Lung-diffusing capacity for carbon monoxide predicts early complications after cardiac surgery

Purpose Preoperative pulmonary dysfunction has been associated with increased operative mortality and morbidity after cardiac surgery. This study aimed to determine whether values for the diffusing capacity of the lung for carbon monoxide (DLCO) could predict postoperative complications after cardiac surgery. Methods This study included 408 consecutive patients who underwent cardiac surgery between June 2008 and December 2015. DLCO was routinely determined in all patients. A reduced DLCO was clinically defined as %DLCO < 70%. %DLCO was calculated as DLCO divided by the predicted DLCO. The association between %DLCO and in-hospital mortality was assessed, and independent predictors of complications were identified by a logistic regression analysis. Results Among the 408 patients, 338 and 70 had %DLCO values of ≥ 70% and < 70%, respectively. Complications were associated with in-hospital mortality (P < 0.001), but not %DLCO (P = 0.275). A multivariate logistic regression analysis with propensity score matching identified reduced DLCO as an independent predictor of complications (OR, 3.270; 95%CI, 1.356–7.882; P = 0.008). Conclusions %DLCO is a powerful predictor of postoperative complications. The preoperative DLCO values might provide information that can be used to accurately predict the prognosis after cardiac surgery. Clinical trial registration number UMIN000029985.


Introduction
Preoperative pulmonary dysfunction in chronic obstructive pulmonary disease (COPD) has been considered to be associated with increased operative mortality and morbidity after cardiac surgery. A careful evaluation of the pulmonary function before and after cardiac surgery demonstrated a significant reduction in lung volume, diffusion capacity, and oxygenation at 2 weeks after surgery, with partial improvement after 4 months [1]. The preoperative identification of patients who are at greater risk of developing complications is important to prevent postoperative complications and obtain a good operative outcome.
The analysis of the diffusing capacity of the lung for carbon monoxide (DL CO ) is a clinically useful pulmonary function test (PFT). Unlike other spirometric measurements, DL CO is less influenced by patient effort [2]. DL CO represents the ability of the lung to diffuse carbon monoxide across its membranes and assesses the transfer of gases from the alveoli to red blood cells. The diffusion of O 2 depends on the following factors: the alveolar ventilation/capillary perfusion ratio, which establishes the partial pressure gradient of O 2 between the alveoli and plasma; the physical characteristics of the alveolar-capillary interface; the capillary blood volume available for gas exchange; the hemoglobin (Hb) concentration; and the reaction rate between O 2 and Hb [3,4]. The diffusion characteristics of the lung are commonly assessed by tests of CO transfer. CO diffuses across the alveoli and binds to Hb with 240-fold greater affinity than O 2 [3]. DL CO depends on two resistances arranged in series according to the following equation: 1/DL CO = 1/D M + 1/θ CO V C [3][4][5], where D M is the alveolar-capillary membrane conductance, θ CO is the rate of CO uptake by the whole blood combined with Hb measured in vitro, and V C is the lung capillary blood volume [3][4][5]. A decline in DL CO can occur as a result of destruction of alveolar structures, distal airway dysfunction, contraction of the pulmonary capillary volume due to ventilation, perfusion abnormalities, and Hb abnormalities. DL CO is an equally powerful predictor of postoperative complications in patients with and without COPD after lung resection. A previous study suggested that DL CO should be routinely measured during preoperative evaluations, regardless of whether a patient's spirometric values are abnormal [2].
Another study reported that reduced alveolar-capillary membrane conductance is associated with pulmonary congestion [6]. Thus, DL CO may be influenced by pulmonary edema and fluid accumulation in the interstitial spaces before and after cardiac surgery. The present study aimed to determine whether DL CO can serve as a predictor of complications arising after cardiac surgery.

Patients
The study protocol was approved by the Institutional Review Board of the Dokkyo Medical University. Between June 2008 and December 2015, 2040 patients underwent cardiac surgery at Dokkyo Medical University Hospital. A total of 408 patients in whom preoperative DL CO values were routinely collected within 1 week before scheduled cardiac surgery were included in this study. The attending physician for each patient made the decision to proceed with the PFT, which included measurement of DL CO , based on clinical indications. The exclusion criteria were any emergency or urgent operation, aortic surgery, beating heart surgery, and approaches other than median sternotomy. We reviewed the medical records of the patients, including the demographics, preoperative clinical data, PFT findings, hemodynamic data from cardiac catheterization, and operative and postoperative data.

DL CO measurement and %DL CO
We measured DL CO in a single-breath-hold maneuver with the patient seated upright in a chair with their nostrils closed with a clip. The patients then breathed normally and exhaled to residual volume, and then, a carbon monoxide-helium mixture was forcefully inhaled to total lung capacity, and held for 10 s and then exhaled. The patients exhaled to wash out the estimated mechanical and anatomical dead space. Alveolar samples were then collected, and DL CO was calculated from the total volume of the lung, breath-hold duration, and the initial and final alveolar concentrations of CO. The exhaled helium concentration was used to determine a single-breath estimate of the total lung capacity and the initial alveolar concentration of CO. The predicted DL CO was determined from regression equations according to age, height, and sex (predicted DL CO for men, 15.5 × body surface area (BSA) − 0.23 × age + 6.8; predicted DL CO for women, 15.5 × BSA − 0.117 × age + 0.5) [7]. %DL CO was calculated by dividing the actual DL CO by the predicted DL CO .

