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Preoperative Aspirin Use and Lung Injury After Aortic Valve Replacement Surgery: A Retrospective Cohort Study

Mazzeffi, Michael MD, MPH; Kassa, Woderyelesh BA; Gammie, James MD; Tanaka, Kenichi MD, MSc; Roman, Philip MD, MPH; Zhan, Min PhD; Griffith, Bartley MD; Rock, Peter MD, MBA

doi: 10.1213/ANE.0000000000000793
Cardiovascular Anesthesiology: Research Report
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BACKGROUND: Acute respiratory distress syndrome (ARDS) occurs uncommonly after cardiac surgery but has a mortality rate as high as 80%. Aspirin may prevent lung injury in at-risk patients by reducing platelet-neutrophil aggregates in the lung. We hypothesized that preoperative aspirin use would be associated with a decreased risk of ARDS after aortic valve replacement surgery.

METHODS: We performed a retrospective single-center cohort study that included all adult patients who had aortic valve replacement surgery during a 5-year period. The primary outcome variable was postoperative ARDS. The secondary outcome variable was nadir PaO2/FIO2 ratio during the first 72 hours after surgery. Both crude and propensity score–adjusted logistic regression analyses were performed to estimate the odds ratio for developing ARDS in aspirin users. Subgroups were analyzed to determine whether preoperative aspirin use might be associated with improved oxygenation in patients with specific risk factors for lung injury.

RESULTS: Of the 375 patients who had aortic valve replacement surgery during the study period, 181 patients took aspirin preoperatively (48.3%) with most taking a dose of 81 mg (72.0%). There were 22 cases of ARDS in the cohort (5.5%). There was no significant difference in the rate of ARDS between aspirin users and nonusers (5.0% vs 6.7%, P = 0.52). There was also no significant difference in the nadir PaO2/FIO2 ratio between aspirin users and nonusers (P = 0.12). The crude odds ratio for ARDS in aspirin users was 0.725 (99% confidence interval, 0.229–2.289; P = 0.47), and the propensity score–adjusted odds ratio was 0.457 (99% confidence interval, 0.120–1.730; P = 0.13).

CONCLUSIONS: Within the constraints of this analysis that included only 22 affected patients, preoperative aspirin use was not associated with a decreased incidence of ARDS after aortic valve replacement surgery or improved oxygenation.

Published ahead of print May 19, 2015

From the Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland.

Accepted for publication March 11, 2015.

Published ahead of print May 19, 2015

Funding: WK was funded by a National Institute of Aging T35 Grant. There was no other funding for the study.

The authors declare no conflicts of interest.

This report was previously presented, in part, at the Society for Cardiovascular Anesthesiologists annual meeting in Washington, DC, 2015.

Reprints will not be available from the authors.

Address correspondence to Michael Mazzeffi, MD, MPH, Department of Anesthesiology, University of Maryland School of Medicine, 22 S. Greene St., S11C00, Baltimore, MD 21201. Address e-mail to mmazzeffi@anes.umm.edu.

Acute respiratory distress syndrome (ARDS) occurs in as many as 20% of cardiac surgery patients and may have a mortality rate as high as 80%.1 There are a number of insults that occur during cardiac surgery that may contribute to lung injury, including exposure to cardiopulmonary bypass, transfusion of allogeneic blood products, and deflation of the lungs leading to atelectrauma.2 To date, few preventive strategies have been investigated in patients who are at high risk for acute lung injury, including patients having cardiac surgery. Identification of high-risk patients is possible, but, unfortunately, many risk factors are not modifiable. Gajic et al.3 proposed a lung injury prediction score that incorporates 8 predisposing conditions, including the presence of shock, sepsis, and emergency surgery, and 7 risk modifiers, including the use of high inspired oxygen concentrations, diabetes mellitus, and smoking, to predict the likelihood of lung injury. The lung injury prediction score has high discriminative value and is well calibrated (area under the curve = 0.84 and Hosmer-Lemeshow Statistic = 0.88) but may not be applicable to all patient populations.4

Aspirin has pleiotropic effects because of its irreversible inhibition of cyclooxygenase leading to downstream inhibition of prostaglandin and leukotriene synthesis.5 For this reason, aspirin has been suggested as a potentially protective strategy against acute lung injury in at-risk patients.6 In a retrospective study of almost 4000 hospitalized medical patients who were at high risk for lung injury, Kor et al.7 found that aspirin was associated with a reduced rate of acute lung injury based on univariate analysis. However, when propensity matching was used to control for potential confounders in that analysis, the association between aspirin use and reduced risk for acute lung injury was negated. In another retrospective study of 575 critically ill hospitalized noncardiac surgery patients, prehospital use of aspirin and statins was associated with a reduced incidence of acute lung injury.8 Other studies have suggested that aspirin may reduce organ failure, other than lung injury, in critically ill patients.9 Currently, the Lung Injury Prevention Study with Aspirin, which is a randomized controlled trial funded by the National Heart, Lung, and Blood Institute, is underway to test the hypothesis that aspirin may prevent acute lung injury in at-risk hospitalized patients.

