Anesth Analg 2005;100:348-353
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000140240.83236.AC
CARDIOVASCULAR ANESTHESIA
The Effect of Volatile Anesthetics on Respiratory System Resistance in Patients with Chronic Obstructive Pulmonary Disease
C. A. Volta, MD,
V. Alvisi, MD,
S. Petrini, MD,
S. Zardi, MD,
E. Marangoni, MD,
R. Ragazzi, MD,
M. Capuzzo, MD, and
R. Alvisi, MD
Department of Surgical, Anesthesiological and Radiological Science, Section of Anesthesia and Intensive Care, S. Anna Hospital, University of Ferrara, Ferrara, Italy
Address correspondence and reprint requests to Carlo Alberto Volta, MD, Department of Surgical, Anesthesiological and Radiological Science, Section of Anesthesia and Intensive Care, S. Anna Hospital, University of Ferrara, Corso Giovecca 203, 44100 Ferrara, Italy. Address e-mail to vlc{at}dns.unife.it.
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Abstract
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We examined the effect of isoflurane and sevoflurane on respiratory system resistance (Rmin,rs) in patients with chronic obstructive pulmonary disease (COPD). The diagnosis of COPD rests on the presence of airway obstruction, which is only partially reversible after bronchodilator treatment. Ninety-six consecutive patients undergoing thoracic surgery for peripheral lung cancer were enrolled. They were divided into two groups: preoperative forced expiratory volume in 1 s/forced vital capacity ratio <70% or >70%. Rmin,rs was measured after 5 and 10 min of maintenance anesthesia by using the constant flow/rapid occlusion method. Maintenance of anesthesia was randomized to thiopental 0.30 mg · kg–1 · min–1 or 1.1 minimum alveolar anesthetic concentration end-tidal isoflurane or sevoflurane. Eleven patients were excluded: two because anesthesia was erroneously induced with propofol and nine because of an incorrect tube position. Maintenance with thiopental failed to decrease Rmin,rs, whereas both volatile anesthetics were able to decrease Rmin,rs in patients with COPD. The percentage of patients who did not respond to volatile anesthetics was larger in those with COPD as well. In conclusion, we have demonstrated that isoflurane and sevoflurane produce bronchodilation in patients with COPD.
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Introduction
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The volatile anesthetics, such as halothane, isoflurane, and sevoflurane, have been proposed for treating bronchospasm induced by endotracheal intubation in humans (1). This could be relevant to the management of intraoperative bronchospasm, for which treatment could include inhaled anesthetics, either by themselves or in conjunction with other drugs, such as ß2-adrenergic drugs. Olsson (2) demonstrated that the most important risk factors for developing bronchospasm during anesthesia were age (i.e., <10 yr old), perioperative respiratory infection, and chronic obstructive pulmonary disease (COPD). Other studies (3,4) have emphasized the role played by endotracheal intubation as a major trigger for bronchospasm during general anesthesia.
Thoracic surgery is made possible by the use of a double-lumen endobronchial tube (DLTs), the diameter of which is much larger than that of a normal single-lumen endotracheal tube; DLTs probably cause more trauma (5). However, despite their larger external diameter, the resistance of flow (V') of DLTs is increased because they are essentially two small-diameter tubes in parallel. Moreover, patients undergoing thoracic surgery frequently exhibit chronic airflow obstruction due to a smoking history, which has been shown to increase the rate of bronchospasm (6). Although bronchodilating drugs are often inhaled in mechanically-ventilated patients with COPD, the improvement in respiratory resistance is, in general, extremely variable (7–10). This may be because permanent structural features lead to a net decrease in bronchial diameter or because patients with COPD exhibit small-airway closure and gas trapping (11).
Hence, we hypothesized that patients with COPD undergoing thoracic surgery cannot respond to volatile anesthetics and theoretically have an increased risk of bronchospasm and pulmonary complication due to pulmonary hyperinflation than patients with normal respiratory function. The aim of this study was to verify the bronchodilating effect of different volatile anesthetics in patients with COPD undergoing thoracic surgery.
