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Pulmonary Hypertension: A Contraindication for Lung Volume Reduction Surgery?
Journal Pre-proof Pulmonary Hypertension: A Contraindication for Lung Volume Reduction Surgery? Sowmyanarayanan Thuppal, MD PhD, Traves Crabtree, MD, Stephen Markwell, MA, Joni Colle, RN BSN, Theresa Boley, RN, MSN, Blaine Manning, MD, Nasaraiah Nallamothu, MD, Stephen Hazelrigg, MD PII:
S0003-4975(19)31578-4
DOI:
https://doi.org/10.1016/j.athoracsur.2019.09.023
Reference:
ATS 33154
To appear in:
The Annals of Thoracic Surgery
Received Date: 4 April 2019 Revised Date:
26 August 2019
Accepted Date: 6 September 2019
Please cite this article as: Thuppal S, Crabtree T, Markwell S, Colle J, Boley T, Manning B, Nallamothu N, Hazelrigg S, Pulmonary Hypertension: A Contraindication for Lung Volume Reduction Surgery?, The Annals of Thoracic Surgery (2019), doi: https://doi.org/10.1016/j.athoracsur.2019.09.023. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 by The Society of Thoracic Surgeons
Pulmonary Hypertension: A Contraindication for Lung Volume Reduction Surgery? Running Head: LVRS in Pulmonary Hypertension
Sowmyanarayanan Thuppal MD PhD1, Traves Crabtree MD1, Stephen Markwell MA1, Joni Colle RN BSN1, Theresa Boley RN, MSN1, Blaine Manning MD1, Nasaraiah Nallamothu MD1, Stephen Hazelrigg MD1
1
Division of Cardiothoracic Surgery, Department of Surgery, Southern Illinois University School of
Medicine, Springfield, IL 62704
Word Count: 3417 words
Corresponding Author (request for reprints and correspondence): Stephen Hazelrigg, MD 701 N. 1st St Springfield, IL 62794-9679 E-mail: [email protected]
Abstract Background: Historically, pulmonary hypertension (PH) is considered as one of the contraindications for lung volume reduction surgery (LVRS). Newer studies have shown that LVRS is successful in select emphysema patients with PH. Methods: In-hospital and one-year functional and quality of life (QOL) outcomes were studied in patients with PH post-LVRS. PH was defined as pulmonary artery pressure (PAP) > 35 mmHg by right heart catheterization (RHC) where available or else > 35 mmHg by ECHO. Results: Of 124 patients who underwent LVRS, 56 (45%) had PH (mean PAP: 41 mmHg) with 48 mildto-moderate and 8 having severe PH. In-hospital outcomes were similar between patients with and without PH: hours of artificial ventilation (1.8 vs 0.06, p-value-0.882), days in intensive care (4 vs 6, pvalue-0.263), prolonged air leak (12% vs 19%, p-value-0.402), and days of hospital stay (13 vs 16, pvalue-0.072). Lung function improved significantly at one-year follow-up in patients with PH: FEV1% (26 vs 38, p-value-0. 001), FVC% (62 vs 90, p-value-0. 001), RV% (224 vs 174, p-value-0. 001), and DLCO% (36 vs 43, p-value-0. 001), 6MWD test (1104 vs 1232, p-value-0.001), and QOL utility scores (0.67 vs 0.77, p-value-0. 001). There were no differences in in-hospital, baseline, and follow-up functional and QOL outcomes between patients with and without PH. Conclusions: In this small single institutional cohort, patients undergoing LVRS for emphysema with PH had similar outcomes to that of patients without PH. LVRS may be a potential option for select emphysema patients with PH. (Word Count- 240 words)
Lung Volume Reduction Surgery is the preferred treatment for appropriately selected patients with severe emphysema. The National Emphysema Treatment Trial (NETT) concluded that LVRS provides a survival advantage for both predominantly upper-lobe emphysema and patients with low exercise capacity (1). In 2003, the Centers for Medicare and Medicaid Services (CMS) issued National Coverage Determination that provides for Medicare coverage for LVRS (2). Memorial Medical Center (MMC) at Springfield Illinois in conjunction with Southern Illinois University School of Medicine is one of the centers for excellence in LVRS and is one of the first medical centers in Illinois to be accredited by the Joint commission for performing LVRS in the year 2006 (3). Based on the inclusion/exclusion criteria suggested by the joint commission, patients are screened for eligibility to undergo LVRS (4). One of the exclusion criteria recommended by the joint commission is pulmonary hypertension (PH) defined as Peak Systolic Pulmonary Artery Pressure (PAP) ≥ 45 mm Hg or (Denver criterion: ≥ 50 mm Hg) or mean PAP ≥ 35 mm Hg (Denver criterion: ≥ 38 mm Hg). Right heart catheterization (RHC) may be required to rule out pulmonary hypertension if peak systolic PAP on echocardiogram (ECHO) is ≥ 45 mm Hg (4) (LVRS Inclusion and Exclusion Criteria-Supplemental Material). However recent studies have shown that patients undergoing