UBC Faculty Research and Publications

Inhaled beta-2 agonist salbutamol and acute lung injury: an association with improvement in acute lung… Manocha, Sanjay; Gordon, Anthony C; Salehifar, Ebrahim; Groshaus, Horacio; Walley, Keith R; Russell, James A Jan 11, 2006

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata


52383-13054_2005_Article_3856.pdf [ 212.4kB ]
JSON: 52383-1.0223315.json
JSON-LD: 52383-1.0223315-ld.json
RDF/XML (Pretty): 52383-1.0223315-rdf.xml
RDF/JSON: 52383-1.0223315-rdf.json
Turtle: 52383-1.0223315-turtle.txt
N-Triples: 52383-1.0223315-rdf-ntriples.txt
Original Record: 52383-1.0223315-source.json
Full Text

Full Text

Available online http://ccforum.com/content/10/1/R12Open AccessVol 10 No 1ResearchInhaled beta-2 agonist salbutamol and acute lung injury: an association with improvement in acute lung injurySanjay Manocha1, Anthony C Gordon2, Ebrahim Salehifar3, Horacio Groshaus4, Keith R Walley5 and James A Russell61Clinical/Research Fellow, Critical Care Research Laboratories, Centre for Cardiovascular and Pulmonary Research, University of British Columbia, Vancouver, BC, Canada2Clinical/Research Fellow, Critical Care Research Laboratories, Centre for Cardiovascular and Pulmonary Research, University of British Columbia, Vancouver, BC, Canada3Pharmacist, Critical Care Research Laboratories, Centre for Cardiovascular and Pulmonary Research, University of British Columbia, Vancouver, BC, Canada4Research Assistant, Critical Care Research Laboratories, Centre for Cardiovascular and Pulmonary Research, University of British Columbia, Vancouver, BC, Canada5Professor of Medicine, Critical Care Research Laboratories, Centre for Cardiovascular and Pulmonary Research, University of British Columbia, Vancouver, BC, Canada6Professor of Medicine, Critical Care Research Laboratories, Centre for Cardiovascular and Pulmonary Research, University of British Columbia, Vancouver, BC, CanadaCorresponding author: James A Russell, jrussel@mrl.ubc.caReceived: 13 Oct 2005 Accepted: 15 Dec 2005 Published: 11 Jan 2006Critical Care 2006, 10:R12 (doi:10.1186/cc3971)This article is online at: http://ccforum.com/content/10/1/R12© 2006 Manocha et al., licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is cited.AbstractIntroduction β2 agonists have several properties that could bebeneficial in acute lung injury (ALI). We therefore chose to studythe effect of inhaled β2 agonist use (salbutamol) on duration andseverity of ALI.Methods We undertook a retrospective chart review of 86consecutive mechanically ventilated patients with ALI, who hadvarying exposure to inhaled salbutamol. The cohort was dividedinto two groups according to the average daily dose of inhaledsalbutamol they received ('high dose' ≥ 2.2 mg/day and 'lowdose' <2.2 mg/day). Severity of ALI and non-pulmonary organdysfunction was compared between the groups by calculatingthe days alive and free of ALI and other organ dysfunctions.Results The high dose and low dose groups received a mean of3.72 mg and 0.64 mg salbutamol per day, respectively. The highdose salbutamol group had significantly more days alive and freeof ALI than the low dose group (12.2 ± 4.4 days versus 7.6 ±1.9 days, p = 0.02). There were no associations between doseof β agonist and non-pulmonary organ dysfunctions. High dosesalbutamol (p = 0.04), APACHE II score (p = 0.02), and causeof ALI (p = 0.02) were independent variables associated withnumber of days alive and free of ALI in a multivariate linearregression model.Conclusion Our retrospective study suggests that salbutamol,an inhaled β2 agonist, is associated with a shorter duration andlower severity of ALI. A dose greater than 2.2 mg/day of inhaledsalbutamol could be a minimal effective dose to evaluate in arandomized controlled trial.IntroductionAcute lung injury (ALI) is defined by impaired oxygenation(arterial partial pressure of oxygen/fraction of inspired oxygen(PaO2/FiO2) <300 mmHg) and bilateral infiltrates on a chestradiograph without clinical evidence of left atrial hypertension[1]. Pulmonary edema in ALI is caused by damage to the alve-olar-capillary interface and increased permeability that leads toaccumulation of protein rich edema fluid in the interstitial