Published ahead of print on April 12, 2007, doi:10.1164/rccm.200612-1864OC
© 2007 American Thoracic Society doi: 10.1164/rccm.200612-1864OC
Gas Exchange Response to Short-Acting
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2-Agonists in Chronic Obstructive Pulmonary Disease Severe Exacerbations |
ABSTRACT |
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 TOP ABSTRACT AT A GLANCE COMMENTARYMETHODSRESULTSDISCUSSIONREFERENCES |
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Rationale: Short-acting
2-agonists are one of the mainstays of bronchodilator strategy for exacerbations of chronic obstructive pulmonary disease (COPD). The assessment of pulmonary gas exchange after salbutamol in COPD severe exacerbations remains unknown. Objectives: We investigated whether the effects of nebulized salbutamol during COPD severe exacerbations are associated with further deterioration of pulmonary gas exchange.
Methods: We examined patients with severe COPD when hospitalized for exacerbation (n = 9), and while in stable convalescence.
Measurements and Main Results: We assessed spirometry, arterial blood gases, systemic hemodynamics, and 
/
relationships 30 and 90 minutes after administration of 5.0 mg salbutamol. At exacerbation, compared with baseline, 30 minutes after salbutamol administration, cardiac output () increased (from 6.5 ± [SEM] 0.4 to 7.3 ± 0.5 L · min–1) (p < 0.03) alone, without inducing changes in gas exchange indices. When in convalescence, compared with baseline, 30 minutes after salbutamol, there was an increase in (from 5.7 ± 0.5 to 7.0 ± 0.6 L · min–1) and O2 (from 211 ± 12 to 232 ± 11 ml · min–1) (p < 0.002 each), whereas PaO2 decreased (from 71 ± 4 to 63 ± 3 mm Hg) and alveolar–arterial PO2 difference increased due to increased perfusion of low–/-ratio regions (from 4.5 ± 2.6 to 9.6 ± 4.1% of ) (p < 0.05); SaO2 (93 ± 2%) and PaCO2 (43 ± 2 mm Hg) remained unchanged. This deleterious gas exchange response persisted at 90 minutes.
Conclusions: At exacerbation, salbutamol does not aggravate pulmonary gas exchange abnormalities. When in convalescence, however, baseline lung function improvement was associated with a detrimental gas exchange response to salbutamol, resulting in further / imbalance and small decreases in PaO2 compounded by small increases in and O2.
Key Words: chronic obstructive pulmonary disease exacerbations and management • pulmonary gas exchange • short-acting bronchodilators • ventilation–perfusion mismatching
Scientific Knowledge of the Subject Short-acting 2-agonist bronchodilators, namely salbutamol and terbutaline, remain the main treatment modality for chronic obstructive pulmonary disease (COPD) exacerbations. Short-acting 2-agonists may induce mild hypoxemia in patients with COPD. However, most of the studies have been performed in stable COPD alone.
What This Study Adds to the Field
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Severe exacerbations are common events in the natural history of chronic obstructive pulmonary disease (COPD), resulting in more airflow obstruction and air trapping (1, 2), with substantial gas exchange (3) and pulmonary hemodynamic deterioration (4). Worsening of pulmonary gas exchange during severe exacerbations associated with hypoxemic respiratory failure is primarily produced by increased
/ imbalance compounded by a decreased mixed-venous PO2 that results from greater O2; interestingly, the common finding of an increased partially offsets the detrimental effect of greater O2 on mixed-venous PO2 (3, 5).
Short-acting 2-agonist (SABA) bronchodilators—namely, salbutamol and terbutaline—remain the main treatment modality for COPD exacerbations, as they alleviate symptoms and improve airflow obstruction (6–10). SABAs may induce mild hypoxemia in patients with COPD (11). However, the vast majority of studies have been performed in stable COPD. Thus far, only two studies have been performed during severe exacerbations; moreover, they used SABAs with relative 2-selectivity (i.e., metaproterenol [12]) or offered at a higher relative dose (i.e., fenoterol [13]), none of which is recommended by current COPD guidelines.