LVRS for emphysema with PH, have improved dyspnea and lung function, along with improvement in pulmonary hemodynamics and PH may not be a contraindication in select emphysema patients (5-10). Surgeons generally prefer RHC instead of ECHO for estimating PAP but it is a more invasive test. Studies have shown that ECHO estimates of PAP correlate very weakly with RHC and the sensitivity and specificity of ECHO are poorer (11, 12). Effect of PH on the outcomes of LVRS in patients with COPD have been studied and the results are inconclusive. The objective of this retrospective data analysis was to study the baseline demographic characteristics, and in-hospital and one-year follow-up clinical and QOL outcomes in patients with and without preexisting pulmonary hypertension. A survey of LVRS surgeons was conducted to understand their perceptions about PH as an exclusion criteria for LVRS.
Patients and Methods Data was collected from all eligible patients who consented and were enrolled in the cardiothoracic surgery database and underwent LVRS at MMC between 2006 and 2016. The study was approved by the Springfield Committee for Research Involving Human Subject, Southern Illinois University School of Medicine. Patients were screened based on the computed tomography (CT) scans and pulmonary function tests. If the patient had a heterogenous hyperinflation then the patients underwent a complete evaluation. Most LVRS patients were older and not eligible for lung transplant. Exclusions for LVRS were based on the NETT trial recommendations ((LVRS Inclusion and Exclusion Criteria-Supplemental Material). Eligible patients were evaluated and discussed in a multi-disciplinary conference prior to surgery. All surgeries were done bilaterally with the intent of removing roughly 30% of the diseased lobe using buttresses for all staple lines. Baseline demographic information including age, gender, race/ethnicity, smoking status, use of supplemental oxygen and body mass index (BMI in kg/m2) were collected. Post-surgery in-hospital outcomes including duration of ventilator use in hours, number of days of chest tube drainage postsurgery, proportion of patients experiencing prolonged air leak (defined as air leak ≥ 14 days) postsurgery, and number of days of ICU stay and in-hospital stay post-surgery were collected and compared between patients with and without PH. Pulmonary function measures including forced expiratory volume (FEV), residual volume (RV), forced vital capacity (FVC), total lung capacity (TLC), diffusing capacity of lungs for carbon monoxide (DLCO), and six-minute walk distance test (6MWD) were collected at baseline pre-surgery and one year post-surgery. Change in lung function at one year follow-up from baseline and change in lung function between patients with and without PH was measured and compared. Quality of life was measured using EQ-5D-3L questionnaires and the mean utility scores (13, 14) were calculated and compared between baseline and one-year follow-up and between patients with and without PH.
Pulmonary artery pressure (PAP) was measured in all patients at baseline. But follow-up ECHO/RHC measurements were available only in 31 patients and the median duration for repeat ECHO/RHC measurement was 82 days (IQR: 12-461 days). If the mean systolic PAP measured by RHC was greater than 35 mmHg then the patient was considered to have PH. If RHC was not performed, then if the right ventricular systolic pressure (RVSP) measured by ECHO was greater than 35 mmHg then the patient was considered to have PH. If patient had both RHC and ECHO measured then PH was assessed based on RHC value. Any patient with a PAP between 35 mmHg and 45 mmHg were considered to have mild-to-moderate PH while those with PAP ≥ 45 mmHg were considered to have severe PH. A questionnaire including four ‘Yes’ or ‘No’ questions and an open-ended question was administered to cardiothoracic surgeons by email or phone from Joint commission accredited LVRS centers and United Network for Organ Sharing (UNOS) accredited organ transplant centers to understand surgeon’s opinion about the use of pulmonary artery pressure as an exclusion criteria for LVRS (Table 1). Continuous variables are reported as mean (standard deviation) while categorical variables are presented as frequency (%). Wilcoxon rank-sum tests were used to compare groups on continuous measures, while Wilcoxon signed-rank tests were employed to assess changes from baseline to follow-up. Chi-squared tests of independence were used to test for group differences on categorical variables. All statistical analyses were performed using SAS v9.4 (SAS Institute Inc., Cary, NC, USA).
