The Effect of Alcohol Consumption on the Risk of ARDS

A Systematic Review and Meta-Analysis
  • Evangelia Simou
    Correspondence
    CORRESPONDENCE TO: Evangelia Simou, MSc, UK Centre for Tobacco & Alcohol Studies, Division of Epidemiology and Public Health, University of Nottingham, Clinical Science Bldg, City Hospital, Nottingham, NG5 1PB, UK
    Affiliations
    UK Centre for Tobacco and Alcohol Studies, Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK
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  • Jo Leonardi-Bee
    Affiliations
    UK Centre for Tobacco and Alcohol Studies, Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK
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  • John Britton
    Affiliations
    UK Centre for Tobacco and Alcohol Studies, Division of Epidemiology and Public Health, University of Nottingham, Nottingham, UK
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Open AccessPublished:December 27, 2017DOI:https://doi.org/10.1016/j.chest.2017.11.041

      Background

      To conduct a systematic review and meta-analysis evaluating the association between alcohol consumption and the risk of ARDS in adults.

      Methods

      Medline, EMBASE and Web of Science were searched to identify observational studies evaluating the association between prior alcohol intake and the occurrence of ARDS among adults, published between 1985 and 2015 and with no language restriction. Reference lists were also screened. Demographic baseline data were extracted independently by two reviewers and random-effects meta-analyses were used to estimate pooled effect sizes with 95% confidence intervals. Subgroup analyses were used to explore heterogeneity.

      Results

      Seventeen observational studies (177,674 people) met the inclusion criteria. Meta-analysis of 13 studies showed that any measure of high relative to low alcohol consumption was associated with a significantly increased risk of ARDS (OR, 1.89; 95% CI, 1.45-2.48; I2 = 48%; 13 studies); no evidence of publication bias was seen (P = .150). Sensitivity analyses indicated that this association was attributable primarily to an effect of a history of alcohol abuse (OR, 1.90; 95% CI, 1.40-2.60; 10 studies). Also, subgroup analyses identified that heterogeneity was explained by predisposing condition (trauma, sepsis/septic shock, pneumonia; P = .003).

      Conclusions

      Chronic high alcohol consumption significantly increases the risk of ARDS. This finding suggests that patients admitted to hospital should be screened for chronic alcohol use.

      Key Words

      Abbreviations:

      ALI (acute lung injury)
      FOR EDITORIAL COMMENT, SEE PAGE 6
      ARDS is a type of acute diffuse alveolar damage with an onset within 7 days of known clinical risk factors or new/worsening respiratory symptoms. The hallmarks for ARDS are hypoxemia and bilateral opacities, using either chest radiography or CT scan.
      • Thompson B.T.
      • Chambers R.C.
      • Liu K.D.
      Acute respiratory distress syndrome.
      Globally, ARDS is responsible for 10.4% of all ICU admissions, and approximately 23% of patients with ARDS need mechanical ventilation.
      • Bellani G.
      • Laffey J.G.
      • Pham T.
      • et al.
      Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries.
      ARDS is associated with high morbidity and mortality.
      • Henderson W.R.
      • Chen L.
      • Amato M.B.
      • Brochard L.J.
      Fifty years of research in ARDS: respiratory mechanics in acute respiratory distress syndrome.
      • Ware L.B.
      • Matthay M.A.
      The acute respiratory distress syndrome.
      A 2009 systematic review assessing the mortality of ARDS over time demonstrated an overall mortality rate of 44% and 36.2% for observational studies and random controlled trials, respectively, and found that these rates were unchanged since 1994.
      • Phua J.
      • Badia J.R.
      • Adhikari N.K.
      • et al.
      Has mortality from acute respiratory distress syndrome decreased over time? A systematic review.
      Risk factors for the development of ARDS and for the closely related diagnosis of acute lung injury (ALI), a term also used before definitions of ARDS were standardized in 2012,
      • Ranieri V.
      • Rubenfeld G.
      • Thompson B.
      • et al.
      Acute respiratory distress syndrome: the Berlin definition.
      include increased age and clinical factors such as sepsis, pneumonia, aspiration, trauma, pancreatitis, shock, blood transfusions, and smoke or toxic gas inhalation.
      • Ware L.B.
      • Matthay M.A.
      The acute respiratory distress syndrome.
      • Boé D.M.
      • Vandivier R.W.
      • Burnham E.L.
      • Moss M.
      Alcohol abuse and pulmonary disease.
      • Umbrello M.
      • Formenti P.
      • Bolgiaghi L.
      • Chiumello D.
      Current concepts of ARDS: a narrative review.
      • Jia X.
      • Malhotra A.
      • Saeed M.
      • Mark R.G.
      • Talmor D.
      Risk factors for acute respiratory distress syndrome in patients mechanically ventilated for greater than 48 hours.
      Alcohol abuse has also been reported to increase the risk of ARDS,
      • Hudson L.D.
      • Milberg J.A.
      • Anardi D.
      • Maunder R.J.
      Clinical risks for development of the acute respiratory distress syndrome.
      • Laycock H.
      • Rajah A.
      Acute lung injury and acute respiratory distress syndrome: a review article.
      perhaps because acute alcohol intoxication increases the risk of aspiration and pulmonary infection, while chronic alcohol ingestion disturbs both immunologic and nonimmunologic host defense mechanisms within the airway, resulting in alveolar macrophage immune dysregulation and alveolar epithelial barrier dysfunction.
      • Mehta A.
      Pulmonary consequences of alcoholism: a critical review.
      To date, however, there remains limited and inconsistent evidence on the relation between alcohol consumption and the risk of ARDS. To synthesize this mixed evidence to estimate an overall magnitude of risk, and to explore whether this varies by predisposing condition for ARDS, we therefore now report a systematic review and meta-analysis of observational studies of the association between alcohol consumption and ARDS.

      Methods

      The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
      and MOOSE (Meta-analysis of Observational Studies in Epidemiology)
      • Stroup D.F.
      • Berlin J.A.
      • Morton S.C.
      • et al.
      Meta-analysis of observational studies in epidemiology: a proposal for reporting.
      guidelines were used for the conduction of this systematic review and meta-analysis (e-Table 1). The protocol was published in the PROSPERO (International Prospective Register of Systematic Reviews database; registration number CRD42015029910).

       Study Selection

      We used the Population-Exposure-Outcome-Study Design criteria throughout the review process, based on type of participants, type of exposure, type of outcome, and study design.

       Type of Participants

      All studies of adults aged 18 years and over were eligible for inclusion in this review.

       Type of Exposure

      We included all studies that had assessed alcohol consumption, either by self-report or a proxy such as clinical records, defined either as drinking level (low, moderate, heavy, alcohol abuse, alcoholism) or as frequency (grams per day).

       Type of Outcome

      The outcome of interest was ARDS. We excluded studies limited to specific clinical diagnoses (HIV, hepatitis B and C viruses).