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Methods
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Ninety-six consecutive patients undergoing thoracic surgery for peripheral lung cancer were enrolled. They were divided into two groups, based on a preoperative forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) ratio >70% or <70%, the latter being the value that implies the presence of chronic airflow obstruction (12). Their clinical characteristics are given in Tables 1 and 2. Exclusion criteria were lung atelectasis diagnosed with computed tomography and treatment with (a) a ß2-adrenergic agonist or anticholinergic inhaler 12 h before anesthesia induction, (b) corticosteroids, or (c) theophylline. The research was approved by our institutional ethics committee, and written, informed consent was obtained from all subjects. Baseline lung function tests were performed before surgery (13).
With the patients lying supine, anesthesia was induced with 4 mg/kg thiopental, 4–5 µg/kg fentanyl, and 0.1 mg/kg vecuronium. The trachea was intubated with a cuffed DLT (37–41F) for exclusion of the right or left lung (Table 1 and 2). The appropriate size of the DLT was based on the anatomical characteristics of the patients.
Immediately after tracheal intubation, ventilation was controlled (Servo 900B; Siemens, Elema) at 12 breaths/min, with a tidal volume (Vt) of approximately 8 mL/kg, a constant inspiratory V' rate of 0.5 L/s, and an inspiratory time percentage of 25%, with an end-inspiratory pause of 10%. The ventilator was set to deliver a Vt with a square-wave V'-time profile. This setting remained constant throughout the study. Extrinsic positive end-expiratory pressure was set to 0.
V' was measured with a heated pneumotachograph connected to a differential pressure transducer. The response of the pneumotachograph was linear over the experimental range of V'. Vt was calculated by integration of the V' signal. Pressure at the airway opening was measured through a side port on the connector between the respiratory circuit and the endotracheal tube by using a differential pressure transducer. The transducer was calibrated before and after each study. Special care was taken to avoid gas leakage in the equipment and around the tracheal and bronchial cuffs.
The V' and pressure signals were amplified, low-pass-filtered at 50 Hz, and digitized at 100 Hz by a 16-bit analog-to-digital converter. The digitized data were stored on computer hard disk for subsequent analysis. Data was analyzed with the Anadat data-analysis software (Version 5.1; RMT-InfoDat Inc., Montreal, Quebec, Canada).
Respiratory mechanics were assessed by the constant V'/rapid occlusion method previously described in detail (14). The end-inspiratory occlusion, obtained by increasing the end-inspiratory pause on the ventilator to 30%, lasted a mean of 1.5 s. This allowed measurement of the inspiratory resistance of the respiratory system. After end-inspiratory airway occlusion, the pressure at the airway opening exhibited an initial rapid decrease from the maximum pressure (Pmax) to the pressure registered at the point of zero V' (P1). During this period, the contribution of reduction in pressure due to volume loss by continuing gas exchange is generally considered negligible. By dividing airway opening Pmax – P1 by the V' immediately preceding the occlusion, the V' resistance of the endotracheal tube plus that of the total respiratory system (Rtot,rs) was obtained. By subtracting the V' resistance of the endotracheal tube, the minimal (Rmin,rs) inspiratory resistances of the respiratory system (upper airways not included) were obtained. In general, the V' resistance of the endotracheal tube is curvilinear and depends on the size of the tubes used. In the case of endotracheal tubes for thoracic surgery, there are two lumens to be considered in computation of resistance. Hence it is necessary to measure the pressure/V' relationships of both lumens, and this is best described by Rohrer’s equation:
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where P represents the pressure decrease across each tube and K1 and K2 are constants related, respectively, to the laminar and turbulent V' (15). Both constants were determined for the gas mixture normally used during anesthesia (oxygen 40% in air). These measurements were taken with the V' of the gas mixture injected in the experimental inspiratory direction. The total resistance of the DLT (tracheal and bronchial lumen) was calculated accordng to
(16) and then subtracted from the calculated value of Rtot,rs. Finally, dynamic positive end expiratory pressure was calculated as the value of airway pressure registered at zero 
'.
Measurements of Rmin,rs began within 2 min after tracheal intubation, as soon as mechanical ventilation was established according to existing guidelines. On completion of the measurements (<30 s), patients were randomized by using sequentially numbered, opaque, sealed envelopes to one of three anesthetic maintenance options: 1) thiopental infusion at 0.30 mg · kg–1 · min–1, 2) 2.3% sevoflurane in oxygen, or 3) 1.4% isoflurane in oxygen. Volatile anesthetic concentrations were chosen to approximate 1.1 minimum alveolar anesthetic concentration (MAC). Overpressure was used to achieve the desired end-tidal concentration as rapidly as possible. Thereafter, the fresh gas concentration was adjusted as necessary to maintain a constant end-tidal concentration throughout the study (1). Rmin,rs was measured 5 and 10 min after maintenance anesthesia was initiated. It should be noted that the correct position of the endotracheal tube was always verified by direct bronchoscopy after completion of the protocol. If an incorrect tube position was detected, the patient was removed from the study and the data were discarded. After completion of the protocol, anesthesia was continued by using volatile anesthetics (either sevoflurane or isoflurane) and appropriate doses of fentanyl and vecuronium.