Therefore, we assessed, in a comprehensive manner, the pulmonary gas exchange response to a therapeutic dose of nebulized salbutamol during COPD severe exacerbations and while in convalescence. We hypothesized that the interaction between intrapulmonary (i.e., / mismatch) and extrapulmonary (i.e., E, , and O2) factors contributing to gas exchange abnormalities after salbutamol during both acute and stable clinical conditions can behave differently. Some of the results of these studies have been previously reported in the form of two abstracts (14, 15).
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METHODS |
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TOPABSTRACTAT A GLANCE COMMENTARYMETHODSRESULTSDISCUSSIONREFERENCES |
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Study Population
We included 9 out of 20 consecutive patients (two died and nine were excluded due to further exacerbations), aged 66 (± 2 [SEM]) years (1 female, 3 smokers, and 6 ex-smokers [48 ± 9 pack-years]) with the diagnosis of COPD in GOLD stages 3 or 4 (6), admitted to hospital for COPD severe exacerbation. A COPD exacerbation was defined as a sustained worsening of respiratory symptoms and beyond normal day-to-day variations that is acute in onset and warrants a change in regular medication in a patient with underlying COPD (16). Patients with associated acute conditions (i.e., pneumonia, pulmonary thromboembolism, pleural effusion), serious comorbidities (i.e., asthma, bronchiectasis, lung cancer, and/or cardiovascular diseases), and/or mechanical support were excluded.
Study Design
Patients were studied on two occasions: within the first 4 days (median, 3 d) of admission to hospital and then 14 (± 3) weeks (median, 10 wk) after hospital discharge when in stable convalescence. Exacerbations were treated with systemic glucocorticoids, SABAs and anticholinergics, intravenous theophylline if needed, antibiotics, controlled oxygen therapy, and adjunct therapies. Mean length of hospital stay was 6 (± 1) days. After discharge, all patients remained on their regular treatment (inhaled short-acting and long-acting bronchodilators and inhaled glucocorticoids) for the duration of the convalescence study. Any new episode of exacerbation after the first assessment excluded the patient for the second (convalescence) assessment.
During measurements, patients breathed room air and were seated in an armchair. Measurements were performed before (at least 6 h after the last doses of short-acting bronchodilators and corticosteroids during exacerbation, or 12 h after those of inhaled, long-acting bronchodilators and corticosteroids when in convalescence) and 30 and 90 minutes after administration of 5.0 mg nebulized salbutamol (1.0 ml). After ensuring steady-state conditions, as assessed by stability (± 5%) of both ventilatory and hemodynamic variables, and by the close agreement (within ± 5%) between duplicate measurements of mixed expired and arterial oxygen and carbon dioxide, a set of duplicate measurements for each variable was obtained at each time point.
Measurements
Forced spirometry and inspiratory capacity (IC; predicted values in References 17, 18), PaO2, PaCO2 and pH, alveolar–arterial PO2 difference (A–a)DO2, SaO2, and O2, VCO2, E, respiratory rate (f), systemic arterial pressure (Psa), and heart rate (HR) were measured, or calculated, as previously described (19). Multiple inert gas elimination technique was used to estimate the distributions of / ratios without sampling mixed-venous inert gases (20), whereas was directly measured by indocyanine green (21). Inert gas measurements were not available in two patients (one during exacerbation and one at convalescence); paired inert gas studies were completed in seven patients. The residual sum of squares, the best descriptor of the quality of multiple inert gas elimination technique data, was within the expected limits (
5.0) (20) (2.8 ± 0.5; range, 0.7–5.0).
Statistical Analysis
Results are expressed as mean (± SEM). The effects of salbutamol on the end-point variables on each clinical condition were assessed by one-way repeated measures analysis of variance. Differences between exacerbation and convalescence were assessed using two-way repeated measures analysis of variance. Unpaired t tests and Pearson's correlation tests were used as appropriate. Significance was set at p less than 0.05.