andalveolar spaces. Reabsorptive mechanisms to clear alveolaredema fluid are impaired in acute lung injury [2-4]. Further-Page 1 of 7(page number not for citation purposes)ALI = acute lung injury; APACHE = Acute Physiology and Chronic Health Evaluation; ARDS = acute respiratory distress syndrome; COPD = chronic obstructive pulmonary disease; DAF = days alive and free (of organ failure); FiO2 = fraction of inspired oxygen; ICU = intensive care unit; IL = inter-leukin; PaO2 = arterial oxygen partial pressure.Critical Care    Vol 10 No 1    Manocha et al.more, there is a dose effect indicated by the association of thegreater degree of impaired edema clearance with longer dura-tion of mechanical ventilation and decreased survival [5,6].β2 agonists have several properties that could be beneficial inALI. First, inhaled β2 agonists improve respiratory mechanicsin patients with ALI as shown by decreased airflow resistanceand peak airway pressures and increased dynamic compli-ance [7-9]. Second, β2 agonists have anti-inflammatory prop-erties. β2-agonists attenuate the release of tumor necrosisfactor-α and increase the production of IL-10 in response toendotoxin in animal models [10,11].Intravenous dobutamine (which has β1 and β2 agonist action)attenuates pro-inflammatory cytokine expression in the lungsof a rat model of septic acute lung injury [12]. Third, β agonistsincrease alveolar edema fluid clearance in animal models ofALI [13-22], in the ex vivo human lung [19] and in patients withALI [23]. Studies on the selective β blockers show that it is theβ2 agonist activities that cause the enhanced edema fluidclearance [24].To date, there have been no studies on the dose associationof inhaled β agonists with duration or severity of human ALI.Our hypothesis was that a higher dose of inhaled β2 agonistuse, compared to a lower dose, is associated with more daysalive and free of ALI (a measure of duration of severity of ALI)in critically ill patients with acute lung injury.Materials and methodsThis study was approved by the Research Ethics Board ofProvidence Health Care and the University of British Colum-bia, which waived the requirement of informed consentbecause of the retrospective nature of this study.Cohort of patients who had acute lung injuryBetween September 2001 and August 2003, consecutivepatients admitted to a tertiary care medical-surgical intensivecare unit (ICU) at St Paul's Hospital, Vancouver, Canada, werescreened and 86 of these met the American-European con-sensus conference definition of ALI who were on mechanicalventilation [1].Quantification of inhaled β2 agonistSalbutamol was the only inhaled β2 agonist used clinically inthe ICU. Salbutamol was administered through the ventilatorcircuit by metered dose inhaler (8 to 10 puffs at 100 µg/puff)or by nebulization of 2.5 to 5 mg of salbutamol solution (2.5 to5 ml). The total daily dose of salbutamol administered and theroute of delivery (metered dose inhaler or nebulizer) wasrecorded for each patient by retrospective chart review. Werecorded salbutamol dose for each day in the ICU for 28 daysor until discharge from the ICU (if less than 28 days). We cal-culated the average daily dose of salbutamol (mg/day) while inthe ICU as the sum of total metered dose inhaler and nebuliza-tion dose (in mg) divided by the number of days in the ICU.Several different doses of inhaled β2 agonists have beenreported in mechanically ventilated patients [7,25,26]. Atabaiand colleagues [27] measured levels of albuterol in plasmaand broncho-alveolar lavage fluid from patients with ALI andfound that doses of 2.5 mg or more of nebulized albuterolresulted in physiologically efficacious levels. In the only dose-response study published for mechanically ventilated patients,Dhand and colleagues [28] reported that a dose of 0.36 mgwas as effective as 1.08 mg and 2.52 mg. This dose givenevery 4 hours would result in a total daily dose of 2.2 mg.Based on this, we classified patients receiving equal to orgreater that 2.2 mg/day as 'high dose' and those patientsreceiving less than 2.2 mg/day as 'low dose'.Primary and secondary outcomesThe primary outcome was days alive and free of ALI over 28days. Secondary outcomes were days alive