       Study Design

      All the primary comparative observational studies were included (longitudinal/cohort, case control, cross sectional).

       Search Strategy

      Medline (via Ovid), EMBASE (via Ovid), and Web of Science were searched independently by two authors from December 1985 to December 2015. Search filters for observational study designs were used,

      Scottish Intercollegiate Guidelines Network (SIGN). Search filters, observational studies. http://www.sign.ac.uk/search-filters.html. Accessed December 4, 2015.

      and search terms for both outcome and exposure were developed from relevant Cochrane Reviews groups

      Cochrane Library. http://www.cochranelibrary.com/. Accessed December 4, 2015.

      (e-Table 2). The search terms using every possible combination were the following: Respiratory Distress Syndrome, Adult/or Adult Respiratory Distress Syndrome/or Acute Lung Injury/or Acute Respiratory Distress Syndrome/or ARDS or ALI. The reference lists were also screened in order to identify additionally eligible studies. There was no language limitation, and where necessary translations of foreign language articles were conducted. In case of duplication the most informative study was used. Two reviewers (E. S., J. L.-B.) independently screened the titles and abstracts. All relevant studies were obtained and the full text was screened independently by two reviewers (E. S., J. L.-B.). Any disagreements were resolved through discussion or with the help of the third reviewer (J. B.).

       Data Extraction

      The data extraction was performed independently by two reviewers, using a previous pilot data extraction form. Variables of interest included author, year of study, study design, definitions of exposure (alcohol) and outcome (ARDS), geographic location, reference population, demographic of study population setting, number of people recruited, and adjustment for confounders.
      For categorical measures of alcohol drinking, where possible we compared any alcohol vs no alcohol consumption (reference group). When the nonalcohol category was not reported in the studies, the lowest exposed category was used as the reference group. Where exposure to alcohol was reported as quantiles or as categories, we compared the highest exposure groups with lowest exposed group. Also, in the analysis, categorical measures of alcohol consumption were further defined as levels of consumption: light/moderate/heavy drinking; alcohol abuse (including alcoholism). Grams of daily alcohol consumption were used as a standard measure, defining one drink as 0.6 ounce, 14.0 g, or 1.2 tablespoons of pure alcohol.

      Centers for Disease Control and Prevention (CDC). Alcohol and Public Health: Fact Sheets: Alcohol Use and Your Health. http://www.cdc.gov/alcohol/fact-sheets/alcohol-use.htm. Accessed December 10, 2015.

      According to the Centers for Disease Control and Prevention guidelines, we defined heavy drinking as a weekly consumption of 15 or more drinks for men, and eight or more drinks for women, whereas binge drinking was defined either as five or more drinks during a single occasion for men, and four or more for women. Excessive drinking was defined as the presence of either binge or heavy drinking.

      Centers for Disease Control and Prevention (CDC). Alcohol and Public Health: Fact Sheets: Alcohol Use and Your Health. http://www.cdc.gov/alcohol/fact-sheets/alcohol-use.htm. Accessed December 10, 2015.

      Moderate alcohol drinking was defined as the daily consumption of up to one drink for women and two drinks for men.

      U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015–2020. Dietary Guidelines for Americans. 8th Ed. Washington, DC; 2015. https://health.gov/dietaryguidelines/2015/resources/2015-2020_Dietary_Guidelines.pdf. Accessed December 15, 2015.

       Assessment of Study Quality

      The quality of the studies was assessed by the Newcastle-Ottawa Scale.

      Wells G, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed February 10, 2016.

      High quality was defined as a grade of ≥ 6. Both case-control and cohort studies had a maximum score of 9; whereas cross-sectional studies had a score of 7. The quality assessment was not conducted for articles published as abstracts, due to the lack of information. Two reviewers (E. S., J. L.-B.) independently assessed the quality of the included studies. Discrepancies were resolved through discussion and consensus.

       Statistical Analysis

      Relative measures of effect were estimated as odds ratios (ORs), relative risks (RRs), or hazard ratios (HRs) with 95% confidence intervals. Results were extracted as either adjusted effect measures, crude measures of effect, or using raw data. We used adjusted estimates in preference. Where more than one adjusted estimate was presented in the paper, we used the estimate that was adjusted for smoking and other socioeconomic factors, where available. For case-control studies we estimated the OR whereas for cohort and cross-sectional studies we estimated the RR. When alcohol exposure was reported either as quantiles or categories, we extracted the effect estimates, taking the highest vs the lowest exposure group. We pooled odds ratios and relative risks together in cases of a rare outcome. Also, studies assessing the effect of definite transfusion-related ALI were analyzed separately and thus not combined in the meta-analysis with other predisposing condition resulting in ALI.
      Because of the anticipated heterogeneity between the studies, DerSimonian and Laird random-effects models were used to weight each study. The I2 statistic was used to indicate between the studies the percentage of variation due to heterogeneity.
      • Higgins J.
      • Thompson S.G.
      Quantifying heterogeneity in a meta-analysis.
      Subgroup analyses were carried out to explain the identified heterogeneity, based on predisposing condition for ARDS, study design, study quality, year of publication, geographic location, and adjustment for confounders. We used Egger’s statistical test for assessment of publication bias, and a funnel plot for visual assessment. Stata software version 14 (StataCorp) and Review manager software version 5.3 (Cochrane Collaboration) were both used for the statistical analysis. A P value < .05 was thought to represent a statistically significant level.

      Results

      Database searches and reference lists yielded a total of 4,392 articles (Fig 1). After the removal of 739 duplicates we identified 3,653 articles for titles/abstracts screening, from which we identified 200 articles for full text review. Of these, 183 were excluded because the study design was a review or a letter (eight studies); or because there was no comparison group (37 studies); insufficient information on exposure and outcome (13 studies); ineligible outcomes such as sleep apnea, pneumonia, asthma, COPD, airway obstruction, oxygen desaturation index (68 studies); irrelevant exposure (55 studies); or duplicate data (two studies). Thus 17 studies met our criteria for inclusion in the review.