We hypothesized that preoperative aspirin use would be associated with a decreased incidence of ARDS after aortic valve replacement surgery. Furthermore, we hypothesized that preoperative aspirin use would be associated with improved oxygenation after surgery.

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METHODS

Subjects

The IRB of the University of Maryland, Baltimore, Maryland, approved the study and waived the requirement for informed consent. We performed a retrospective single-center cohort study that included all adult patients having aortic valve replacement surgery with cardiopulmonary bypass between July 1, 2008 and June 30, 2013. Patients having aortic valve replacement surgery were selected for the cohort because there was a relatively equal distribution of aspirin users and nonusers in this group. The study period was selected because electronic medical record data and data entered into our institutional Society for Thoracic Surgeons (STS) database were uniformly available for all patients who had cardiac surgery during that period, and a 5-year duration was thought to represent relatively homogenous perioperative care.

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Definitions

Definitions for patient variables were based on the STS database definitions (versions 2.61 and 2.73; www.sts.org). ARDS was defined using the Berlin definition: onset of acute lung injury within 1 week of an identifiable insult, bilateral lung opacities on chest radiography, noncardiogenic pulmonary edema, and PaO2/FIO2 ratio of 201 to 300 mm Hg for mild ARDS, 101 to 200 mm Hg for moderate ARDS, and ≤100 mm Hg for severe ARDS. Pulmonary edema was assumed to be noncardiogenic if the most recent echocardiogram of the patients did not suggest left ventricular systolic or diastolic heart failure and the daily progress note of the intensive care physicians did not indicate a cardiogenic etiology. All cases of ARDS had sustained impairment in oxygenation represented by ≥48 hours of hypoxemia, defined by a PaO2/FIO2 ≤300 mm Hg, and were confirmed by the principal investigator and one other investigator.

PaO2/FIO2 ratios were calculated using arterial blood gas measurements obtained at frequent intervals after surgery. The baseline PaO2/FIO2 ratio was calculated using the first arterial blood gas in the operating room. Some patients had this blood gas collected before anesthesia induction and others had it collected after the induction of general anesthesia. For patients who had their first blood gas collected before anesthesia induction, FIO2 was estimated using the number of liters per minute of nasal cannula oxygen that they were receiving (3% FIO2 added to 21% for each liter per minute of oxygen). Postoperative arterial blood gas measurements from the first 72 hours after surgery were used to determine the lowest PaO2/FIO2 ratio during that time period. Preoperative aspirin use was defined as having received aspirin within 5 days of surgery. All blood products given during the operative period were recorded.

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Outcome Variables

The primary outcome variable was the occurrence of ARDS. The secondary outcome variable was nadir PaO2/FIO2 ratio during the first 72 hours after surgery.

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Statistical Analysis

All statistical analyses were performed using SAS 9.3 (Cary, NC). The cohort was separated into aspirin users and nonusers. Categorical variables were reported as number (%) and continuous variables were examined for normality using histograms and the Shapiro-Wilk test. Normally distributed continuous variables were reported as mean ± SD and nonnormally distributed continuous variables were reported as median (Q1, Q3). Comparisons were made between patient characteristics and outcomes for aspirin users and nonusers using the Fisher exact test for categorical variables, t tests for normally distributed continuous variables, and Wilcoxon rank sum tests for nonnormally distributed continuous variables. Ninety-nine percent confidence intervals (CIs) were calculated for risk differences in outcome variables.

Logistic regression analysis was performed with aspirin as the independent variable and ARDS as the dependent variable to determine the crude odds ratio for ARDS in patients taking aspirin. A 99% CI was calculated for the crude odds ratio. In addition to estimating a crude odds ratio, we used the following preoperative variables to create a propensity score for the probability of receiving aspirin: age, cerebral vascular disease, congestive heart failure, diabetes mellitus, dyslipidemia, end-stage renal disease, sex, height, hypertension, infectious endocarditis, international normalized ratio, left ventricular ejection fraction, peripheral vascular disease, and body weight.