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RESULTS |
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TOPABSTRACTAT A GLANCE COMMENTARYMETHODSRESULTSDISCUSSIONREFERENCES |
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Effects of Salbutamol during Exacerbation
Before salbutamol, patients had severe airflow limitation and air trapping, mild increases in
E and f, and severe hypoxemia with normocapnia (Tables 1 and 2; Figures 1 and 2). The dispersion (second moment) as the standard deviation of pulmonary blood flow (log of standard deviation of perfusion (SDQ); normal 0.60) and that of ventilation (log SDV; normal 0.65) distributions on a logarithmic scale (22) and an overall index of / heterogeneity (dispersion of retention minus excretion of inert gases corrected for dead space [DISP R-E*]; normal 3.0) (23) (all dimensionless) were increased. Both intrapulmonary shunt (percentage of blood flow to units with / units < 0.005) and regions of high / ratio (> 10, excluding dead space) were virtually absent, whereas both regions of low / ratio (< 0.1, excluding shunt) (i.e., the low / mode) and inert dead space (/ units > 100) were increased. These / findings were consistent with previous data shown in COPD exacerbations (3). Patients showed increased HR and with normal Psa and O2. PaO2 was inversely correlated with areas of low / ratio (r = –0.81; p < 0.03) and log SDQ (r = –0.98; p < 0.001), whereas (A–a)DO2 was positively correlated with log SDQ (r = 0.88; p < 0.01). Except for a moderately greater HR (96 ± 5 beats · min–1; p < 0.03), no other differences were observed between the 9 patients who completed the study and the 11 who were withdrawn.
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Compared with baseline, at 30 minutes after salbutamol administration, FEV1 (by 15%; p < 0.02) and IC (by 12%; NS) increased, whereas
E, f, PaO2, PaCO2, (A–a)DO2, SaO2, both areas of low and high / ratio, log SDQ, log SDV, and DISP R-E* remained essentially unchanged (Tables 1 and 2; Figures 1 and 2). Salbutamol increased HR (p < 0.01) and (by 12%; p < 0.03), and decreased Psa (p < 0.04). PaO2 was inversely correlated with log SDQ (r = –0.91; p < 0.01).
Compared with baseline, at 90 minutes after salbutamol administration, FEV1 (p < 0.01) and IC still remained elevated, and most of the respiratory and inert gas exchange indices were unchanged; HR persisted at an altered level (p < 0.002), but Psa and showed a trend to return to baseline. (A–a)DO2 was positively correlated with log SDQ (r = 0.93; p < 0.005).
Effects of Salbutamol during Convalescence
Before salbutamol administration, patients still exhibited severe airflow limitation, air trapping, and mild to moderate hypoxemia without hypercapnia (Tables 1 and 2). The inert gas exchange indices were increased with increments in low / regions and dead space. FEV1 was inversely correlated with DISP R-E* (r = –0.76; p < 0.05) and IC with log SDV (r = –0.77; p < 0.05), suggesting that the lower the airflow limitation and air trapping, the better the / balance; PaO2 was inversely correlated with log SDQ (r = –0.83; p < 0.03).
When compared with baseline, 30 minutes after salbutamol, both FEV1 (p < 0.02) and IC (p < 0.03) increased (by 17% each) without changes in the ventilatory pattern (Table 1). By contrast, gas exchange deteriorated, as assessed by small decreases in PaO2 (by 6.7 mm Hg; p < 0.01) and increases in (A–a)DO2 (by 5.3 mm Hg; p < 0.02) (Table 2 and Figures 1 and 2), whereas both SaO2 and PaCO2 remained unchanged. There was further / imbalance as assessed by increases in regions of low / ratio (by 113%; p < 0.05) and DISP R-E* (by 29%; p < 0.01); log SDQ, log SDV, and dead space did not increase significantly. In parallel, salbutamol increased HR (by 16%; p < 0.01), (by 23%; p < 0.001), and O2 (by 10%; p < 0.002), and decreased Psa (p < 0.05). PaO2 was inversely correlated with areas of low / ratio (r = –0.86; p < 0.01), log SDQ (r = –0.78; p < 0.04), and DISP R-E* (r = –0.90; p < 0.01).