       Study Characteristics

      The characteristics of the 17 included studies in the review are shown in Table 1. Twelve studies used a cohort design
      • Afshar M.
      • Smith G.S.
      • Terrin M.L.
      • et al.
      Blood alcohol content, injury severity, and adult respiratory distress syndrome.
      • Calfee C.S.
      • Matthay M.A.
      • Eisner M.D.
      • et al.
      Active and passive cigarette smoking and acute lung injury after severe blunt trauma.
      • Calfee C.S.
      • Matthay M.A.
      • Kangelaris K.N.
      • et al.
      Cigarette smoke exposure and the acute respiratory distress syndrome.
      • Cardinal-Fernandez P.
      • Ferruelo A.
      • El-Assar M.
      • et al.
      Genetic predisposition to acute respiratory distress syndrome in patients with severe sepsis.
      • Gajic O.
      • Dabbagh O.
      • Park P.K.
      • et al.
      U.S. Critical Illness and Injury Trials Group: Lung Injury Prevention Study Investigators (USCIITG-LIPS)
      Early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study.
      • Ge Q.
      • Yao Z.
      • Wang T.
      • et al.
      [Risk factors of the occurrence and death of acute respiratory distress syndrome: a prospective multicenter cohort study] [article in Chinese].
      • Iribarren C.
      • Jacobs Jr., D.R.
      • Sidney S.
      • Gross M.D.
      • Eisner M.D.
      Cigarette smoking, alcohol consumption, and risk of ARDS: a 15-year cohort study in a managed care setting.
      • Iscimen R.
      • Cartin-Ceba R.
      • Yilmaz M.
      • et al.
      Risk factors for the development of acute lung injury in patients with septic shock: an observational cohort study.
      • Licker M.
      • de Perrot M.
      • Spiliopoulos A.
      • et al.
      Risk factors for acute lung injury after thoracic surgery for lung cancer.
      • Moss M.
      • Bucher B.
      • Moore F.A.
      • Moore E.E.
      • Parsons P.E.
      The role of chronic alcohol abuse in the development of acute respiratory distress syndrome in adults.
      • Moss M.
      • Parsons P.E.
      • Steinberg K.P.
      • et al.
      Chronic alcohol abuse is associated with an increased incidence of acute respiratory distress syndrome and severity of multiple organ dysfunction in patients with septic shock.
      • Thakur L.
      • Kojicic M.
      • Thakur S.J.
      • et al.
      Alcohol consumption and development of acute respiratory distress syndrome: a population-based study.
      ; four were case-control studies
      • Ahmed A.
      • Biehl M.
      • Kashyap R.
      • Hanson A.C.
      • Schenck L.A.
      • Gajic O.
      The impact of acute respiratory distress syndrome (ARDS) on short and long-term survival: a population-based nested case-control study.
      • Gajic O.
      • Rana R.
      • Winters J.L.
      • et al.
      Transfusion-related acute lung injury in the critically ill: prospective nested case-control study.
      • Kojicic M.
      • Li G.X.
      • Hanson A.C.
      • et al.
      Risk factors for the development of acute lung injury in patients with infectious pneumonia.
      • Toy P.
      • Gajic O.
      • Bacchetti P.
      • et al.
      Transfusion-related acute lung injury: incidence and risk factors.
      , and one was a cross-sectional study using survey data.
      • TenHoor T.
      • Mannino D.M.
      • Moss M.
      Risk factors for ARDS in the United States: analysis of the 1993 National Mortality Followback Study.
      A total population of 177,674 people was included. Patients with ARDS had a mean age ranging from 33 to 72.7 years, were more likely to be male (range, 50% to 85%; 13 studies), and the majority were white (range, 50% to 88%; eight studies).
      Table 1Characteristics of the Included Studies
      Study/YearStudy DesignCountryPopulation/Main Predisposing ConditionCharacteristics of Patients With ARDSNo. of People IncludedAlcohol AscertainmentDefinition of Exposure to AlcoholDefinition Used to Ascertain ARDSAdjustment
      Afshar et al
      • Afshar M.
      • Smith G.S.
      • Terrin M.L.
      • et al.
      Blood alcohol content, injury severity, and adult respiratory distress syndrome.
      /2014
      CohortUSAHospital/TraumaAge: 33 y
      a Median presented.


      Male: 80.6%

      White: 57.7%
      26,305Blood alcohol content> 0 mg/dLBerlinAdjusted for: age, sex, race, tobacco, diabetes mellitus, immunosuppression medication
      Ahmed et al
      • Ahmed A.
      • Biehl M.
      • Kashyap R.
      • Hanson A.C.
      • Schenck L.A.
      • Gajic O.
      The impact of acute respiratory distress syndrome (ARDS) on short and long-term survival: a population-based nested case-control study.
      /2014
      Nested case controlUSAHospitalAge: —

      Male: —

      White: —
      828Any useMatched for: age, sepsis, sex, surgery, ratio of oxygen saturation to fraction of inspired oxygen, and lung injury prediction score
      Calfee et al
      • Calfee C.S.
      • Matthay M.A.
      • Eisner M.D.
      • et al.
      Active and passive cigarette smoking and acute lung injury after severe blunt trauma.
      /2011
      b Outcome definition used within the study is acute lung injury.
      CohortUSAHospital/TraumaAge: 44 y

      Male: 81%

      White: 66%
      144AUDIT QuestionnaireAlcohol abuseAECCNo adjustment/matching performed
      Calfee et al
      • Calfee C.S.
      • Matthay M.A.
      • Kangelaris K.N.
      • et al.
      Cigarette smoke exposure and the acute respiratory distress syndrome.
      /2015
      CohortUSAHospitalAge: 56 y

      Male: 53%

      White: 88%
      426AUDIT QuestionnaireAlcohol abuseAECCAdjusted for: log-NNAL, APACHE II scores, race, diabetes, time elapsed between admission and enrollment
      Cardinal-Fernandez et al
      • Cardinal-Fernandez P.
      • Ferruelo A.
      • El-Assar M.
      • et al.
      Genetic predisposition to acute respiratory distress syndrome in patients with severe sepsis.
      /2013
      CohortEuropeHospital/SepsisAge: 57 y

      Male: 71.4%

      White: —
      149QuestionnaireAlcoholismAECCNo adjustment/matching performed
      Gajic et al
      • Gajic O.
      • Rana R.
      • Winters J.L.
      • et al.
      Transfusion-related acute lung injury in the critically ill: prospective nested case-control study.
      /2007
      b Outcome definition used within the study is acute lung injury.
      Nested case controlUSAHospital/ICUAge: 61 y
      a Median presented.


      Male: 50%

      White: —
      74Medical recordsAlcohol abuseAECCMatched for: age, sex, and admission diagnosis
      Gajic et al
      • Gajic O.
      • Dabbagh O.
      • Park P.K.
      • et al.
      U.S. Critical Illness and Injury Trials Group: Lung Injury Prevention Study Investigators (USCIITG-LIPS)
      Early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study.
      /2011
      b Outcome definition used within the study is acute lung injury.
      CohortUSAHospitalAge: 57 y
      a Median presented.


