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Copyright © 2015 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

Thoughts and Progress Changes in Spirometry After Left Ventricular Assist Device Implantation *Burhan Mohamedali, †Geetha Bhat, †Gardner Yost, and †Antone Tatooles *Department of Cardiology, Rush University; and †Division of Cardiology and Cardiothoracic Surgery, Advocate Christ Medical Center, Chicago, IL, USA Abstract: Left ventricular assist devices (LVADs) are increasingly being used as life-saving therapy in patients with end-stage heart failure. The changes in spirometry following LVAD implantation and subsequent unloading of the left ventricle and pulmonary circulation are unknown. In this study, we explored long-term changes in spirometry after LVAD placement. In this retrospective study, we compared baseline preoperative pulmonary function test (PFT) results to post-LVAD spirometric measurements. Our results indicated that pulmonary function tests were significantly reduced after LVAD placement (forced expiratory volume in one second [FEV1]: 1.9 vs.1.7, P = 0.016; forced vital capacity [FVC]: 2.61 vs. 2.38, P = 0.03; diffusing capacity of the lungs for carbon monoxide [DLCO]: 14.75 vs. 11.01, P = 0.01). Subgroup analysis revealed greater impairment in lung function in patients receiving HeartMate II (Thoratec, Pleasanton, CA, USA) LVADs compared with those receiving HeartWare (HeartWare, Framingham, MA, USA) devices. These unexpected findings may result from restriction of left anterior hemi-diaphragm; however, further prospective studies to validate our findings are warranted. Key Words: Pulmonary function tests—Left ventricular assist device— Spirometry—Mechanical assist device—Ventricular assist device—Thoracic surgery—Diffusing capacity of the lungs for carbon monoxide.

Left ventricular assist devices (LVADs) and orthotropic heart transplantation (OHT) are mainstays of therapy for advanced heart failure (ADHF). However, due to limited donor availability and the increased incidence of ADHF in the aging population, the use of LVADs has grown exponentially in the past decade. Stringent patient selection criteria are employed during the pre-LVAD implantation

screening process. Although numerous cardiovascular risk profiles are assessed during screening, the assessment of spirometry to evaluate future risk of adverse outcomes post-LVAD implantation is not well understood. Often, patients with ADHF are considered to have poor baseline spirometric measurements. These abnormal pulmonary function tests (PFTs) may be attributed to interstitial and alveolar edema, reactive fibrosis, previous pulmonary infarctions, pleural effusions, and decreased lung volumes with compressive atelectasis. These changes can cause a marked reduction in lung compliance, an increase in the work of breathing, and a redistribution of pulmonary blood flow from the bases to the apices of the lungs (1–6). Additionally, it is hypothesized that sternotomy can further perturb this delicate lung physiology leading to a restrictive lung pattern. The complex interplay between postoperative physiological changes related to cardiopulmonary bypass (CPB), mechanical changes resultant to sternotomy, surgical manipulation, and anesthesia may also contribute to postoperative decline in pulmonary function (7,8). Furthermore, direct pulmonary injury from cardioplegia and subsequent pulmonary endothelial cell damage may affect post-LVAD spirometry (9,10). Though functional capacity is often thought to improve post-LVAD implantation, and abnormal preoperative spirometry is considered “an unknown” risk to LVAD recipients, post-LVAD changes in PFT profiles are not well known. In this study, we sought to evaluate the changes in spirometry after LVAD placement.

Hypothesis Spirometric measurements will improve significantly from preoperative values following LVAD implantation.

PATIENTS AND METHODS doi:10.1111/aor.12507 Received November 2014; revised February 2015. Address correspondence and reprint requests to Dr. Burhan Mohamedali, Department of Cardiology, Rush University, 1725 West Harrison Street, Chicago, IL 60612, USA. E-mail: [email protected] Artificial Organs 2015, 39(12):1046–1068

In this retrospective, single-center, institutional review board-approved study, we examined a cohort of patients who had undergone LVAD placement between 2007 and 2013. Within this group, 24 patients underwent spirometry both before and

THOUGHTS AND PROGRESS TABLE 1. Baseline demographic, device type, and echocardiographic data for all patients (N = 24) Variable

Mean (SD) or n (%)