and free of PaO2/FiO2 <300, days alive and free of cardiovascular, renal,hepatic, neurological, and hematological dysfunction, and 28-day mortality.Organ dysfunction for each organ system was defined asbeing present during each 24 hour period if there was evi-dence of moderate, severe, or extreme organ dysfunctionaccording to the Brussels criteria [29]. To assess duration oforgan dysfunction and to correct organ dysfunction scoring fordeaths in the 28-day observation period, we calculated daysalive and free of organ dysfunction (DAF) as previouslyreported. Briefly, during each 24 hour period for each variable,DAF was scored as 1 if the patient was alive and free of organdysfunction (normal or mild dysfunction). DAF was scored as0 if the patient had organ dysfunction (moderate, severe, orextreme) or was not alive. Each of the 28 days after meetingthe inclusion criteria was scored. A low score is indicative ofmore organ dysfunction because a low score indicates fewerdays alive and free of organ dysfunction. Because data werenot always available during the 24 hour period for each organdysfunction variable, we used the carry forward assumption asdefined previously [29]. For any 24 hour period in which therewas no measurement of a variable, we carried forward thepresent or absent criteria from the previous 24 hour period. Ifany variable was never measured, it was assumed to be normalthroughout the 28-day period.Baseline demographics were age, gender, surgical versusmedical diagnosis on admission to the ICU (based on theAcute Physiology and Chronic Health Evaluation (APACHE) III[30] diagnostic codes), admission APACHE II score [31],baseline PaO2/FiO2 ratio, history of chronic obstructive pulmo-nary disease (COPD), asthma, and/or smoking, cause of ALI(pulmonary versus extra-pulmonary), and proportion ofPage 2 of 7(page number not for citation purposes)Available online http://ccforum.com/content/10/1/R12patients that had sepsis or septic shock as defined by theACCP/SCCM consensus conference [32].Statistical analysisA comparison between the high and low dose salbutamolgroups was made using the t test for continuous baselinedemographic variables and outcomes. A chi-squared test wasused for categorical variables. A forward selection multivariatelinear regression model was constructed to evaluate the inde-pendence of salbutamol (high or low dose) against days aliveand free of ALI. In the forward selection model, the followingcovariates were included: salbutamol (high or low dose), age(as a continuous variable), gender (female versus male), surgi-cal versus medical diagnosis, history of COPD, asthma, and/or smoking, APACHE II score on admission (as a continuousvariable), cause of ALI (pulmonary versus extrapulmonary),presence or absence of septic shock, and severity of ALI asdefined by presence or absence of PaO2/FiO2 ratio ≤ 200.Variables were entered sequentially from the smallest to larg-est univariate p values and removed if they no longer met theinclusion cut-off after adjustment for the other variables. A two-tailed p value of <0.05 was used for statistical significance.The data were analyzed using SPSS 11.5 for Windows(SPSS Inc., Chicago, IL, USA, 2003). Continuous variablesare presented as mean ± standard deviation unless otherwisestated.ResultsThe daily dose of salbutamol ranged from 0 to 6.4 mg/day. Thecohort was divided into two groups using the cut-off point of2.2 mg/day to compare the primary and secondary outcomesin those who received high dose salbutamol to those whoreceived low dose. The mean salbutamol doses in the high andlow dose groups were 3.72 mg/day and 0.64 mg/day respec-tively.Patients who received high dose salbutamol had significantlymore days alive and free of ALI (12.2 ± 4.4 days versus 7.6 ±1.9 days, p = 0.02; Figure 1). Similarly, there was an associa-tion between the higher average daily dose of salbutamol andmore days alive and free of PaO2/FiO2 ratio <300 (p = 0.05;Figure 2). There was no association between salbutamol doseand days alive and free of any of the non-pulmonary organ dys-functions (Table 1). Mortality was not significantly differentbetween the low and high dose groups (46.9% versus 50.0%,respectively).The baseline