Compared with baseline, at 90 minutes, FEV1 and IC were still elevated (p < 0.01 each), and abnormalities in PaO2 (p < 0.02), (A–a)DO2 (p < 0.01), areas with low / ratio (p < 0.05), log SDQ (p < 0.02), and DISP R-E* differences (p < 0.01) were abnormally altered; HR (p < 0.04) and (p < 0.003) were also increased, but O2 returned toward baseline. FEV1 was inversely correlated with DISP R-E* (r = –0.81; p < 0.03) and IC with log SDV (r = –0.88; p < 0.01), whereas PaO2 was inversely correlated with log SDQ (r = –0.79; p < 0.04) and DISP R-E* (r = –0.88; p < 0.02). Baseline FEV1 (at 30 min, r = 0.75; p < 0.03; at 90 min, r = 0.82; p < 0.01) and PaO2 (at 90 min only, r = –0.76; p < 0.02) were significantly correlated with their respective differences after salbutamol, indicating that the better the basal FEV1 and PaO2, the greater the bronchodilation and the hypoxemia.
Similarities and Differences between Exacerbation and Convalescence Studies
As expected, compared with exacerbations (Tables 1 and 2; Figures 1 and 2), patients had better baseline lung function status during convalescence: IC (p < 0.02) was greater, E (p = 0.051) and HR (p < 0.04) lower, and pulmonary gas exchange abnormalities less deteriorated: higher PaO2 (p < 0.02), and lower (A–a)DO2 (p < 0.005) and log SDQ (p = 0.05). When the differences between variables measured at exacerbation and while in convalescence were assessed (Figure 1), only the most representative pulmonary gas exchange indices (i.e., PaO2, [A–a]DO2, log SDQ, and DISP R-E*) were significantly different. Thus, all four gas exchange descriptors deteriorated when in convalescence, at variance with the lack of differences at exacerbation. This gas exchange response sharply contrasted with the parallel improvements in FEV1 and IC induced by salbutamol at both exacerbation and convalescence.
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DISCUSSION |
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TOPABSTRACTAT A GLANCE COMMENTARYMETHODSRESULTSDISCUSSIONREFERENCES |
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This study highlights that, in COPD severe exacerbations requiring hospitalization, the underlying severe pulmonary gas exchange abnormalities remain essentially unchanged after salbutamol nebulization. By contrast, while in convalescence, when patients show clinical and lung function improvement, the pulmonary gas exchange response to salbutamol is deleterious, resulting in small decrements in PaO2 due to further
/ worsening.
Exacerbation
Contrary to our original hypothesis (i.e., the interplay between intrapulmonary and extrapulmonary factors governing arterial blood gases during exacerbations would be more influential than during convalescence), pulmonary gas exchange abnormalities after salbutamol remained essentially unvaried. It is most likely that the lack of gas exchange response to salbutamol suggests a weaker (or even absent) hypoxic pulmonary vascular response related more to acutely severe alveolar hypoxia than to a permanent structural derangement of the pulmonary vasculature. Moreover, the high dosage of SABAs usually given during the most critical days of exacerbation may facilitate an underlying vasodilatory state of the pulmonary vasculature. However, there remains the potential of SABA-induced inhibitory effects on the postcapillary bronchial venoconstriction and airway microvascular leakage (24), possibly amplified by their potent relaxant effect on conducting airways, which cannot be overlooked (25). Likewise, SABAs can minimize the subsequent release of other inflammatory mediators into the pulmonary circulation, with vasodilator effects during COPD exacerbations that can disturb the underlying / imbalance (25). The latter two effects could offset further / inequality, thus reinforcing hypoxic pulmonary vasoconstriction. It may also be plausible that both collateral ventilation and hypoxic vasoconstriction can be more effective, hence maximizing a more adequate / balance.
Convalescence
During stable convalescence, salbutamol caused further / worsening and hypoxemia, compounded by increases in both and O2. Increased can increase the amount of blood flow diverted to areas with low / ratio, reflected in increases in the regions of low / ratio, the log SDQ, and the DISP R-E*. Conceivably, arterial hypoxemia is amplified by the parallel increase in O2 that decreases mixed-venous PO2, other things being equal (5). However, this situation is not sufficiently counterbalanced by the simultaneous increase in mixed-venous PO2 induced by a high , the net effect being a small decrease in PaO2. Nevertheless, from our data it is not possible to differentiate between an increased , with passive relaxation of the pulmonary vessels and/or active reduction in pulmonary vascular tone—namely, release of hypoxic vasoconstriction. In patients with stable COPD, there is a short-term blunted airway vascular response to low doses of albuterol, possibly an expression of systemic vascular inflammation and endothelial dysfunction, which is restored after combined therapy in COPD (26), a therapeutic regime that our patients followed after hospitalization.