Surgical technique
A median sternotomy approach was applied under general anesthesia to all patients. Cardiopulmonary bypass (CPB) was established through the ascending aorta or by right atrial or bicaval cannulation. The myocardium was protected by antegrade and retrograde cardioplegia with intermittent cold-blood cardioplegia and reperfusion with warm-blood cardioplegia. A normothermic temperature was maintained during CPB. The patients were transferred to the intensive care unit immediately after the procedure with ventilator assistance and monitoring.

Definitions of complications
Postoperative outcomes were defined according to the Society of Thoracic Surgeons National Database as follows. In-hospital death was defined as the death of a patient due to any cause during hospitalization in the institution, where they underwent cardiac surgery. Stroke was defined as a central neurologic deficit persisting for > 72 h. Wound infection was defined as infection involving subcutaneous tissue, muscle, bone, or the mediastinum, and requiring surgical intervention. Respiratory complications were also included. The incidence of postoperative respiratory complications was scored on an ordinal scale of 1-4, using the operational definitions of postoperative pulmonary complications described by Kroenke et al. [8] (Table 1) . Clinically significant respiratory complications were defined as one item among grade 3 or 4 complications.

Statistical analysis
Continuous variables are expressed as the mean ± standard deviation (SD) and were compared using Student's t test or the Mann-Whitney test, as appropriate. Nominal variables are expressed as percentages and were analyzed using the χ 2 test or Fisher's exact probability test. All variables with P values of < 0.20 in the univariate analysis were included in the multivariable analyses. Other clinically relevant variables, namely, sex, age, body mass index (BMI), and BSA, were adjusted in the multivariable analysis. Independent predictors of postoperative complications after cardiac surgery were identified using a multivariate logistic regression model with the forced entry method. Odds ratios (OR), 95% confidence intervals (95%CI), and P values are reported. To minimize selection bias derived from the retrospective observational study design, propensity score analyses were performed to generate two groups, considering the following covariates: age, sex, BMI, %VC, and hemoglobin. 70 patients with %DL CO < 70% and 67 patients with %DL CO ≥ 70% were matched. A logistic regression analysis for the abovementioned covariates, with nearestneighbor one-to-one matching, was performed to determine the propensity scores. All statistical tests were two-sided, and P values of < 0.05 were considered to indicate statistical significance. All statistical analyses were performed using the IBM SPSS statistics 24 software program (IBM, Armonk, NY, USA). Table 2 summarizes the characteristics of the 408 patients (age, 66.0 ± 10.0 years; male, n = 295 [72.3%]), whose data were analyzed in this study. Isolated coronary artery bypass grafting (CABG) was performed for 224 (54.9%) patients, and 184 (45.9%) underwent valve surgery (including concomitant cardiac surgery). Six (1.47%) patients died in hospital due to multi-organ failure (n = 1), sudden death (n = 1), and sepsis (n = 4). Operative complications developed in 91 (22.3%) patients and consisted of gastrointestinal disorder The incidence of all complications significantly differed in Q1 (OR, 3.323; 95%CI, 1.472-7.500; P = 0.005); the OR for respiratory complications was 3.462 (95%CI, 1.434-8.357; P = 0.005). Although a DLco value of < 80% of the predicted value was considered abnormal, according to a previous definition by Steenhuis et al. [9], the incidence of complications differed in Q1 (%DLco < 74.6%). A DLco value of < 70% the predicted value was considered to be the cut-off value. The area under the receiver operating characteristic curve values was 0.625 (95%CI 0.558-0.692) for all complications and 0.632 (95%CI 0.557-0.707) for respiratory complications. The sensitivity and specificity of %DLco, with a cut-off value of 70%, were 0.864 and 0.297, respectively, for all complications (0.861 and 0.324 for respiratory complications). Table 2 shows the preoperative and perioperative factors of patients with %DL CO of ≥ 70% (n = 338) or < 70% (n = 70). Significant differences were observed in age (66. 5 Table 6).