demographics (Table 2) were similar betweenthe groups except for a lower age in the low dose versus thehigh dose group (54.7 ± 16.6 years versus 65.7 ± 15.1 years,p < 0.05) and a lower proportion of patients with a history ofCOPD, asthma, and/or smoking in the low dose group versusthe high dose group (15.6% versus 45.5%, p < 0.05).Figure 2Days alive and free of PaO2/FiO2 <300 in low dose (<2.2 mg/day) and high dos (≥ 2.2 mg/day) salbutamol groups (mean and 95% confi-dence interval)high dose (≥ 2.2 mg/day) salbutamol groups (mean and 95% confi-dence interval).Figure 1Days alive and free of acute lung injury in low dose (<2.2 mg/day) and high dos (≥ 2.2 mg/d y) sa butamol groups (mean and 95% confi-dence interval)high dose (≥ 2.2 mg/day) salbutamol groups (mean and 95% confi-dence interval).Page 3 of 7(page number not for citation purposes)Critical Care    Vol 10 No 1    Manocha et al.Because of these differences at baseline between the twogroups in age and in COPD/asthma/smoking status, a multi-variate linear regression model was used to determinewhether high dose salbutamol was independently associatedwith days alive and free of ALI when adjusting for other factors.High dose salbutamol remained a predictor of days alive andfree of ALI in this model (p = 0.04). APACHE II score (p =0.02) and cause of ALI (p = 0.02) were also independentlyassociated with days alive and free of ALI (Table 3).DiscussionWe found that high dose salbutamol, an inhaled β2 agonist,was associated with more days alive and free of ALI in criticallyill patients who had ALI. This finding was supported by a simi-lar significant association between dose of salbutamol anddays alive and free of PaO2/FiO2 <300, a marker of severity oflung injury. Even after adjusting for differences in baselinecharacteristics between the high dose and low dose groupsusing a multivariate analysis, salbutamol was an independentpredictor of more days alive and free of ALI.Supporting the theory that β agonists have a direct effect onthe pathophysiology of ALI, salbutamol dose was not signifi-cantly associated with days alive and free of any non-pulmo-nary organ dysfunction. To the best of our knowledge, this isthe first study to show an association of the dose of an inhaledβ-adrenergic agonist with a measure of duration of severity ofALI. Furthermore, this study suggests that a dose greater than2.2 mg/day would be a reasonable dose to evaluate in a futureprospective randomized controlled trial.Our findings could be explained by one or more potentiallybeneficial actions of β2 agonists. β2 agonists such as salbuta-mol can improve pulmonary dysfunction in ALI by at least threemechanisms: increased alveolar fluid clearance, anti-inflamma-Table 1Comparison between the low versus high dose salbutamol groups and non-pulmonary organ dysfunction and mortalityDays alive and free Low dose (n = 64)a High dose (n = 22)a p valueCardiovascular 11.5 ± 2.6 13.2 ± 4.2 0.50Renal 14.3 ± 2.9 16.0 ± 4.5 0.55Hepatic 17.4 ± 2.8 19.6 ± 4.4 0.42Hematological 15.9 ± 2.9 19.6 ± 4.5 0.10Neurological 16.6 ± 2.6 19.0 ± 3.9 0.35Mortality (%) 46.9% 50.0% 0.80aValues are mean ± standard error of the mean.Table 2Baseline characteristics of patients who had acute lung injuryCharacteristic Low dose (n = 64) High dose (n = 22) p valueMean salbutamol dose (mg/day, range) 0.64 (0–2.19) 3.72 (2.2–6.4) <0.001Age (years) 54.7 ± 16.6 65.7 ± 15.1 0.007Gender (% female) 41% 45% 0.70Surgical diagnosis 31.3% 31.8% 0.96APACHE II 27.2 ± 8.1 25.2 ± 7.1 0.27Cause of ALIPulmonary 51.6% 50%Extra-pulmonary 48.4% 50% 0.90History of COPD, asthma, and/or smoking 15.6% 45.5% 0.007PaO2/FiO2 ≤ 200 81.3% 68.2% 0.20Sepsis 95% 100% 0.41Septic shock 81.3% 72.7% 0.29ALI, acute lung injury; COPD, chronic obstructive pulmonary disease; FiO , fraction of inspired oxygen; PaO , arterial oxygen partial pressure.Page 4 of 7(page number not for citation purposes)2 2Available online http://ccforum.com/content/10/1/R12tory effects, and bronchodilation. The actions of β2 agonists inacute lung injury have recently been reviewed [33,34].Stimulation of alveolar epithelial β2 receptors activates amilo-ride-sensitive sodium channels and ouabain-sensitive Na+/K+-ATPase to increase transepithelial