The electrocardiogram, heart rate, systemic arterial blood pressure, pulsatile oxygen saturation, end-tidal carbon dioxide, and inhaled anesthetic end-tidal concentrations were continuously monitored. Boluses of 1 to 2 mg of etilefrine were administered IV by the treating physician in case of hypotension (mean arterial blood pressure decrease >25% from preinduction baseline).
Results are expressed as means ± sd. The Kolmogorov-Smirnov one-sample test was used to verify the normal distribution. Comparisons for continuous variables within and between groups were performed with the Friedman repeated-measures analysis of variance on ranks. To isolate divergent variables, pairwise multiple comparison procedures (Dunnett’s method) were used. Measurements of Rmin,rs at 5 and 10 min were analyzed as the percentage change from the thiopental baseline before initiation of gas or infusion. Categorical variables were compared by using the 
2 statistic. P < 0.05 was considered statistically significant.
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Results
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Eleven patients were excluded from the study: two because anesthesia was erroneously induced with propofol and nine because an incorrect tube position was detected by direct bronchoscopy after completion of the protocol. Therefore, 85 patients were finally included in the study.
The control group (42 patients) and the patients with COPD were similar in terms of sex, age, height, percentage of smokers, and smoking history. They differed mainly in terms of spirometric and Rmin,rs values (Tables 1 and 2). In this regard, it should be noted that the values of FEV1 (<80% of predicted) for patients in the COPD group (Table 2) allowed them to be classified as having moderate COPD (12). After tracheal intubation but before the commencement of maintenance anesthesia, Rmin,rs was not significantly different among the three subgroups treated with different anesthetics (Tables 1 and 2).
Control Group (FEV1/FVC >70%)
At 5 and 10 min of maintenance anesthesia, Rmin,rs had decreased significantly and to the same extent for the two volatile anesthetic subgroups (Table 3, Fig. 1), but not for the patients who had received thiopental. In one patient given isoflurane, resistance did not decrease.
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Figure 1. The percentage change (mean ± sd) in respiratory system resistance (Rmin,rs) is shown after 5 and 10 min of maintenance anesthesia with thiopental (TPS), 1.1 minimum alveolar anesthetic concentration (MAC) isoflurane (ISO), or 1.1 MAC sevoflurane (SEVO) in patients with a forced expiratory volume in 1 s/forced vital capacity ratio >70% (control group)
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Group with COPD (FEV1/FVC <70%)
At 5 min of maintenance anesthesia, Rmin,rs decreased significantly in the subgroup given sevoflurane, while this occurred at 10 min in the group receiving isoflurane (Table 3, Fig. 2). At 10 min, the percentage of Rmin,rs decrease was similar in the two subgroups (Fig. 2).
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Figure 2. The percentage change (mean ± sd) in respiratory system resistance (Rmin,rs) is shown after 5 and 10 min of maintenance anesthesia with thiopental (TPS), 1.1 minimum alveolar anesthetic concentration (MAC) isoflurane (ISO), or 1.1 MAC sevoflurane (SEVO) in patients with chronic obstructive pulmonary disease.
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Approximately 90% of the total decrease in Rmin,rs from immediately after tracheal intubation to 10 min of 1.1 MAC of anesthesia was obtained by 5 min of sevoflurane, while this percentage was only approximately 54% for isoflurane administration.
Finally, a variable percentage of COPD patients did not respond to volatile anesthetics with a decrease in pulmonary resistance. This percentage, statistically larger compared with the control group (P = 0.013), was approximately 12% for sevoflurane and 18% for isoflurane and did not differ between volatile anesthetics (P = 0.58).