The propensity score methods used were based on previously published methods.10,11 Propensity scores were calculated using logistic regression with preoperative variables entered into the model as independent variables and aspirin use entered as the dependent variable. Independent variables were selected for inclusion in the model based on whether they were thought to be associated with aspirin use and the outcome variable. To assess the balance of propensity scores across the aspirin users and nonusers, the distributions of propensity scores were plotted using histograms. Also, a receiver operating characteristic curve was created, and the area under the curve was calculated as a measure of model discrimination.

Propensity scores were used to control for confounding by entering them into a logistic regression model as a second independent variable with aspirin and ARDS as the dependent variable. A 99% CI was calculated for the propensity score–adjusted odds ratio of ARDS in aspirin users.

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Subgroup Analyses

A priori we decided to perform 3 subgroup analyses based on biological plausibility. The subgroups were stratified by age, predicted prolonged (>24 hours) mechanical lung ventilation, and the number of units of fresh-frozen plasma transfused intraoperatively. The strata in the subgroups were based on the distributions of the data and what we perceived as logical increments. In the subgroup analyses, we examined only the secondary outcome variable (nadir PaO2/FIO2 ratio during the 72 hours after surgery) because the incidence of ARDS was low in the cohort, and cell counts would otherwise be very low for individual strata. Ninety-nine percent CIs were calculated for risk differences between aspirin users and nonusers at different levels of oxygenation impairment.

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RESULTS

Three hundred seventy-five patients met study inclusion criteria. Medical and demographic data are listed in Table 1. The prevalence of chronic lung disease in the cohort was 14.4%, and the baseline PaO2/FIO2 ratio was 317 mm Hg. Patients who received aspirin preoperatively were older, had more dyslipidemia, and were more likely to have aortic stenosis than aortic insufficiency as their primary diagnosis. Cardiopulmonary bypass duration did not differ significantly between the groups. Preoperative aspirin was taken by 181 patients (48.3%) with the majority of patients taking 81 mg/d (72%).

Table 1

Table 1

There were 22 cases of ARDS in the cohort (5.6%). Nine cases occurred in patients who were receiving aspirin preoperatively (5.0%), and 12 cases occurred in patients who were not receiving aspirin preoperatively (6.7%). There was no difference in the frequency of ARDS between the 2 groups (P = 0.52). Furthermore, there were no differences between the groups in the duration of mechanical lung ventilation, the number of tracheal reintubations, frequency of pneumonias, or the nadir PaO2/FIO2 ratio 72 hours after surgery as listed in Table 2.

Table 2

Table 2

Based on the crude logistic regression analysis, the odds ratio point estimate for the frequency of ARDS among aspirin users was 0.725 (99% CI, 0.229–2.289; P = 0.47). The variables included in the propensity score model are shown in Table 3 along with the odds ratio point estimates, 99% CIs, and respective P values. The distributions of propensity scores for aspirin users and nonusers are shown in Figure 1. The area under the receiver operating characteristic curve for the propensity score model was 0.69. Based on the propensity score–adjusted logistic regression analysis, the frequency of ARDS among aspirin users was 0.457 (99% CI, 0.120–1.730; P = 0.13).

Table 3

Table 3

Figure 1

Figure 1

Stratification by age and predicted prolonged (>24 hours) mechanical lung ventilation did not affect the relation between preoperative aspirin use and the nadir PaO2/FIO2 ratio after surgery (Tables 4 and 5). Stratification by the number of intraoperative units of fresh-frozen plasma transfused suggested a trend toward improved oxygenation in patients who were taking aspirin preoperatively (Table 6). Specifically, in the group of patients transfused 5 to 6 units of fresh-frozen plasma, aspirin users were potentially less likely to have a PaO2/FIO2 ratio <200 mm Hg in comparison with patients not taking aspirin (risk difference = 57.1%; 99% CI, 1.9%–88.4%; P = 0.015). There was no dose-response relation, however, between the number of units of fresh-frozen plasma transfused and the PaO2/FIO2 ratio for patients receiving >6 units of plasma.

Table 4

Table 4

Table 5

Table 5

Table 6

Table 6

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DISCUSSION

In a retrospective cohort study of 375 patients having aortic valve replacement surgery, the overall rate of ARDS was 5.9% with the majority of ARDS patients having an associated infectious process (pneumonia or sepsis). Aspirin use within 5 days of surgery did not appear to be associated with a reduced risk of ARDS or improved postoperative oxygenation. However, the small number of individuals with ARDS (n = 22) in this series resulted in wide CIs associated with this risk assessment.