sodium transport and alve-olar fluid clearance via cAMP second messenger systems [35-37], which increases alveolar fluid clearance and alveolar epi-thelial function [38]. Beta-adrenergic agonists increase alveo-lar fluid clearance in normal lung [13-19] and in several animalmodels of acute lung injury [20-22] as well as in ex vivo humanlungs [19] and in patients with ALI [23]. Terbutaline increasessodium transport across intact alveolar epithelium in isolatedperfused rat lung, an effect that was inhibited by propranolol,indicating the importance of β receptor agonist activity [13].Terbutaline also increases alveolar fluid clearance in anesthe-tized ventilated sheep [14], in dog lung [15], and in severalmodels of ALI, such as hyperoxic lung injury [20], high tidal vol-ume-associated lung injury [21] and the in vivo hypoxic ratmodel [22]. Resolution of alveolar edema is accelerated byisoproterenol [16,17,21] and epinephrine. Salmeterol, a spe-cific β2 agonist, increased fluid clearance in both ex vivohuman and rat lung [19]. In a recent double-blinded placebocontrolled trial, intravenous salbutamol was shown to reduceextra vascular lung water in patients with ALI [23]. We did notmeasure lung water in our study so we cannot comment onwhether salbutamol changed edema clearance in our study.Beta-adrenergic agonists also have anti-inflammatory proper-ties as β agonists decrease polymorphonuclear cell chemo-taxis and accumulation in the lung [39] and decrease IL-1 [40],tumor necrosis factor-α [41] and IL-6 [42] production frommacrophages. In a murine model of endotoxin-induced lunginjury, dobutamine and dopexamine (both β1 and β2 agonists)decreased lung IL-6 protein and mRNA expression, and atten-uated neutrophil accumulation in the lung [12]. We did notmeasure markers of inflammation in our study.The third potential benefit of salbutamol on lung function in ALIis bronchodilation. β2 agonists decrease the elevated respira-tory system resistance and airway pressure of patients whohave acute respiratory distress syndrome (ARDS) [7-9]. In par-cheal tube) [7] and continuous intravenous infusion ofsalbutamol (15 µg/minute for at least 30 minutes) [9]decrease respiratory system resistance and airway pressure inARDS. Wright and colleagues [8] also showed that a β2 ago-nist, aerosolized metaproterenol (5 mg), not only decreaseshigh airway resistance and improves oxygenation, but alsoincreases static compliance in human ARDS. This improve-ment of static compliance may be related to decreased lungedema or reduction in intrinsic positive end-expiratory pres-sure [7]. Overall, there may be clinical benefit from a reductionin respiratory resistance by β2 agonists in ALI because of apotential to decrease the risk of barotrauma.There are few studies on the effects of β2 agonists on respira-tory function in human ALI. Ware and Matthay [6] demon-strated that alveolar fluid clearance is impaired in mostpatients with ALI/ARDS and that impaired clearance is asso-ciated with a poor outcome. Basran and colleagues [43] stud-ied the effect of intravenous terbutaline on plasma proteinextravasation in ten patients with ALI/ARDS. Systemic terbu-taline significantly reduced plasma transferrin movement intothe lungs, a marker of lung permeability, in survivors but notnon-survivors of ALI/ARDS. Perkins and colleagues [23] haverecently reported that patients with ALI randomized to receiveintravenous salbutamol (15 µg/kg/hr) for 7 days had a signifi-cant reduction in extra-vascular lung water index at days 4 and7 compared to patients receiving placebo. They did not reportany outcome data.Several limitations of our study should be considered. First,there are limitations of retrospective studies such as ours. Forexample, the indications for salbutamol and the dose givenwere not controlled because our study was retrospective.Indeed, previous studies suggest even the high dose wedefined (average of 3.7 mg/day) may be inadequate to attemptto increase alveolar fluid clearance. An alveolar concentrationof 10-6 M of salmeterol was associated with increased alveolarfluid clearance in an ex vivo human lung study [19]. An aver-age dose of 3.5 ± 2.6 mg of albuterol in the previous 6 hourswas associated