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Discussion
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The most important finding of this study was that in patients with chronic airflow obstruction, both sevoflurane and isoflurane significantly decreased Rmin,rs, whereas this remained unchanged during maintenance of anesthesia with thiopental. The diagnosis of COPD rests on the presence of airway obstruction, which is only partially reversible after bronchodilator treatment (12). Two different types of airway resistance are expected in patients with COPD: peripheral ("fixed") and central ("labile") (17). The fixed intrinsic narrowing of the airway is disease specific, occurs in peripheral airways <3 mm in diameter, and is unlikely to respond to bronchodilators (17). Conversely, the labile resistance, presumably due to bronchial muscle contraction, usually responds to volatile drugs. The same decrease of Rmin,rs was observed in patients with less compromised respiratory function (control group), suggesting that the bronchodilating ability of volatile anesthetics is not disease specific. The difference between groups in terms of Rmin,rs baseline values (Tables 1 and 2) probably reflects differences in fixed airway narrowing, because resistance decreased to the same extent in both groups (Table 3, Figs. 1 and 2) given volatile anesthetics.
Our results are of clinical relevance because patients with COPD undergoing thoracic surgery are theoretically at the most risk of intraoperative bronchospasm, both because of their frequent smoking and because of the use of a DLT, which is probably more traumatic than a normal single-lumen endotracheal tube (5). Surprisingly, this was not the case when volatile anesthetics were used. The clinical implication of this finding could be seen in the ability of volatile anesthetics to reverse intraoperative bronchospasm. The latter can be responsible for pulmonary dynamic hyperinflation (DH) in the presence of expiratory V' limitation (EFL). Eltayara et al. (18) have previously demonstrated that patients with COPD with an FEV1 
60% of predicted, as in our study, could exhibit EFL in the supine position because of the reduction of functional residual capacity that also normally occurs during anesthesia. Because EFL implies concomitant DH, the latter can be responsible for deleterious effects on lung mechanics and hemodynamics (19). Even a small improvement in airway resistance caused by volatile anesthetic administration can decrease the extent of DH and reduce the intrathoracic pressure.
Although COPD did not alter responsiveness to either isoflurane or sevoflurane compared with patients with almost normal lung function (control group), not all patients with COPD responded to volatile anesthetics. The percentage of patients with COPD who did not respond varied from 18% to 12% for isoflurane and sevoflurane, respectively. The inability of this study to demonstrate a significant difference between isoflurane and sevoflurane in this respect may have been the result of the number of patients. In any case, this phenomenon was barely present in the control group and was not reported in patients with mild lung disease (1,20). This could be of clinical interest because it may imply that the more severe the lung disease, the smaller the number of patients in whom volatile anesthetics can reverse bronchospasm.
COPD seems responsible for another finding of our study, because sevoflurane acted faster than isoflurane only in patients with COPD. We are unable to explain the ability of sevoflurane to bronchodilate more rapidly than isoflurane in patients with COPD, although its lower solubility would theoretically permit faster tissue equilibration, thereby giving it an advantage over the other volatile anesthetics. We can speculate that the nonhomogeneous lung of patients with COPD, characterized by regional differences in mechanical properties and time constant inequalities, could delay the end-organ anesthetic concentration to a point at which the physical differences between the two volatile anesthetics could play a role. However, isoflurane can cause an unspecific airway irritation, which can enhance an initial difference between sevoflurane and isoflurane.
Although only sevoflurane significantly decreased Rmin,rs at 5 minutes of volatile anesthesia, this ability did not result in a larger reduction at 10 minutes compared with isoflurane (Table 3). This partially contradicts the data reported by Rooke et al. (1), who showed that sevoflurane decreased Rmin,rs more than isoflurane. However, a different effect from volatile anesthetic administration could have been expected in our study because it has been characterized by a patient population with more severe lung disease and by the use of a more traumatic DLT.
In conclusion, we have demonstrated that both sevoflurane and isoflurane can bronchodilate patients with COPD. Although the results are superimposed after 10 minutes of volatile anesthesia, sevoflurane acts faster than isoflurane. COPD does not alter the individual’s responsiveness to volatile anesthetics, but rather increases the possibility that patients will not respond to either sevoflurane or isoflurane.
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Footnotes
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This study was supported in part by a grant from Ministero Dell’ Università e Ricerca Scientifica e Technologica.
Presented at the 12th World Congress of Anesthesiologists, Montreal, Canada, June 2000.
Accepted for publication July 9, 2004.
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Abstract
Introduction