Recent attention has been given to aspirin as a potential prophylactic therapy for patients at high risk of acute lung injury based on consistent results of laboratory studies showing that aspirin attenuates lung injury via multiple mechanisms including reduction of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity, decreased intracellular adhesion molecule 1 (ICAM-1) and P-selectin expression, reduction in platelet-derived chemokine production, and increased production of aspirin-triggered 15-epi-lipoxin A4.12–17 Other evidence suggests that aspirin improves postoperative gas exchange in patients undergoing cardiac surgery18 and reduces thromboxane B2 production during cardiopulmonary bypass leading to lung protection.19 Animal models have shown that aspirin may also reduce the risk of transfusion-related acute lung injury by modulating platelet-neutrophil aggregation in the lung.20,21 Specifically, when platelets are activated, they induce neutrophil extracellular traps, which are composed of chromatin and granular proteins. By inhibiting cyclooxygenase and subsequently thromboxane production, aspirin has the ability to decrease neutrophil extracellular trap formation in the lung, potentially reducing lung injury.

The findings of our study are consistent with the findings by Kor et al.,7 who in an observational study from 2011, which included almost 4000 noncardiac surgery patients who were at risk for lung injury, found no association between prehospital aspirin use and acute lung injury after adjusting for the likelihood of receiving aspirin. In our study, the incidence of ARDS was below what we anticipated. Previous studies have estimated the incidence of ARDS after cardiac surgery to be between 0.4% and 3.4%.22–25 However, these studies preceded the Berlin definition and did not classify patients who had a PaO2/FIO2 ratio between 201 and 300 mm Hg as having ARDS. Also, these studies included a large percentage of patients having coronary artery bypass grafting surgery, and our cohort was composed entirely of patients having valve surgery.

In our subgroup analyses, there was a trend toward improved postoperative oxygenation when patients were stratified by the number of intraoperative fresh-frozen plasma units that they received, but there was no dose-response observed between aspirin use and the number of fresh-frozen plasma units transfused. One possible reason for not observing a dose-response is that we grouped patients who received > 6 units of fresh-frozen plasma into a single stratum. This stratum had a high level of variation in transfusion (median 10 units and maximum 34 units), and, thus, any potential benefit of aspirin on oxygenation might have been confounded by the higher risk for transfusion-related acute lung injury or other factors in patients receiving larger volumes of fresh-frozen plasma transfusion. In addition, we stratified by intraoperative fresh-frozen plasma transfusion and not by total fresh-frozen plasma transfusion during surgery and the first 72 hours after, which may have introduced some bias in our risk estimation.

Our study has a number of important limitations. First, we examined a specific population of patients undergoing aortic valve replacement surgery. Thus, our findings may not be generalizable to patients undergoing other types of cardiac surgery. Second, because data were collected retrospectively, they may be more prone to error or misclassification. Third, not all patients in the study had mechanical lung ventilation using a lung-protective strategy.26 Fourth, aspirin data were recorded in the STS database dichotomously as having taken aspirin within 5 days of surgery or not. This does not account for the variability in aspirin use during this period or the variability in pharmacokinetics for a particular patient. The trend toward improved oxygenation with aspirin use that was observed when patients were stratified by intraoperative fresh-frozen plasma transfusion may have been due to a type 1 error. Finally, we only observed 22 cases of ARDS in this series, which led to wide CIs for our ARDS risk estimates for aspirin users and nonusers.

The strengths of our study are that it represents a relatively homogenous cohort of patients who were at risk for acute lung injury and were almost equally divided between aspirin users and nonusers. Also, data were collected in a consistent manner using consistent definitions and practices.

In conclusion, within the constraints of this analysis that included only 22 affected patients, preoperative aspirin use does not appear to be associated with a decreased incidence of ARDS after aortic valve replacement surgery or improved oxygenation.

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DISCLOSURES

Name: Michael Mazzeffi, MD, MPH.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Michael Mazzeffi has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Name: Woderyelesh Kassa, BA.

Contribution: This author helped conduct the study, analyze the data, and write the manuscript.

Attestation: Woderyelesh Kassa has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: James Gammie, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: James Gammie has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Kenichi Tanaka, MD, MSc.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Kenichi Tanaka has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Philip Roman, MD, MPH.

Contribution: This author helped design the study, analyze the data, and write the manuscript.

Attestation: Philip Roman has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Min Zhan, PhD.

Contribution: This author helped analyze the data and write the manuscript.

Attestation: Min Zhan has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Bartley Griffith, MD.

Contribution: This author helped conduct the study, analyze the data, and write the manuscript.

Attestation: Bartley Griffith has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Peter Rock, MD, MBA.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Peter Rock has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

This manuscript was handled by: Charles W. Hogue, Jr., MD.

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