with alveolar edema albuterol levels of 10-6 Min patients who had ALI [27]. The intravenous dose Perkinsand colleagues [23] reported is approximately ten-fold greaterTable 3Multivariate linear regression model for prediction of days alive and free of acute lung injuryCovariates β (slope) 95% CI of β p valueSalbutamol (high dose) 4.08 0.17 8.00 0.04APACHE II -0.25 -0.47 -0.03 0.02Cause of ALI -3.96 -7.37 -0.56 0.02Covariates: salbutamol (high referenced to low dose), age (as a continuous variable), gender (female referenced to male), surgical versus medical diagnosis, history of chronic obstructive pulmonary disease, asthma, and/or smoking, APACHE II score on admission (as a continuous variable), cause of acute lung injury (ALI; pulmonary referenced to extrapulmonary), presence or absence of septic shock, and severity of ALI as defined by presence or absence of arterial oxygen partial pressure/fraction of inspired oxygen (PaO2/FiO2) ratio ≤ 200. CI, confidence interval.Page 5 of 7(page number not for citation purposes)ticular, both nebulized salbutamol (1 mg through the endotra- than our inhaled high dose threshold. A second limitation ofCritical Care    Vol 10 No 1    Manocha et al.our study is that other medications that can affect alveolar fluidclearance (such as infused catecholamines, diuretics, and cor-ticosteroids) were not measured. However, Ware and Matthay[6] did not find a significant association between these medi-cations and rate of edema fluid clearance. Therefore, thesethree medications may not have had a significant influence onalveolar fluid clearance in our patients. A third limitation is thatour study was an association study that did not address mech-anisms of improvement.Finally, there were differences between the two dose groupsin age and history of COPD, asthma and/or smoking, whichcould confound the association we found between the highdose of salbutamol and more days alive and free of ALI. Toaddress this limitation, we did a multivariate analysis to adjustfor differences in baseline characteristics. Importantly, thehigher salbutamol dose remained independently associatedwith significantly more days alive and free of ALI even aftermultivariate analysis adjustment of baseline characteristics.ConclusionThis preliminary retrospective study demonstrates for the firsttime that the aerosolized β2 agonist salbutamol at a dosegreater than 2.2 mg/day (average dose of 3.72 mg/day) givento mechanically ventilated patients with ALI was associatedwith more days alive and free of ALI. This possible beneficialassociation requires prospective studies, such as a rigorousrandomized controlled trial, to determine whether inhaled β2agonists improve relevant outcomes of ALI.Competing interestsThe authors declare that they have no competing interests.Authors' contributionsSM, ES and HG collected and analyzed the data. ACG ana-lyzed the data. KRW and JAR conceived and coordinated thestudy. All the authors contributed to, read and approved thefinal manuscript.AcknowledgementsSanjay Manocha is a Post-doctoral Fellow of the Canadian Institutes of Health Research IMPACT program and a Post-doctoral Fellow of the Michael Smith Foundation for Health Research. Anthony C Gordon is a recipient of the UK Intensive Care Society Visiting Fellowship and a recipient of the Merck Frosst/Canadian Lung Association Fellowship. Keith R Walley is a Michael Smith Foundation for Health Research Dis-tinguished ScholarReferences1. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L,Lamy M, LeGall JR, Morris A, Spragg R: Report of the American-European consensus conference on ARDS: definitions, mech-anisms, relevant outcomes and clinical trial coordination. TheConsensus Committee.  Intensive Care Med 1994, 20:225-232.2. Lecuona E, Saldias F, Comellas A, Ridge K, Guerrero C, SznajderJI: Ventilator-associated lung injury decreases lung ability toclear edema in rats.  Am J Respir Crit Care Med 1999,159:603-609.3. Pittet JF, Wiener-Kronish JP, Serikov V, Matthay MA: Resistanceof the alveolar epithelium to injury from septic shock in sheep.Am J Respir Crit Care Med 1995, 151:1093-1100.4. Modelska K, Pittet JF, Folkesson HG, Courtney Broaddus V, Mat-thay MA: Acid-induced lung injury. Protective effect of anti-interleukin-8 pretreatment on alveolar epithelial barrier func-tion in rabbits.  