Age (years) Male sex African American Caucasian Smoker BMI (kg/m2) LVAD type: HeartMate II LVAD type: HeartWare Ischemic cardiomyopathy History of RV failure Hypertension Coronary artery disease Diabetes COPD CKD History of stroke LVEDD (cm) LVESD (cm) EF (%)

61 (±9) 16 (67%) 10 (42%) 12 (50%) 10 (42%) 30.2 (±5.7) 14 (58%) 10 (42%) 14 (58%) 9 (38%) 16 (67%) 14 (58%) 11 (46%) 7 (29%) 15 (63%) 4 (17%) 7.2 (±1.1) 6.5 (±1.4) 19 (±7)

COPD, chronic obstructive pulmonary disease; CKD, chronic kidney disease; LVEDD, left ventricular end diastolic dimension; LVESD, left ventricular end systolic dimension; EF, ejection fraction; RV, right ventricular; BMI, body mass index; LVAD, left ventricular assist device.

after LVAD placement. All study subjects were bridge to transplantation (BTT) patients who had undergone routine post-LVAD outpatient PFTs for heart transplant evaluation. In addition to baseline demographic information, data pertaining to indications, outcomes, and mortality were collected. Cardiac risk factors and admission echocardiographic data were analyzed. Pulmonary and systemic hemodynamic data prior to, and after LVAD placement were obtained. Admission laboratory parameters were also reviewed. Spirometric data, including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), FEV1/ FVC ratio, and diffusing capacity of the lungs for carbon monoxide (DLCO) measurements prior to and after LVAD placement were analyzed. Statistical analysis Data were analyzed using SPSS 19 statistical software package (IBM, Chicago, IL, USA). Continuous variables were summarized as mean ± standard deviation (SD). Shapiro–Wilk’s tests were used to assess distribution of the data arrays. Paired Student’s t-tests were used to assess differences in continuous variables between pre- and post-LVAD PFTs. Categorical variables were displayed as percentages and were compared using chi-square tests. RESULTS Twenty-four patients who had undergone pre- and post-LVAD PFTs were enrolled in this study. Base-

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line demographic features are summarized in Table 1. Our cohort comprised predominantly older, obese, male patients with a mean age of 61 years. Fifty percent of the patients were Caucasian, while 42% were African American. A majority of the patients had ischemic cardiomyopathy (58%), hypertension (67%), and chronic kidney disease (CKD) (63%). Fourteen (58%) patients were implanted with HeartMate II (HMII) (Thoratec, Pleasantville, CA, USA) LVADs, while the remaining 10 (42%) received HeartWare (HVAD) (HeartWare, Framingham, MA, USA) LVADs. Echocardiographic and hemodynamic data demonstrated a cohort with advanced stage heart failure. Mean left ventricular end-diastolic dimension was 7.2 cm and mean left ventricular end-systolic dimension was 6.5 cm. The mean ejection fraction (EF) was calculated at 19% (Table 1). Pulmonary capillary wedge pressure in this cohort was elevated at 24 mm Hg; mean cardiac index was 2.1 L/min/m2 and mean pulmonary vascular resistance (PVR) was 3.5 WU (Table 2). A trend toward improvement in hemodynamic parameters after LVAD implantation (median 387 days [interquartile range {IQR} 253– 558]) was observed, with statistically significantly improved pulmonary artery diastolic pressures (PADP), mean PA pressures (MPAP), cardiac index, and systemic vascular resistance (SVR) compared to baseline (Table 2). Mean body mass index (BMI) was not significantly changed at follow-up (30.2 ± 5.7 preLVAD vs. 31.05 ± 5.5 post-LVAD, P = 0.878). PFT results Pre-LVAD spirometric measurements were obtained at a median of 7.5 (IQR 19) days prior to LVAD implantation, while follow-up PFTs were obtained at a median duration of 302 (IQR 368) days TABLE 2. Hemodynamic data for all patients pre- and post-LVAD

Variable

Pre-LVAD mean (SD) or n (%)

Post-LVAD mean (SD) or n (%)

P value

CVP (mm Hg) PASP (mm Hg) PADP (mm Hg) PCWP (mm Hg) Cardiac index (L/m2) SVR (dynes·sec/cm5) PVR (Woods Units)

12 (±5) 56 (±16) 26 (±6) 24 (±8) 2.1 (±0.7) 1370 (±410) 3.5 (±2)

14 (±6) 50 (±13) 21 (±6) 21 (±9) 2.7 (±0.8) 953 (±306) 3.1 (±2.2)