      Male: 65%

      White: 60%
      5,584QuestionnaireAlcohol abuseAECCAdjusted for predisposing conditions, high-risk surgery, high-risk trauma, male sex, body mass index, chemotherapy, diabetes, smoking, emergency surgery, tachypnea, hypoalbuminemia, acidosis, Spo2, Fio2
      Ge et al
      • Ge Q.
      • Yao Z.
      • Wang T.
      • et al.
      [Risk factors of the occurrence and death of acute respiratory distress syndrome: a prospective multicenter cohort study] [article in Chinese].
      /2014
      CohortChinaHospital/ICUAge: —

      Male: —

      White: —
      343QuestionnaireAlcohol abuseAECCAdjusted for: age, sex, smoking, use of alcohol, history of diabetes, sepsis, septic shock, trauma, pneumonia, aspiration, massive blood transfusion, bacteremia, pulmonary contusion
      Iribarren et al
      • Iribarren C.
      • Jacobs Jr., D.R.
      • Sidney S.
      • Gross M.D.
      • Eisner M.D.
      Cigarette smoking, alcohol consumption, and risk of ARDS: a 15-year cohort study in a managed care setting.
      /2000
      CohortUSAHospitalAge: 52.8 y

      Male: 59%

      White: 73%
      121,012Questionnaire≥ 3 drinks/d in previous yearAECCAdjusted for: age, sex, race, smoking, body mass index, education
      Iscimen et al
      • Iscimen R.
      • Cartin-Ceba R.
      • Yilmaz M.
      • et al.
      Risk factors for the development of acute lung injury in patients with septic shock: an observational cohort study.
      /2008
      b Outcome definition used within the study is acute lung injury.
      CohortEuropeHospital/Septic shockAge: —

      Male: —

      White: —
      160Medical recordsAlcohol abuseAdjusted for: delayed goal-directed resuscitation, delayed antibiotics, chemotherapy, transfusion, diabetes mellitus
      Kojicic et al
      • Kojicic M.
      • Li G.X.
      • Hanson A.C.
      • et al.
      Risk factors for the development of acute lung injury in patients with infectious pneumonia.
      /2012
      b Outcome definition used within the study is acute lung injury.
      Case controlUSAHospital/PneumoniaAge: 64.5 y
      a Median presented.


      Male: 50%

      White: —
      596Medical recordsAlcohol abuseAECCMatched for: specific pathogen, isolation site, sex, and age
      Licker et al
      • Licker M.
      • de Perrot M.
      • Spiliopoulos A.
      • et al.
      Risk factors for acute lung injury after thoracic surgery for lung cancer.
      /2003
      b Outcome definition used within the study is acute lung injury.
      CohortUSAHospitalAge: 67 y

      Male: —

      White: —
      869Medical recordsAlcohol abuse

      > 60 g/d
      AECCAdjusted for: pneumonectomy, ventilator hyperpressure index, fluid infused
      Moss et al
      • Moss M.
      • Bucher B.
      • Moore F.A.
      • Moore E.E.
      • Parsons P.E.
      The role of chronic alcohol abuse in the development of acute respiratory distress syndrome in adults.
      /1996
      CohortUSAHospital/Sepsis, traumaAge: 45.2 y

      Male: 63%

      White: 50%
      351Medical recordsAlcohol abuseAECCAdjusted for: sex, at- risk diagnosis, APACHE II score
      Moss et al
      • Moss M.
      • Parsons P.E.
      • Steinberg K.P.
      • et al.
      Chronic alcohol abuse is associated with an increased incidence of acute respiratory distress syndrome and severity of multiple organ dysfunction in patients with septic shock.
      /2003
      CohortUSAHospital/Septic shockAge: 50.1 y

      Male: 68%

      White: —
      220SMAST QuestionnaireAlcohol abuseAECCAdjusted for: source of infection, sex, age, chronic hepatic dysfunction, diabetes, severity of illness, nutritional status, and smoking status
      TenHoor et al
      • TenHoor T.
      • Mannino D.M.
      • Moss M.
      Risk factors for ARDS in the United States: analysis of the 1993 National Mortality Followback Study.
      /2001
      Cross sectionalUSAHospital/DecedentsAge: 72.7 y

      Male: 51%

      White: 86%
      19,003Interview≥ 3 drinks/wkDeath certificateAdjusted for: sepsis, cirrhosis, medical or surgical misadventure, injury, nonwhite, male, age > 64 y, current smoking/former smoking
      Thakur et al
      • Thakur L.
      • Kojicic M.
      • Thakur S.J.
      • et al.
      Alcohol consumption and development of acute respiratory distress syndrome: a population-based study.
      /2009
      CohortUSAHospital/ICUAge: 55 y

      Male: 85%

      White: —
      1,357Interview> 14 drinks/wkAECCAdjusted for: aspiration, chemotherapy, high-risk surgery, pancreatitis, sepsis, shock, smoking, cirrhosis, and sex
      Toy et al
      • Toy P.
      • Gajic O.
      • Bacchetti P.
      • et al.
      Transfusion-related acute lung injury: incidence and risk factors.
      /2012
      b Outcome definition used within the study is acute lung injury.
      Case controlUSAHospitalAge: 54 y