Am J Respir Crit Care Med 1999,160:1450-1456.5. Verghese GM, Ware LB, Matthay BA, Matthay MA: Alveolar epi-thelial fluid transport and the resolution of clinically severehydrostatic pulmonary edema.  J Appl Physiol 1999,87:1301-1312.6. Ware LB, Matthay MA: Alveolar fluid clearance is impaired inthe majority of patients with acute lung injury and the acuterespiratory distress syndrome.  Am J Respir Crit Care Med2001, 163:1376-1383.7. Morina P, Herrera M, Venegas J, Mora D, Rodriguez M, Pino E:Effects of nebulized salbutamol on respiratory mechanics inadult respiratory distress syndrome.  Intensive Care Med 1997,23:58-64.8. Wright PE, Carmichael LC, Bernard GR: Effect of bronchodila-tors on lung mechanics in the acute respiratory distress syn-drome (ARDS).  Chest 1994, 106:1517-1523.9. Pesenti A, Pelosi P, Rossi N, Aprigliano M, Brazzi L, Fumagalli R:Respiratory mechanics and bronchodilator responsiveness inpatients with the adult respiratory distress syndrome.  CritCare Med 1993, 21:78-83.10. van der Poll T, Coyle SM, Barbosa K, Braxton CC, Lowry SF:Epinephrine inhibits tumor necrosis factor-alpha and potenti-ates interleukin 10 production during human endotoxemia.  JClin Invest 1996, 97:713-719.11. Zhang H, Kim YK, Govindarajan A, Baba A, Binnie M, Marco Rani-eri V, Liu M, Slutsky AS: Effect of adrenoreceptors on endo-toxin-induced cytokines and lipid peroxidation in lungexplants.  Am J Respir Crit Care Med 1999, 160:1703-1710.12. Dhingra VK, Uusaro A, Holmes CL, Walley KR: Attenuation oflung inflammation by adrenergic agonists in murine acute lunginjury.  Anesthesiology 2001, 95:947-953.13. Crandall ED, Heming TA, Palombo RL, Goodman BE: Effects ofterbutaline on sodium transport in isolated perfused rat lung.J Appl Physiol 1986, 60:289-294.14. Berthiaume Y, Staub NC, Matthay MA: Beta-adrenergic agonistsincrease lung liquid clearance in anesthetized sheep.  J ClinInvest 1987, 79:335-343.15. Berthiaume Y, Broaddus VC, Gropper MA, Tanita T, Matthay MA:Alveolar liquid and protein clearance from normal dog lungs.  JAppl Physiol 1988, 65:585-593.16. Garat C, Carter EP, Matthay MA: New in situ mouse model toquantify alveolar epithelial fluid clearance.  J Appl Physiol1998, 84:1763-1767.17. Norlin A, Finley N, Abedinpour P, Folkesson HG: Alveolar liquidclearance in the anesthetized ventilated guinea pig.  Am JKey messages• β2 agonists have several properties that could be bene-ficial in ALI, including improving respiratory mechanics, reducing inflammation and increasing edema clearance.• To date there have been no published studies examin-ing the effect of β2 agonists on outcome from ALI.• This retrospective study demonstrates an improved out-come from ALI with higher doses (average 3.72 mg/day) of inhaled salbutamol.• A prospective randomized controlled trial examining the effect of β2 agonists on outcome from acute lung injury is required.Page 6 of 7(page number not for citation purposes)Physiol 1998, 274:L235-243.Available online http://ccforum.com/content/10/1/R1218. Fukuda N, Folkesson HG, Matthay MA: Relationship of intersti-tial fluid volume to alveolar fluid clearance in mice: ventilatedversus in situ studies.  J Appl Physiol 2000, 89:672-679.19. Sakuma T, Folkesson HG, Suzuki S, Okaniwa G, Fujimura S, Mat-thay MA: Beta-adrenergic agonist stimulated alveolar fluidclearance in ex vivo human and rat lungs.  Am J Respir Crit CareMed 1997, 155:506-512.20. Lasnier JM, Wangensteen OD, Schmitz LS, Gross CR, Ingbar DH:Terbutaline stimulates alveolar fluid resorption in hyperoxiclung injury.  J Appl Physiol 1996, 81:1723-1729.21. Saldias FJ, Lecuona E, Comellas AP, Ridge KM, Rutschman DH,Sznajder JI: Beta-adrenergic stimulation restores rat lung abil-ity to clear edema in ventilator-associated lung injury.  Am JRespir Crit Care Med 2000, 162:282-287.22. Vivona ML, Matthay M, Chabaud MB, Friedlander G, Clerici C:Hypoxia reduces alveolar epithelial sodium and fluid transportin rats: reversal by beta-adrenergic agonist treatment.  Am JRespir Cell Mol Biol 2001, 25:554-561.23. Perkins GD, McAuley DF, Thickett DR, Gao F: The Beta agonistlung injury trial [abstract].  