0.31 0.15 0.005 0.045 0.018 0.02 0.36

LVAD, left ventricular assist device; CVP, central venous pressure; PASP, pulmonary artery systolic pressure; PADP, pulmonary artery diastolic pressure; PCWP, pulmonary capillary wedge pressure; SVR, systemic vascular resistance; PVR, pulmonary vascular resistance. Artif Organs, Vol. 39, No. 12, 2015

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THOUGHTS AND PROGRESS TABLE 3. Comparison of PFT testing parameters pre- and post-LVAD in all patients Pre-LVAD PFTs

FEV1 (L) FVC (L) FEV1/FVC DLCO

Post-LVAD PFTs

Mean

SD

Mean

SD

P value

1.937 2.608 72.57 14.75

0.73643 0.926 10.233 6.88

1.703 2.38 71.35 11.01

0.53 0.738 11.757 4.88

0.02 0.03 0.42 0.01

FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity, FEV1/FVC, ratio of FEV1 to FVC; DLCO, diffusing capacity of lungs for carbon monoxide.

post-LVAD placement. PFT data revealed that all FEV1, FVC, and DLCO were statistically significantly decreased on follow-up measurements compared with baseline pre-LVAD PFTs (FEV1: 1.9 vs. 1.7, P = 0.016; FVC: 2.61 vs. 2.38, P = 0.03; DLCO: 14.75 vs. 11.01, P = 0.01) (Table 3). Multivariate regression analysis to predict decrease in PFT did not achieve statistical significance. To evaluate the effect of pump type on the above results, a subgroup analysis was conducted. Subgroup analysis Data stratification by device type revealed that in HMII patients, both FEV1 (2.0 vs. 1.72, P = 0.04) and DLCO (16.92 vs. 11.78, P = 0.03) were statistically significantly decreased following LVAD placement, while FVC showed a strong statistical trend toward worsening after surgery (2.66 vs. 2.40, P = 0.09). Although a similar trend of worsening PFT parameters was seen in HVAD patients, none of the changes were statistically significant (Table 4). DISCUSSION While spirometric measurements can decline transiently after cardiothoracic surgery (11–14), changes in spirometry have not been quantified in patients undergoing LVAD placement. In this study, we sought to evaluate changes in PFTs in patients under-

going LVAD placement. The results of our study were largely unexpected. We demonstrate a universal decrease in average post-LVAD spirometry in all groups analyzed. Our hemodynamic data revealed that there was a statistically significant improvement in post-LVAD hemodynamic parameters. With unloading of the left ventricle and reduction in thoracic congestion, PFTs were expected to significantly improve after LVAD placement. The pattern of decreased PFT in patients undergoing thoracotomy for coronary artery bypass graft (CABG) or valvular surgery is well established (15,16). Immediate postoperative decrease in pulmonary capacity is thought to be greatly influenced by atelectasis, significant reduction in respiratory muscle performance, and pain from surgical trauma (17,18). DLCO is a surrogate marker for pulmonary function and is often reduced in heart failure patients due to thickening of the alveolar-capillary membrane with subsequent impairment of gas exchange (1). Though it remains unclear whether pulmonary function improves over time, much of the literature is focused on the improvement of baseline PFT levels at approximately 3 months after cardiac surgery (13,19–21). A number of studies have demonstrated prevalence of abnormal spirometry in heart failure patients (5,6). Left ventricular dysfunction in such patients is thought to result in pulmonary edema, altered lung

TABLE 4. Subgroup analysis for device type Pre-LVAD PFTs Variable HeartMate II (n = 14) HeartWare (n = 10)

FEV1 (L) FVC (L) DLCO FEV1 (L) FVC (L) DLCO

Post-LVAD PFTs

Mean

SD

Mean

SD

P value

2.00 2.66 16.92 1.86 2.54 11.34

0.80 0.97 7.88 0.68 0.91 2.96

1.72 2.40 11.78 1.68 2.36 9.80

0.58 0.85 5.94 0.49 0.60 2.44

0.04 0.09 0.03 0.23 0.25 0.15

FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; FEV1/FVC, ratio of FEV1 to FVC; DLCO, diffusing capacity of lungs for carbon monoxide; LVAD, left ventricular assist device; PFT, pulmonary function test. Artif Organs, Vol. 39, No. 12, 2015