      Male: 49%

      White: 71%
      253Medical recordsAlcohol abuseAECCNo adjustment/matching performed
      AECC = American-European Consensus Conference definition; APACHE II = Acute Physiology and Chronic Health Evaluation II; AUDIT = Alcohol Use Disorders Identification Test; Fio2 = fraction of inspired oxygen; log-NNAL = log-transformed NNAL [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol] level; SMAST = Short Michigan Alcohol Screening Test; Spo2 = oxygen saturation as measured by pulse oximetry.
      a Median presented.
      b Outcome definition used within the study is acute lung injury.
      All studies were conducted in a hospital setting, with 14 being conducted in the United States, two in Europe,
      • Cardinal-Fernandez P.
      • Ferruelo A.
      • El-Assar M.
      • et al.
      Genetic predisposition to acute respiratory distress syndrome in patients with severe sepsis.
      • Iscimen R.
      • Cartin-Ceba R.
      • Yilmaz M.
      • et al.
      Risk factors for the development of acute lung injury in patients with septic shock: an observational cohort study.
      and one in China.
      • Ge Q.
      • Yao Z.
      • Wang T.
      • et al.
      [Risk factors of the occurrence and death of acute respiratory distress syndrome: a prospective multicenter cohort study] [article in Chinese].
      Fourteen studies adjusted for confounders
      • Afshar M.
      • Smith G.S.
      • Terrin M.L.
      • et al.
      Blood alcohol content, injury severity, and adult respiratory distress syndrome.
      • Calfee C.S.
      • Matthay M.A.
      • Kangelaris K.N.
      • et al.
      Cigarette smoke exposure and the acute respiratory distress syndrome.
      • Gajic O.
      • Dabbagh O.
      • Park P.K.
      • et al.
      U.S. Critical Illness and Injury Trials Group: Lung Injury Prevention Study Investigators (USCIITG-LIPS)
      Early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study.
      • Ge Q.
      • Yao Z.
      • Wang T.
      • et al.
      [Risk factors of the occurrence and death of acute respiratory distress syndrome: a prospective multicenter cohort study] [article in Chinese].
      • Iribarren C.
      • Jacobs Jr., D.R.
      • Sidney S.
      • Gross M.D.
      • Eisner M.D.
      Cigarette smoking, alcohol consumption, and risk of ARDS: a 15-year cohort study in a managed care setting.
      • Iscimen R.
      • Cartin-Ceba R.
      • Yilmaz M.
      • et al.
      Risk factors for the development of acute lung injury in patients with septic shock: an observational cohort study.
      • Licker M.
      • de Perrot M.
      • Spiliopoulos A.
      • et al.
      Risk factors for acute lung injury after thoracic surgery for lung cancer.
      • Moss M.
      • Bucher B.
      • Moore F.A.
      • Moore E.E.
      • Parsons P.E.
      The role of chronic alcohol abuse in the development of acute respiratory distress syndrome in adults.
      • Moss M.
      • Parsons P.E.
      • Steinberg K.P.
      • et al.
      Chronic alcohol abuse is associated with an increased incidence of acute respiratory distress syndrome and severity of multiple organ dysfunction in patients with septic shock.
      • Thakur L.
      • Kojicic M.
      • Thakur S.J.
      • et al.
      Alcohol consumption and development of acute respiratory distress syndrome: a population-based study.
      • Ahmed A.
      • Biehl M.
      • Kashyap R.
      • Hanson A.C.
      • Schenck L.A.
      • Gajic O.
      The impact of acute respiratory distress syndrome (ARDS) on short and long-term survival: a population-based nested case-control study.
      • Gajic O.
      • Rana R.
      • Winters J.L.
      • et al.
      Transfusion-related acute lung injury in the critically ill: prospective nested case-control study.
      • Kojicic M.
      • Li G.X.
      • Hanson A.C.
      • et al.
      Risk factors for the development of acute lung injury in patients with infectious pneumonia.
      • TenHoor T.
      • Mannino D.M.
      • Moss M.
      Risk factors for ARDS in the United States: analysis of the 1993 National Mortality Followback Study.
      and seven of these had reported results adjusted for smoking.
      Study quality was assessed using the Newcastle-Ottawa Scale for 15 studies (two studies were published as an abstract only) and of these, eight (53.3%) were found to be of high quality. The median risk of bias score was 6, indicating a medium risk of bias (Table 2). The main reasons for lower scores in risk of bias were as follows: flawed study design (lack of objective/validated methods for exposure definition), selection bias (representativeness of sample population) and information bias (lack of provided information description in outcome assessment), or nonadequacy of follow-up.
      Table 2Critical Appraisal of the Included Studies, Using Newcastle-Ottawa Scale
      Study/YearNo. of Stars
      Selection
      a Maximum, four stars.
      Comparability
      b Maximum, two stars.
      Exposure
      c Maximum, three stars.
      Overall Score
      Afshar et al
      • Afshar M.
      • Smith G.S.
      • Terrin M.L.
      • et al.
      Blood alcohol content, injury severity, and adult respiratory distress syndrome.
      /2014
      3238
      Ahmed et al
      • Ahmed A.
      • Biehl M.
      • Kashyap R.
      • Hanson A.C.
      • Schenck L.A.
      • Gajic O.
      The impact of acute respiratory distress syndrome (ARDS) on short and long-term survival: a population-based nested case-control study.
      /2014
      d Only abstract available—not quality assessment.
      Calfee et al
      • Calfee C.S.
      • Matthay M.A.
      • Eisner M.D.
      • et al.
      Active and passive cigarette smoking and acute lung injury after severe blunt trauma.
      /2011
      3025
      Calfee et al
      • Calfee C.S.
      • Matthay M.A.
      • Kangelaris K.N.
      • et al.
      Cigarette smoke exposure and the acute respiratory distress syndrome.
      /2015
      3126
      Cardinal-Fernandez et al
      • Cardinal-Fernandez P.
      • Ferruelo A.
      • El-Assar M.
      • et al.
      Genetic predisposition to acute respiratory distress syndrome in patients with severe sepsis.
      /2013
      1034
      Gajic et al
      • Gajic O.
      • Rana R.
      • Winters J.L.
      • et al.
      Transfusion-related acute lung injury in the critically ill: prospective nested case-control study.
      /2007
      2114
      Gajic et al
      • Gajic O.
      • Dabbagh O.
      • Park P.K.
      • et al.
      U.S. Critical Illness and Injury Trials Group: Lung Injury Prevention Study Investigators (USCIITG-LIPS)
      Early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study.
      /2011
      2024
      Ge et al
      • Ge Q.
      • Yao Z.
      • Wang T.
      • et al.
      [Risk factors of the occurrence and death of acute respiratory distress syndrome: a prospective multicenter cohort study] [article in Chinese].
      /2014
      2237
      Iribarren et al
      • Iribarren C.
      • Jacobs Jr., D.R.
      • Sidney S.
      • Gross M.D.
      • Eisner M.D.
      Cigarette smoking, alcohol consumption, and risk of ARDS: a 15-year cohort study in a managed care setting.
      /2000
      2226
      Iscimen et al
      • Iscimen R.
      • Cartin-Ceba R.
      • Yilmaz M.
      • et al.
      Risk factors for the development of acute lung injury in patients with septic shock: an observational cohort study.
      /2008
      d Only abstract available—not quality assessment.
      Kojicic et al
      • Kojicic M.
      • Li G.X.
      • Hanson A.C.
      • et al.
      Risk factors for the development of acute lung injury in patients with infectious pneumonia.
      /2012
      2114
      Licker et al
      • Licker M.
      • de Perrot M.
      • Spiliopoulos A.
      • et al.
      Risk factors for acute lung injury after thoracic surgery for lung cancer.
      /2003
      2136
      Moss et al
      • Moss M.
      • Parsons P.E.
      • Steinberg K.P.
      • et al.
      Chronic alcohol abuse is associated with an increased incidence of acute respiratory distress syndrome and severity of multiple organ dysfunction in patients with septic shock.
      /2003
      2237
      Moss et al
      • Moss M.
      • Bucher B.
      • Moore F.A.
      • Moore E.E.
      • Parsons P.E.
      The role of chronic alcohol abuse in the development of acute respiratory distress syndrome in adults.
      /1996
      1124
      TenHoor et al
      • TenHoor T.
      • Mannino D.M.
      • Moss M.
      Risk factors for ARDS in the United States: analysis of the 1993 National Mortality Followback Study.
      /2001
      2226
      Thakur et al
      • Thakur L.
      • Kojicic M.
      • Thakur S.J.
      • et al.
      Alcohol consumption and development of acute respiratory distress syndrome: a population-based study.
      /2009
      2226
      Toy et al
      • Toy P.
      • Gajic O.
      • Bacchetti P.
      • et al.
      Transfusion-related acute lung injury: incidence and risk factors.
      /2012
      2013
      a Maximum, four stars.
      b Maximum, two stars.
      c Maximum, three stars.
      d Only abstract available—not quality assessment.