Discussion
The principal finding of this study was that the preoperative DL CO was correlated with postoperative complications after cardiac surgery. Others have described significant and prolonged impairment of the pulmonary function after cardiac surgery [1]. Decreased ventilation, pulmonary disease, and reduced alveolar perfusion caused by poor cardiac output and chronic heart failure might also influence DL CO [10]. DL CO is a clinically useful indicator of the lung function, because it assesses gas transfer from the alveoli to the red blood cells. The preoperative DL CO is not routinely measured in patients in most cardiac surgery units. Reduced postoperative capillary filtration due to basal membrane thickening, enhanced alveolar fluid clearance, and increased lymphatic drainage leads to restricted lung spirometry and impaired gas transfer [6]. We hypothesized that the postoperative DL CO might be more decreased than the preoperative DL CO and that this could serve as a predictor of early complications after cardiac surgery. The present study found that more postoperative complications developed among patients with %DL CO of < 70% than among those with %DL CO of > 70%. A previous study also found that patients with stable chronic heart failure had decreased %VC values, in addition to decreased DL CO and D M values [11]. The present study showed that the %VC values were decreased and the BNP levels were increased in patients with lower DL CO values; however, these patients might have had preoperative chronic heart failure. Thus, %DL CO might be a marker of heart failure.  The ORs were adjusted as described in the Fig. 1 legend. DL CO diffusing capacity of lung for carbon monoxide, OR odds ratio. Error bars represent 95% confidence intervals A previous study suggested that cardiac surgery may also contribute to a greater reduction in DL CO . The mechanism underlying the reduction of DL CO after cardiac surgery is unclear. One hypothesis is that it might reflect pathophysiological changes in the pulmonary microcirculation initiated by CPB, such as a systemic inflammatory response with coagulopathy and altered microvascular permeability [12]. That CPB interferes with pulmonary function has been established. It can induce adverse effects on alveolar stability by activating the complement cascade, sequestering neutrophils in the pulmonary microvascular bed, releasing oxygen-derived free radicals, and changing the composition of alveolar surfactant [13]. The mechanism underlying the diffusion impairment after cardiac surgery could be caused by pulmonary edema and the accumulation of fluid in interstitial spaces, ventilation-perfusion mismatches, or changes in Hb concentrations [14]. A few studies have identified a relationship between DL CO and the outcomes after cardiac surgery. Published data show that a %DL CO value of < 50% the predicted value at the preoperative PFT is an independent risk factor for a > threefold increase in mortality after adjustment for mortality risk estimates [15]. Few patients in the present study had a %DL CO value of < 50%. Thus, our analysis included %DL CO < 70% as an approximation for Q1. The findings of the present study showed that %DL CO < 70% in a preoperative PFT was independently associated with a > 3.3-fold increase in Table 3 Demographics of patients and the clinical variables according to complications Continuous data are presented as mean ± SD BMI body mass index, BNP brain natriuretic peptide, BSA body surface area, CABG coronary artery bypass graft, EF ejection fraction, Ex. arteriopathy extracardiac arteriopathy, FEV 1.0 % percent predicted forced expiratory volume in 1 s, NYHA New York Heart Association, %VC percent predicted vital capacity, Recent AMI acute myocardial infarction within 3 months, Resp respiratory, STS Society of Thoracic Surgeons, %DL CO percent predicted diffusing capacity of lung for carbon monoxide *Fisher exact test or Mann-Whitney test Postoperative respiratory complications continue to affect patient morbidity and mortality, length of hospital stay, and overall resource utilization, despite advances in preoperative, intraoperative. and postoperative care [16][17][18]. Respiratory muscle dysfunction due to surgery can lead to a reduced vital capacity, tidal volume, and total lung capacity [19]. This could cause atelectasis in the basal lung segments and decrease the functional residual capacity, which affects pulmonary gas exchange properties by increasing ventilation/perfusion mismatches. Thus, DL CO might also decrease after surgery. Preoperative and postoperative chest physical therapy has significantly reduced the number of patients who develop atelectasis, but it does not significantly benefit patients who develop respiratory complications due to infection [20]. Improving the preoperative respiratory status of these patients via the fine adjustment of medication therapy and strict physiotherapeutic control seems important. Preoperative short-term pulmonary rehabilitation for such patients improves the pulmonary function and reduces the incidence of atelectasis, consolidation, and pneumothorax [16]. Preoperative physical therapy with inspiratory muscle training for at least 2 weeks reduced the incidence of postoperative pulmonary complications by 50% [18]. Although the present study did not uncover evidence as to whether surgical outcomes would improve with preoperative shortterm pulmonary rehabilitation, determining the correct timing of surgery is also important for avoiding respiratory decompensation. The present study is associated with several limitations. Although all data were prospectively recorded, this was a retrospective, single-institute study. The retrospective design is susceptible to various sources of bias, which might have not been identified or controlled. The preoperative PFTs were performed according to requests from clinicians, who were not blinded to the results of the PFT. Thus, the possibility that patient management might have been affected by the PFT results cannot be excluded.
In conclusion, the %DL CO seems to be a powerful predictor of postoperative complications. To the best of our knowledge, this is one of the few studies to assess whether DL CO is a potential risk factor for adverse outcomes of patients after cardiac surgery. Preoperative DL CO values might provide more accurate prognostic information about outcomes after cardiac surgery. Preoperative PFT findings might provide clinicians with more accurate risk profiles as well as additional prognostic information. Thus, pulmonary function testing, including measurement of DL CO , should be a routine component of preoperative evaluations.
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