. A detailed history for asthma symptoms, smoking exposure, and asthma medication was collected to detect a possible bias of differences in asthma severity. Children with upper respiratory infection in the previous 2 wk or who were symptomatic at the time of enrollment into the study were excluded, as were children who had obstructive apnea disorders.
The day of surgery, patients did not receive any medication before anesthesia. They were randomly assigned to receive, 30 to 60 min before the induction of anesthesia, either 200 µg of salbutamol or placebo through a nonstatic spacer (VolumaticTM; GlaxoSmithKline, Uxbridge, Middlesex, UK). Randomization was based on a coded table that had been generated at the beginning of the study by use of a normal random function. Double-blinded pressurized metered-dose inhalation canisters were made available through the respiratory department. The placebo pressurized metered-dose inhalation canisters contained only propellant and were similar to those routinely used for patient education. All children had anesthesia induced with sevoflurane (up to 8%) in a mixture of 50% nitrous oxide in oxygen (total fresh gas flow of 6 L/min) until an IV line was secured and a blood sample for ECP assay was drawn. Children were then maintained at a 3% concentration of sevoflurane while breathing spontaneously via face mask and Jackson-Rees modification of the T-piece. A first set of measurements of airway opening pressure (Pao) and flow (V') was achieved when a steady-state end-tidal concentration of 3% sevoflurane was obtained. Then, sevoflurane concentration was increased to 5%, and end-tidal sevoflurane concentration was monitored until the 95% effective dose for tracheal intubation was obtained (4.68%; 95% confidence interval, 3.91%–12.74%) (10). After insertion of an oral endotracheal tube (ETT), regular spontaneous respiration was reestablished during 3% (1.2 minimum alveolar anesthetic concentration) sevoflurane anesthesia in a mixture of 50% nitrous oxide in oxygen, and measurements of respiratory mechanics were repeated. All measurements were achieved under the same concentration of carrier gas, 50% nitrous oxide in oxygen.
A pressure port and transducer were used to measure Pao (pressure transducers, TG-40; SCIREQ Inc., Montreal, Canada), and a heated screen pneumotachograph (Hans Rudolph Inc., Kansas City, MO) was used to measure V'. This equipment was placed between the patient’s facial mask or ETT and the Jackson-Rees modification of the T-piece. The Pao and V' signals were sampled at 100 Hz and low-pass filtered by using scientific respiratory equipment (amplifier and signal conditioner, SC-14C; SCIREQ, Inc., Montreal, Canada) and stored through a 12-bit analog-digital converter on a personal computer. All data were collected and analyzed by using a data acquisition software package (Anadat and Labdat; RHT Infodat, Montreal, Canada).
Respiratory mechanics were calculated as previously described by applying a single-compartment model with multilinear regression analysis (MLR) to calculate dynamic compliance (Crs) and Rrs by use of the equation (11)
equation
where V is the tidal volume and PA,EE reflects the end-expiratory alveolar pressure. The MLR analysis calculates the coefficients Crs and Rrs by fitting the equation of this model to measured Pao and V'. The goodness of fit of the model to the data is judged by the coefficient of determination r2. Only data for which r2 
0.96 were included for analysis.
For the ECP assay, all blood samples were drawn immediately after line insertion (2.5 mL, SST Tube; Becton Dickinson, Franklin Lakes, NJ). After clotting at room temperature, the tube was centrifuged within 30 min, and serum was then frozen and stored at -80°C pending analysis (UniCAP ECP kit; Pharmacia & Upjohn, Australian Laboratory Services Pty Ltd, Rockdale NSW, Australia).
An unpaired two-tailed Mann-Whitney U-test was used to compare demographic data, Kruskal-Wallis nonparametric analysis of variance was performed for respiratory variables, and Fisher’s exact test was used for categorical data. Dunn’s multiple comparison correction was applied where appropriate. The significance level was taken at 0.05. Data are presented as mean ± SEM.
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Results
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Five of 35 consecutive eligible patients refused participation. Data from six patients were discarded because they did not satisfy methodological criteria: five patients (three salbutamol, two placebo) showed clinical evidence of active expiration and therefore had no adequate model fit, and one laryngospasm occurred (salbutamol) before any measurement.
The two groups were comparable with respect to age, weight, height, sex, and size of ETT (Table 1). No difference was found in asthma history or in previous or current asthma treatment (Table 2). Four patients in the Placebo and three in the Salbutamol group had been hospitalized for asthma treatment in the previous 12 mo; none of them had been admitted to the intensive care unit. In addition, manifestation of asthma was similar in both groups regarding frequency of symptoms, occurrence of symptoms at night or morning, and occurrence with exercise or infection. The mean ECP level was 15.0 ± 2.8 µg/L in the Placebo group and 16.9 ± 3.6 µg/L in the Salbutamol group. Three patients in each group had levels more than 20 µg/L, which is the 97th percentile in a normal pediatric population (12). No correlation was found between ECP levels and Rrs before or after intubation (P = 0.95, r2 = 0.01; and P = 0.56, r2 = 0.02, respectively) within groups or for the two groups combined.