THOUGHTS AND PROGRESS compliance, enlarged cardiac dimensions, altered receptor function, neurohormonal changes, and elevated PVR (2,4,22–25). Despite poorly understood multifactorial etiology of spirometric abnormalities in such patients, the prognostic implications of spirometric changes in heart failure patients have been well reported. Olson et al. showed that FVC, FEV1, and DLCO can be used to predict outcomes in specific heart failure patients (6). Others have shown similar findings (26,27). It is thought that posttransplantation elimination of cardiomegaly, decrease in left ventricular end-diastolic pressure, decompression of the pulmonary circulation, and reverse remodeling of PVR may partly explain the improvement in PFT in heart transplant recipients (28–30). Using the same logic, we expected at least some improvement in pulmonary function after LVAD therapy. The improvement in spirometry back to baseline in patients undergoing thoracotomy for CABG or valvular surgeries at around 3 months is an interesting finding as it is not reflected in our cohort of patients receiving an LVAD for advance heart failure therapies (13,19). Our median duration for follow-up PFT was 302 days, well beyond the 3 month mark reported for postthoracotomy patients. The phenomenon of persistent decline in PFT after LVAD implantation has appeared in a previous case report. Arena et al. reported a patient with significant, persistent decline in pulmonary function after a Thoratec HeartMate XVE LVAD placement. Fluoroscopic evaluation confirmed a two-interspace decrease in lung excursion from a restricted diaphragm without any evidence of diaphragmatic paralysis (31). Although it is plausible that a restricted left hemidiaphragm may cause a decline in baseline PFTs after implantation, data to assess whether such diaphragmatic restriction causes reduction in spirometry are absent. Subgroup analysis by device type Due to the retrospective nature of our study, we could not validate the findings of Arena et al. in our patients. However, because our cohort comprised both the relatively bulkier HMII device and the smaller HVAD, we investigated potential differences in PFTs between groups with either pump. Our data revealed that reduction in spirometric measurements in the cohort as a whole was mainly driven by the HMII group (Table 4). Although a decline from index PFTs was also seen in the HVAD group, these differences were not statistically significant. Accordingly, though further prospective validation may be required, we concluded that the results reported in

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XVE patients may be extrapolated to our HMII patients, where a restriction of the left anterior hemidiaphragm by the relatively larger HMII device may play a role in reduced spirometric markers. Several differences in surgical implantation techniques between the two pumps may also contribute to this trend. Implantation of the HMII LVAD requires resection of the left anterior hemidiaphragm which may lead to partial postoperative diaphragmatic paralysis. Typical HMII implantation requires more extensive dissection than implantation of the HVAD, likely leading to greater postoperative fibrotic tissue formation. CONCLUSION This is the first study to evaluate changes in spirometry after left ventricular assist device placement. We demonstrate that in our cohort of 24 patients, forced expiratory volume in one second, forced vital capacity, and diffusing capacity of the lungs for carbon monoxide are statistically significantly decreased post-LVAD implantation. The implications of such findings are unknown. Nevertheless, this novel study, in the setting of conventional LVADs, depicts an interesting trend that has not been previously reported. Subgroup analysis revealed a signal toward reduction of pulmonary function tests in patients with HeartMate II devices. Our study is hypothesis generating and further prospective studies to validate our findings are warranted. Limitations This is a retrospective study and is subject to limitations inherent within the study design. Our sample size was small, and only patients listed for BTT were enrolled. Because device selection was not random, selection bias may have influenced comparison between the HMII and HVAD devices. The large size of the HMII device can make implantation challenging in smaller patients. Surgical preference for the HVAD device in these individuals may have driven a selection bias. Post-LVAD patients who underwent repeat PFTs did so for unclear reasons, and undetermined underlying confounders that led to the repeating of study may have not been accounted for. We did not have any follow-up histological or imaging data to confirm worsening lung parameters that may correlate to worsening spirometric data. Despite these limitations, we believe that our study is hypothesis generating and lays out the groundwork for future investigations. Artif Organs, Vol. 39, No. 12, 2015

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THOUGHTS AND PROGRESS

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Changes in Spirometry After Left Ventricular Assist Device Implantation.

Left ventricular assist devices (LVADs) are increasingly being used as life-saving therapy in patients with end-stage heart failure. The changes in sp...
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