Previous Studies
Our current findings are at variance with the only two studies so far performed during COPD severe exacerbations after metaproterenol sulfate (12) and a dose–response of fenoterol (13), both resulting in minor PaO2 decreases. It is likely that differences in the selectivity and the dosage of SABAs and in the design of each study are behind these results. Notwithstanding, our findings are in line with those of Ringsted and colleagues (27), who showed that, in a small subset of stable patients with very severe COPD and moderate hypoxemia, intravenous terbutaline decreased PaO2, whereas mixed-venous PO2 and O2 increased. In parallel, increased, and both Psa and pulmonary vascular resistance decreased with further / imbalance related to the increased . In another small subset of patients with stable COPD, but with more severe functional abnormalities, the gas exchange response was unmodified after terbutaline, suggesting that, in more severe COPD with more prominent hypoxemia, the pulmonary vascular tone is more disturbed than in patients with less severe disease, with the vessels more rigid and fixed, hence less liable to be vasodilated by SABAs.
Our findings are partially consistent with those shown after intravenous salbutamol in patients with acute severe asthma, in whom PaO2 remained essentially unchanged despite marked increases in and significant / worsening (28), likely modulated by a distinct inflammatory pulmonary vascular involvement (29).
There were both strengths and shortcomings in our study. First, this is the first study so far that has addressed, in a comprehensive manner, the pulmonary gas exchange response, including measurements of / distributions, to one of the most recommended existing SABAs to improve COPD severe exacerbations. Second, the patients are fully representative of the day-by-day clinical practice. Finally, the same patients were investigated at exacerbations and then at convalescence, thus providing a comparative insight into the difficult interplay of pulmonary gas exchange status. We acknowledge, however, that the number of patients studied at convalescence was small due to the stringent criteria imposed, and that the lack of pulmonary hemodynamic assessment, considered beforehand too aggressive in the setting of our design, are weaknesses.
In summary, there is evidence that, in the more vulnerable conditions of COPD severe exacerbations, nebulized salbutamol does not aggravate pulmonary gas exchange. By contrast, while in convalescence, there is a small deterioration in the gas exchange response to salbutamol in the same patients whose baseline lung function has improved. Overall, these findings support the current recommendations of COPD guidelines to increase the dose and the frequency of existing bronchodilator therapy with SABAs during COPD severe exacerbations.
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Acknowledgments |
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The authors very specially thank J.L. Valera, D.E., for technical support, and Alejandro Peña, M.D., for his unselfish contributions.
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FOOTNOTES |
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* These investigators contributed equally to this article.
Supported by grants-in-aid from GlaxoSmithKline (UK), Esteve (Spain), and AstraZeneca (Peru), COST Action B29, Generalitat de Catalunya grant 2005SGR-00822, the CIBER grant ISCIII-CB06/06, an educational grant from Università di Pisa, Pisa, Italy (E.P.), and by European Respiratory Society–SEPAR 2005 LTR Fellowship No. 182 (H.M.). R.R.-R. holds a Career Scientist Award (2001–2007) from the Generalitat de Catalunya.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.200612-1864OC on April 12, 2007
Conflict of Interest Statement: E.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. F.P.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. H.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. N.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.A.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.R.-R. has participated as a lecturer and speaker in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Pfizer; consulted with several pharmaceutical companies with relevance to the topics discussed in the present article (Altana, AstraZeneca, Aventis, Boehringer Ingelheim, GlaxoSmithKline, Laboratorios Dr Esteve SA, Novartis, Pfizer, and Veichi); serves on advisory boards for Almirall, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Procter & Gamble, Viechi; has been sponsored for several clinical trials by, and received laboratory research support from, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Laboratorios Dr Esteve SA, and Pfizer.
Received in original form December 21, 2006; accepted in final form April 11, 2007
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