Baseline ventilation variables and respiratory mechanics were not different between asthmatic patients pretreated with salbutamol or placebo when they breathed spontaneously via face mask at 3% sevoflurane in a mixture of 50% nitrous oxide in oxygen (Table 3). After intubation there was no difference in V, respiration rate, and expiratory time within each group or between the two groups. Although mean Rrs was similar in each group, there was a significant difference in percentage change between the two groups. Rrs increased by 17.7% (95% confidence interval, +4.4% to +30.9%) in the Placebo group, whereas Rrs decreased by 6.0% (-25.2% to +13.2%) in the Salbutamol group (Fig. 1, P = 0.04). In addition, a significantly larger proportion of patients in the Placebo group increased their Rrs after tracheal intubation in comparison to patients who were pretreated (10 of 11 [91%] vs 6 of 13 [46%], P = 0.03). Neither single-history items nor ECP values were predictive of an Rrs increase in either group. Finally, no changes were observed in Crs in either group.
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Table 3. Changes in Ventilation and Respiratory Mechanics After Endotracheal Intubation with Sevoflurane in Asthmatic Children Pretreated with Placebo or Salbutamol
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Figure 1. Medians with interquartile boxplots of respiratory resistance change (Rrs, %) in mildly to moderately asthmatic children after intubation with sevoflurane (placebo versus salbutamol, *P = 0.04).
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Discussion
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Endotracheal intubation under sevoflurane in asthmatic children induces an increase in Rrs, whereas sevoflurane was able to prevent any increase in nonasthmatics (5). This study has demonstrated that salbutamol prevents the increase in total Rrs after endotracheal intubation under sevoflurane in asthmatic children. The findings in this study are in agreement with previous reports in adults with and without asthma, in which inhaled ß2-adrenergic agonists were given before surgery to prevent an increase in lung resistance after endotracheal intubation; these studies demonstrate the effectiveness of a ß2-adrenergic agonist as a prophylactic treatment to protect against reflex bronchoconstriction induced by endotracheal intubation (13–15).
Children with mild to moderate asthma (Table 2) were included in this study. All patients’ asthma was well controlled, and most of them received regular inhaled medication until the day before surgery. We investigated a similar population previously (5). In both studies a similar increase in Rrs after endotracheal intubation under sevoflurane was evident in patients who did not receive any prophylactic bronchodilator treatment the day of surgery. Although a significantly larger proportion of patients in the Salbutamol group showed an Rrs decrease after endotracheal intubation, the preventive effect was present in only approximately half of the treated patients. Partitioning respiratory mechanics into its airways and parenchyma components has demonstrated that salbutamol has a bronchodilatory effect only on the airways (16,17). In this study, we determined total Rrs, which includes both the airway and the tissue visco-elastic component. Therefore, only bronchospasm induced by endotracheal intubation was prevented, whereas any increase in the resistance caused by the parenchyma component may not have been counteracted. This may partially explain the lack of complete prophylactic effect observed in the Salbutamol group.
Identifying individual asthmatic children at high risk of bronchospasm could be an alternative approach to routine prophylactic treatment to optimize the effectiveness of an adequate preoperative assessment. Our data illustrate, however, that it might be difficult to clearly predict a patient’s risk. All patients had one or more asthma attacks during the previous 12 months: most were taking regular medication, and their asthma was considered to be well controlled. On the basis of clinical history, it was not possible to predict which patients would have an increase in Rrs on intubation.
Recently ECP has been claimed to be a useful marker of airway responsiveness in mild asthmatic children and to be an objective measurement of asthma severity (18,19). It could therefore be useful in guiding asthma treatment (20). In this study all patients, except three in each group, had ECP levels within the normal range reported for children (12). This observation confirms that the majority of the study patients’ asthma was well controlled, either spontaneously or with their usual medication. Nevertheless, we failed to find any correlation between either asthma history or serum ECP levels and Rrs response to endotracheal intubation. The small patient number with increased ECP levels did not allow us to conclude the predictive value of serum ECP regarding an Rrs increase.
Preanesthetic lung function would have given objective information on preexisting bronchial hyperreactivity. However, considering the age of the study population, performing lung function measurements in all children would have been difficult to achieve. We applied a validated technique for respiratory mechanic measurements in intubated children (11). The MLR produces a weighted average for dynamic Crs and Rrs throughout the respiratory cycle. Given that expiration is entirely passive, Pao is the driving pressure that is applied to the respiratory system to overcome the combined resistive and visco-elastic forces of the lung-thorax system according to equation of motion (11). Partitioning of Rrs into its different components was not mandatory for this study. We therefore calculated the respiratory mechanics without measuring esophageal pressure. Also, the use of data collected only during passive expiration allows avoiding the influence of leak around the ETT (21).
In conclusion, salbutamol prevented an increase in Rrs in asthmatic children having their trachea intubated under sevoflurane induction. Our preliminary data suggest a possible benefit in the routine use of an inhaled ß2-adrenergic agonist before anesthesia with endotracheal intubation in all asthmatic children. Given the small number of patients in our study, large prospective trials are necessary to evaluate the potential clinical benefits, such as a reduction in perioperative respiratory adverse events, when routinely using adrenergic ß2-agonists before intubation. Moreover, further studies are being conducted to establish the usefulness of serum ECP levels to predict an impairment in respiratory mechanics in asthmatic children under anesthesia.
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Acknowledgments
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Supported in part by the Swiss National Science Foundation (Grant No. 81LA-51210 to PS). Eosinophilic cationic protein assay was offered by Australian Laboratory Services Pty Ltd, Rockdale NSW, Australia.
The authors thank theater staff for their hands-on support and the laboratory staff at Princess Margaret Hospital for Children (Dr. R. Loh) for performing the ECP assay.
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Accepted for publication June 4, 2001.
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Abstract
Introduction