       Exposure Reporting

      Sixteen studies investigated the effects of chronic alcohol exposure, and one the effect of acute exposure assessed by blood alcohol levels.
      • Afshar M.
      • Smith G.S.
      • Terrin M.L.
      • et al.
      Blood alcohol content, injury severity, and adult respiratory distress syndrome.
      Most of the studies reported chronic alcohol exposure assessed alcohol by self-report from a questionnaire
      • Calfee C.S.
      • Matthay M.A.
      • Eisner M.D.
      • et al.
      Active and passive cigarette smoking and acute lung injury after severe blunt trauma.
      • Calfee C.S.
      • Matthay M.A.
      • Kangelaris K.N.
      • et al.
      Cigarette smoke exposure and the acute respiratory distress syndrome.
      • Cardinal-Fernandez P.
      • Ferruelo A.
      • El-Assar M.
      • et al.
      Genetic predisposition to acute respiratory distress syndrome in patients with severe sepsis.
      • Gajic O.
      • Dabbagh O.
      • Park P.K.
      • et al.
      U.S. Critical Illness and Injury Trials Group: Lung Injury Prevention Study Investigators (USCIITG-LIPS)
      Early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study.
      • Ge Q.
      • Yao Z.
      • Wang T.
      • et al.
      [Risk factors of the occurrence and death of acute respiratory distress syndrome: a prospective multicenter cohort study] [article in Chinese].
      • Iribarren C.
      • Jacobs Jr., D.R.
      • Sidney S.
      • Gross M.D.
      • Eisner M.D.
      Cigarette smoking, alcohol consumption, and risk of ARDS: a 15-year cohort study in a managed care setting.
      • Moss M.
      • Parsons P.E.
      • Steinberg K.P.
      • et al.
      Chronic alcohol abuse is associated with an increased incidence of acute respiratory distress syndrome and severity of multiple organ dysfunction in patients with septic shock.
      or interview
      • Thakur L.
      • Kojicic M.
      • Thakur S.J.
      • et al.
      Alcohol consumption and development of acute respiratory distress syndrome: a population-based study.
      • TenHoor T.
      • Mannino D.M.
      • Moss M.
      Risk factors for ARDS in the United States: analysis of the 1993 National Mortality Followback Study.
      ; six used alcohol consumption documented in medical records
      • Iscimen R.
      • Cartin-Ceba R.
      • Yilmaz M.
      • et al.
      Risk factors for the development of acute lung injury in patients with septic shock: an observational cohort study.
      • Licker M.
      • de Perrot M.
      • Spiliopoulos A.
      • et al.
      Risk factors for acute lung injury after thoracic surgery for lung cancer.
      • Moss M.
      • Bucher B.
      • Moore F.A.
      • Moore E.E.
      • Parsons P.E.
      The role of chronic alcohol abuse in the development of acute respiratory distress syndrome in adults.
      • Gajic O.
      • Rana R.
      • Winters J.L.
      • et al.
      Transfusion-related acute lung injury in the critically ill: prospective nested case-control study.
      • Kojicic M.
      • Li G.X.
      • Hanson A.C.
      • et al.
      Risk factors for the development of acute lung injury in patients with infectious pneumonia.
      • Toy P.
      • Gajic O.
      • Bacchetti P.
      • et al.
      Transfusion-related acute lung injury: incidence and risk factors.
      and in one study the method of assessment and the definition of alcohol consumption were not defined.
      • Ahmed A.
      • Biehl M.
      • Kashyap R.
      • Hanson A.C.
      • Schenck L.A.
      • Gajic O.
      The impact of acute respiratory distress syndrome (ARDS) on short and long-term survival: a population-based nested case-control study.
      Measures of alcohol consumption included drinks per day,
      • Iribarren C.
      • Jacobs Jr., D.R.
      • Sidney S.
      • Gross M.D.
      • Eisner M.D.
      Cigarette smoking, alcohol consumption, and risk of ARDS: a 15-year cohort study in a managed care setting.
      drinks per week,
      • Thakur L.
      • Kojicic M.
      • Thakur S.J.
      • et al.
      Alcohol consumption and development of acute respiratory distress syndrome: a population-based study.
      • TenHoor T.
      • Mannino D.M.
      • Moss M.
      Risk factors for ARDS in the United States: analysis of the 1993 National Mortality Followback Study.
      milligrams of alcohol per deciliter of blood,
      • Afshar M.
      • Smith G.S.
      • Terrin M.L.
      • et al.
      Blood alcohol content, injury severity, and adult respiratory distress syndrome.
      alcoholism,
      • Cardinal-Fernandez P.
      • Ferruelo A.
      • El-Assar M.
      • et al.
      Genetic predisposition to acute respiratory distress syndrome in patients with severe sepsis.
      and alcohol abuse ascertained either from medical records or questionnaire.
      • Calfee C.S.
      • Matthay M.A.
      • Eisner M.D.
      • et al.
      Active and passive cigarette smoking and acute lung injury after severe blunt trauma.
      • Calfee C.S.
      • Matthay M.A.
      • Kangelaris K.N.
      • et al.
      Cigarette smoke exposure and the acute respiratory distress syndrome.
      • Gajic O.
      • Dabbagh O.
      • Park P.K.
      • et al.
      U.S. Critical Illness and Injury Trials Group: Lung Injury Prevention Study Investigators (USCIITG-LIPS)
      Early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study.
      • Ge Q.
      • Yao Z.
      • Wang T.
      • et al.
      [Risk factors of the occurrence and death of acute respiratory distress syndrome: a prospective multicenter cohort study] [article in Chinese].
      • Iscimen R.
      • Cartin-Ceba R.
      • Yilmaz M.
      • et al.
      Risk factors for the development of acute lung injury in patients with septic shock: an observational cohort study.
      • Licker M.
      • de Perrot M.
      • Spiliopoulos A.
      • et al.
      Risk factors for acute lung injury after thoracic surgery for lung cancer.
      • Moss M.
      • Bucher B.
      • Moore F.A.
      • Moore E.E.
      • Parsons P.E.
      The role of chronic alcohol abuse in the development of acute respiratory distress syndrome in adults.
      • Moss M.
      • Parsons P.E.
      • Steinberg K.P.
      • et al.
      Chronic alcohol abuse is associated with an increased incidence of acute respiratory distress syndrome and severity of multiple organ dysfunction in patients with septic shock.
      • Gajic O.
      • Rana R.
      • Winters J.L.
      • et al.
      Transfusion-related acute lung injury in the critically ill: prospective nested case-control study.
      • Kojicic M.
      • Li G.X.
      • Hanson A.C.
      • et al.
      Risk factors for the development of acute lung injury in patients with infectious pneumonia.
      • Toy P.
      • Gajic O.
      • Bacchetti P.
      • et al.
      Transfusion-related acute lung injury: incidence and risk factors.
      Specifically, alcohol abuse was defined in three of the 11 studies using a validated questionnaire, two defined alcohol abuse using the AUDIT (Alcohol Use Disorders Identification Test),
      • Calfee C.S.
      • Matthay M.A.
      • Eisner M.D.
      • et al.
      Active and passive cigarette smoking and acute lung injury after severe blunt trauma.
      • Calfee C.S.
      • Matthay M.A.
      • Kangelaris K.N.
      • et al.
      Cigarette smoke exposure and the acute respiratory distress syndrome.
      and one using the SMAST (Short Michigan Alcohol Screening Test).
      • Moss M.
      • Parsons P.E.
      • Steinberg K.P.
      • et al.
      Chronic alcohol abuse is associated with an increased incidence of acute respiratory distress syndrome and severity of multiple organ dysfunction in patients with septic shock.
      All studies analyzed the effects of alcohol exposure as a binary measure, contrasting high with low intake, or a history of abuse with no history of abuse, or any alcohol intake with none.