Thorax 2004, 59ii:A1.24. Tibayan FA, Chesnutt AN, Folkesson HG, Eandi J, Matthay MA:Dobutamine increases alveolar liquid clearance in ventilatedrats by beta-2 receptor stimulation.  Am J Respir Crit Care Med1997, 156:438-444.25. Manthous CA, Chatila , Schmidt GA Hall JB: Treatment of bron-chospasm by metered-dose inhaler albuterol in mechanicallyventilated patients.  Chest 1995, 107:210-213.26. Benoit D, Vahdewoude K, Colardyn F: Effects of nebulised salb-utamol in ARDS.  Intensive Care Med 1998, 24:88-89.27. Atabai K, Ware LB, Snider ME, Koch P, Daniel B, Nuckton TJ, Mat-thay MA: Aerosolized beta(2)-adrenergic agonists achievetherapeutic levels in the pulmonary edema fluid of ventilatedpatients with acute respiratory failure.  Intensive Care Med2002, 28:705-711.28. Dhand R, Duarte AG, Jubran A, Jenne JW, Fink JB, Fahey PJ, TobinMJ: Dose-response to bronchodilator delivered by metered-dose inhaler in ventilator-supported patients.  Am J Respir CritCare Med 1996, 154:388-393.29. Bernard GR, Wheeler AP, Arons MM, Morris PE, Paz HL, RussellJA, Wright PE: A trial of antioxidants N-acetylcysteine and pro-cysteine in ARDS. The Antioxidant in ARDS Study Group.Chest 1997, 112:164-172.30. Knaus WA, Wagner DP, Draper EA, Zimmerman JE, Bergner M,Bastos PG, Sirio CA, Murphy DJ, Lotring T, Damiano A, et al.: TheAPACHE III prognostic system. Risk prediction of hospitalmortality for critically ill hospitalized adults.  Chest 1991,100:1619-1636.31. Knaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II: aseverity of disease classification system.  Crit Care Med 1985,13:818-829.32. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA,Schein RM, Sibbald WJ: Definitions for sepsis and organ failureand guidelines for the use of innovative therapies in sepsis.The ACCP/SCCM Consensus Conference Committee. Ameri-can College of Chest Physicians/Society of Critical Care Med-icine.  Chest 1992, 101:1644-1655.33. Groshaus HE, Manocha S, Walley KR, Russell JA: Mechanisms ofbeta-receptor stimulation induced improvement of acute lunginjury and pulmonary edema.  Crit Care 2004, 8:234-242.34. Perkins GD, McAuley DF, Richter A, Thickett DR, Gao F: Bench-to-bedside review: β2-Agonists and the acute respiratory dis-tress syndrome.  Crit Care 2004, 8:25-32.35. Matalon S, Benos DJ, Jackson RM: Biophysical and molecularproperties of amiloride-inhibitable Na+ channels in alveolarepithelial cells.  Am J Physiol 1996, 271:L1-22.36. Goodman BE, Anderson JL, Clemens JW: Evidence for regula-tion of sodium transport from airspace to vascular space bycAMP.  Am J Physiol 1989, 257:L86-93.37. Saumon G, Basset G, Bouchonnet F, Crone C: cAMP and beta-adrenergic stimulation of rat alveolar epithelium. Effects onfluid absorption and paracellular permeability.  Pflugers Arch1987, 410:464-470.38. Minakata Y, Suzuki S, Grygorczyk C, Dagenais A, Berthiaume Y:Impact of beta-adrenergic agonist on Na+ channel and Na+-39. Whelan CJ, Johnson M: Inhibition by salmeterol of increasedvascular permeability and granulocyte accumulation inguinea-pig lung and skin.  Br J Pharmacol 1992, 105:831-838.40. Koff WC, Fann AV, Dunegan MA, Lachman LB: Catecholamine-induced suppression of interleukin-1 production.  LymphokineRes 1986, 5:239-247.41. Severn A, Rapson NT, Hunter CA, Liew FY: Regulation of tumornecrosis factor production by adrenaline and beta-adrenergicagonists.  J Immunol 1992, 148:3441-3445.42. van der Poll T, Jansen J, Endert E, Sauerwein HP, van Deventer SJ:Noradrenaline inhibits lipopolysaccharide-induced tumornecrosis factor and interleukin 6 production in human wholeblood.  Infect Immun 1994, 62:2046-2050.43. Basran GS, Hardy JG, Woo SP, Ramasubramanian R, Byrne AJ:Beta-2-adrenoceptor agonists as inhibitors of lung vascularpermeability to radiolabelled transferrin in the adult respira-tory distress syndrome in man.  Eur J Nucl Med 1986,12:381-384.Page 7 of 7(page number not for citation purposes)K+-ATPase expression in alveolar type II cells.  Am J Physiol1998, 275:L414-422.


Citation Scheme:


Citations by CSL (citeproc-js)

Usage Statistics



Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            async >
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:


Related Items