       Outcome Reporting

      Outcome definitions for ARDS included the American-European Consensus Conference definition,
      • Calfee C.S.
      • Matthay M.A.
      • Eisner M.D.
      • et al.
      Active and passive cigarette smoking and acute lung injury after severe blunt trauma.
      • Calfee C.S.
      • Matthay M.A.
      • Kangelaris K.N.
      • et al.
      Cigarette smoke exposure and the acute respiratory distress syndrome.
      • Cardinal-Fernandez P.
      • Ferruelo A.
      • El-Assar M.
      • et al.
      Genetic predisposition to acute respiratory distress syndrome in patients with severe sepsis.
      • Gajic O.
      • Dabbagh O.
      • Park P.K.
      • et al.
      U.S. Critical Illness and Injury Trials Group: Lung Injury Prevention Study Investigators (USCIITG-LIPS)
      Early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study.
      • Ge Q.
      • Yao Z.
      • Wang T.
      • et al.
      [Risk factors of the occurrence and death of acute respiratory distress syndrome: a prospective multicenter cohort study] [article in Chinese].
      • Iribarren C.
      • Jacobs Jr., D.R.
      • Sidney S.
      • Gross M.D.
      • Eisner M.D.
      Cigarette smoking, alcohol consumption, and risk of ARDS: a 15-year cohort study in a managed care setting.
      • Licker M.
      • de Perrot M.
      • Spiliopoulos A.
      • et al.
      Risk factors for acute lung injury after thoracic surgery for lung cancer.
      • Moss M.
      • Bucher B.
      • Moore F.A.
      • Moore E.E.
      • Parsons P.E.
      The role of chronic alcohol abuse in the development of acute respiratory distress syndrome in adults.
      • Moss M.
      • Parsons P.E.
      • Steinberg K.P.
      • et al.
      Chronic alcohol abuse is associated with an increased incidence of acute respiratory distress syndrome and severity of multiple organ dysfunction in patients with septic shock.
      • Thakur L.
      • Kojicic M.
      • Thakur S.J.
      • et al.
      Alcohol consumption and development of acute respiratory distress syndrome: a population-based study.
      • Gajic O.
      • Rana R.
      • Winters J.L.
      • et al.
      Transfusion-related acute lung injury in the critically ill: prospective nested case-control study.
      • Kojicic M.
      • Li G.X.
      • Hanson A.C.
      • et al.
      Risk factors for the development of acute lung injury in patients with infectious pneumonia.
      • Toy P.
      • Gajic O.
      • Bacchetti P.
      • et al.
      Transfusion-related acute lung injury: incidence and risk factors.
      death certificates,
      • TenHoor T.
      • Mannino D.M.
      • Moss M.
      Risk factors for ARDS in the United States: analysis of the 1993 National Mortality Followback Study.
      and the Berlin definition.
      • Afshar M.
      • Smith G.S.
      • Terrin M.L.
      • et al.
      Blood alcohol content, injury severity, and adult respiratory distress syndrome.
      Two studies did not provide clear information on outcome definition.
      • Iscimen R.
      • Cartin-Ceba R.
      • Yilmaz M.
      • et al.
      Risk factors for the development of acute lung injury in patients with septic shock: an observational cohort study.
      • Ahmed A.
      • Biehl M.
      • Kashyap R.
      • Hanson A.C.
      • Schenck L.A.
      • Gajic O.
      The impact of acute respiratory distress syndrome (ARDS) on short and long-term survival: a population-based nested case-control study.

       Meta-Analysis

      Thirteen of the studies provided data that could be included in a pooled analysis, which demonstrated that any measure of high exposure to alcohol significantly increased the risk of ARDS by a ratio of 1.89 (95% CI, 1.45-2.48; I2 = 48%) (Fig 2). No evidence of publication bias was found (funnel plot [Fig 3 and Egger’s asymmetry test], P = .150).
      Figure thumbnail gr2
      Figure 2Forest plot of alcohol consumption and the risk of ARDS; subgroup analysis based on alcohol abuse vs high alcohol consumption.
      Figure thumbnail gr3
      Figure 3Funnel plot of any high alcohol consumption and the risk of ARDS.
      Similar magnitudes of increased risk were seen in sensitivity analyses limited to studies categorizing alcohol intake as alcohol abuse (OR, 1.90; 95% CI, 1.40-2.60; I2 = 56%) (Fig 2), and limited to studies comparing only high alcohol with low or no alcohol consumption (OR, 1.96; 95% CI, 1.07-3.57; I2 = 17%) (Fig 2). However, the only study to use a zero intake as the reference group
      • Iribarren C.
      • Jacobs Jr., D.R.
      • Sidney S.
      • Gross M.D.
      • Eisner M.D.
      Cigarette smoking, alcohol consumption, and risk of ARDS: a 15-year cohort study in a managed care setting.
      found no significant effect of consuming of ≥ 3 drinks per day during the last year (OR, 0.97; 95% CI, 0.30-3.16). A further sensitivity analysis excluding one study, which compared decedents with a diagnosis of ARDS compared with decedents with other diagnoses,
      • TenHoor T.
      • Mannino D.M.
      • Moss M.
      Risk factors for ARDS in the United States: analysis of the 1993 National Mortality Followback Study.
      had a marginal effect on the magnitude of the association (OR, 1.91; 95% CI, 1.43-2.54; 12 studies) compared with the unrestricted analysis.
      Subgroup analysis found that the predisposing condition (trauma, sepsis/septic shock, pneumonia) for ARDS explained heterogeneity between the studies (P value for subgroup differences, .003); where an increased risk of ARDS associated with alcohol consumption was apparent only in patients with sepsis/septic shock (OR, 2.76; 95% CI, 1.80-4.24; four studies) (Fig 4). Further analyses to explore reasons for heterogeneity in the meta-analysis (e-Table 3) showed no statistically significant interaction by study design (case control, longitudinal/cohort, cross sectional; P = .22), study quality (high vs low; P = .09), country of study (United States, Europe, China; P = .19), effect estimate (adjusted vs unadjusted analysis; P = .21), and year of publication (1995-2005 vs 2006-2015; P = .20).
      Figure thumbnail gr4
      Figure 4Forest plot of alcohol consumption and the risk of ARDS; subgroup analysis in patients with trauma, sepsis, and pneumonia. aData presented for the subset of trauma patients; bData presented for the subset of sepsis patients.
      Two studies were identified that assessed the effects of alcohol on the risk of transfusion-related ALI.
      • Gajic O.
      • Rana R.
      • Winters J.L.
      • et al.
      Transfusion-related acute lung injury in the critically ill: prospective nested case-control study.
      • Toy P.
      • Gajic O.
      • Bacchetti P.
      • et al.
      Transfusion-related acute lung injury: incidence and risk factors.
      Both studies found that alcohol increased the risk of transfusion-related ALI (results: P = .006 [37% vs 18%]; OR, 3.0; 95% CI, 1.07-8.7). A meta-analysis of these two studies could not be performed as the first study
      • Gajic O.
      • Rana R.
      • Winters J.L.
      • et al.
      Transfusion-related acute lung injury in the critically ill: prospective nested case-control study.
      did not provide sufficient information to allow ORs to be estimated, due to the study using individual matching to identify the control subjects. Two further studies could not be included in the meta-analysis. The first of these compared risks of ARDS in those with alcohol detected in blood compared with those with no detectable alcohol
      • Afshar M.
      • Smith G.S.
      • Terrin M.L.
      • et al.
      Blood alcohol content, injury severity, and adult respiratory distress syndrome.
      ; as the effects of acute alcohol intoxication are very different from those of chronic alcohol exposure, this study was not included in the meta-analysis. This study found that the presence of alcohol in blood was associated with an increased risk of ARDS (OR, 1.50). The second study was published only in abstract form,
      • Ahmed A.
      • Biehl M.
      • Kashyap R.
      • Hanson A.C.
      • Schenck L.A.
      • Gajic O.
      The impact of acute respiratory distress syndrome (ARDS) on short and long-term survival: a population-based nested case-control study.
      which did not provide sufficient information to allow ORs to be estimated, due to the study using individual matching. Briefly, this study showed that patients with ARDS were more likely to consume alcohol (17% vs 10%) compared with control subjects.

      Discussion

      This article reports the first meta-analysis of observational studies of the association between alcohol consumption and the risk of ARDS among adults. We found evidence of a 1.89-fold increase in the odds of ARDS in persons with high alcohol consumption, which in subgroup analyses appeared to be attributable to the effect of exposure defined as alcohol abuse and also in those with sepsis or septic shock as the predisposing condition for ARDS.
      Our review is based on a comprehensive search of the worldwide literature held in key medical databases and using search terms from recognized sources, complemented by searches of reference lists from identified publications. We imposed no language restriction in our searches. It is therefore likely that our results are representative and generalizable. The absence of publication bias further validates our findings.
      Being based largely on observational studies raises the possibility of bias, which may be introduced in our analysis. However, misclassification bias due to the inclusion of former/lower drinkers in the reference group is likely, if anything, to have reduced the magnitudes of estimated effects. However, the subgroup analyses were conducted in an attempt to explore reasons for heterogeneity, and we found that there were no significant differences according to study quality, study design, effect estimate, continent, or year of publication.
      A previous narrative review has drawn attention to the potential importance of chronic alcohol abuse in the etiology of ARDS,
      • Moss M.
      • Burnham E.L.
      Chronic alcohol abuse, acute respiratory distress syndrome, and multiple organ dysfunction.
      finding an increased incidence of ARDS in alcohol abusers. Also, a narrative review published in 2009, which included only four studies on alcohol and ARDS, concluded that alcohol abuse is a risk factor for the development of ARDS.
      • Boé D.M.
      • Vandivier R.W.
      • Burnham E.L.
      • Moss M.
      Alcohol abuse and pulmonary disease.
      Our findings extend the conclusions of this work, identifying a summary effect estimate and that the increased risk applies predominantly to ARDS arising from sepsis.
      The mechanism or mechanisms by which alcohol consumption might increase the risk of ARDS, particularly among patients with sepsis, are not fully understood. However, effects on membrane permeability,
      • Burnham E.L.
      • Halkar R.
      • Burks M.
      • Moss M.
      The effects of alcohol abuse on pulmonary alveolar-capillary barrier function in humans.
      • Fan X.
      • Joshi P.C.
      • Koval M.
      • Guidot D.M.
      Chronic alcohol ingestion exacerbates lung epithelial barrier dysfunction in HIV-1 transgenic rats.
      glutathione depletion,
      • Guidot D.M.
      • Modelska K.
      • Lois M.
      • et al.
      Ethanol ingestion via glutathione depletion impairs alveolar epithelial barrier function in rats.
      • Velasquez A.
      • Bechara R.I.
      • Lewis J.F.
      • et al.
      Glutathione replacement preserves the functional surfactant phospholipid pool size and decreases sepsis-mediated lung dysfunction in ethanol-fed rats.
      • Yeh M.Y.
      • Burnham E.L.
      • Moss M.
      • Brown L.A.S.
      Non-invasive evaluation of pulmonary glutathione in the exhaled breath condensate of otherwise healthy alcoholics.
      Toll-like receptor up-regulation,
      • Bailey K.L.
      • Romberger D.J.
      • Katafiasz D.M.
      • et al.
      TLR2 and TLR4 expression and inflammatory cytokines are altered in the airway epithelium of those with alcohol use disorders.
      expression of transforming growth factor-β1,
      • Curry-McCoy T.V.
      • Venado A.
      • Guidot D.M.
      • Joshi P.C.
      Alcohol ingestion disrupts alveolar epithelial barrier function by activation of macrophage-derived transforming growth factor beta1.
      • Sueblinvong V.
      • Kerchberger V.E.
      • Saghafi R.
      • Mills S.T.
      • Fan X.
      • Guidot D.M.
      Chronic alcohol ingestion primes the lung for bleomycin-induced fibrosis in mice.
      and impairment of macrophage function are all potential explanations.
      • Joshi P.C.
      • Mehta A.
      • Jabber W.S.
      • Fan X.
      • Guidot D.M.
      Zinc deficiency mediates alcohol-induced alveolar epithelial and macrophage dysfunction in rats.
      Our study thus provides comprehensive evidence that high alcohol consumption increases the risk of ARDS.

      Acknowledgments

      Author contributions: E. S. acts as guarantor of the manuscript, and all authors approved the final version of the article to be published. E. S., J. B., and J. L.-B. designed the study and wrote the protocol. E. S. wrote the search strategy and undertook the literature searches, and wrote the draft of the manuscript. E. S. and J. L.-B. undertook study screening, data extraction, and quality assessment. E. S. undertook all data analysis, supervised by J. L.-B. All authors contributed to the interpretation of the findings. J. B. and J. L.-B. provided critical revisions to the article.
      Financial/nonfinancial disclosure: None declared.
      Other contributions: The author thanks Erica Brasil, Magdalena Opazo-Breton, PhD, and Yue Huang, PhD, from the University of Nottingham for help in translations.
      Additional information: The e-Tables can be found in the Supplemental Materials section of the online article.

      Supplementary Data

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