Results Data was collected from 124 patients who underwent LVRS for emphysema. Of which, 56 (45%) patients had elevated PAP (mean (SD) PAP - 41 (5) mm HG) while the remaining 68 (55%) did not have PH (PAP- 28 (6) mm Hg) prior to surgery. Forty-eight patients had mild-to-moderate PH while 8 had severe PH. The mean (SD) age of all participants was 66 (8) years, 60% were men, 98% were nonHispanic White, with a mean (SD) BMI of 25 (5) kg/m2. There were no statistically significant differences in baseline characteristics between participants with and without pulmonary hypertension (Table 2).
There were no significant differences in the post-surgery in-hospital clinical outcomes between patients with and without PH including duration of artificial ventilation (1.8 vs 0.1, p-value: 0.882), number of days in intensive care unit (4 vs 6, p-value: 0.263), proportion of patients with prolonged air leak (12 vs 19, p-value: 0.402), and number of days of hospital stay (13 vs 16, p-value: 0.072). Duration of chest tube drainage in days was significantly lower in patients with PH compared to patients without PH (11 vs 16 days, p-0.033) (Table 3). There were no significant bleeding issues. In patients with PH, there was a significant improvement in lung function parameters from baseline to one-year follow-up post LVRS: FEV1% (26 vs 38, p-value: <0.001), FVC% (62 vs 90, pvalue: <0.001), RV% (224 vs 174, p-value: <0.001), and DLCO% (36 vs 43, p-value: <0.001), 6MWD test (1104 vs 1232, p-value: 0.001), and QOL utility scores (0.67 vs 0.77, p-value: <0.001) (Figure 1). Similar improvements were seen in patients without PH and the magnitude (% change) of improvement at one-year follow-up from baseline was similar between patients with and without PH for FEV1%, FVC%, FEV1/FVC, TLC, RV and DLCO measures, 6MWD test, and QOL utility scores (Table 4). Clinical and QOL outcomes at one-year follow-up were available only for 96 patients. Of the remaining 28 patients, 11 patients died (without PH-5, with PH-6), 17 were lost to follow-up (without PH-9, with PH-8). Of the 11 deaths 6 were in-hospital deaths (respiratory failure-5, gastrointestinal complications-1) while the remaining five were within one-year post discharge (respiratory failure-3, unknown-2). Follow-up ECHO/RHC were available only in 31 patients and the median duration for repeat ECHO/RHC measurement was 82 days (IQR: 12-461 days). Of the 31 patients with follow-up ECHO/RHC, 14 had PH at baseline and 9 of these still had elevated PAP at follow-up, while 17 did not have PH at baseline but 5 of these subsequently developed PH post-LVRS. No significant changes in PAP from baseline to follow-up were noted in those with PH at baseline (mean mm Hg, 41 vs. 39, p=0.519) or in those without PH at baseline (mean mm Hg, 29 vs. 34, p=0.376). Among the 56 patients who had PH, 27 (48%) patients were diagnosed PH solely based on ECHO results, while 23 (41%) were diagnosed using RHC results only. The remaining six (11%) had ECHO followed by RHC. There were no differences in the in-hospital clinical outcomes or changes in
functional measures and QOL at one-year post-surgery in the ECHO only group vs RHC only group (Supplemental Tables 1 and 2). Of the 111 questionnaires sent to LVRS surgeons at six Joint Commission accredited LVRS centers and 48 questionnaires sent to UNOS accredited lung transplant centers, 51 (46%) of the LVRS surgeons responded. Of those responders 50% of the surgeons believed that LVRS should not be denied solely based on PH. Approximately 71% and 42% believed elevated PAP is not a predictor of intraoperative and in-hospital/30 day outcomes respectively. Only 22% believed that elevated PAP will have an effect on functional outcomes post LVRS. Some of the surgeons (16%) believed that the clinical outcomes depend on the severity of PH and hence recommended studying clinical outcomes as a function of PH.
Comment Clinical, functional and QOL outcomes improved significantly in patients with PH and were similar to patients without PH at one-year follow-up post-LVRS. The results of this study demonstrates that at one-year post surgery, patients with and without PH who underwent LVRS for emphysema had improved lung function with improved QOL. Number of deaths at one-year follow-up were similar in both the groups. All patients had a successful thoracoscopic surgery and none of them required a conversion to thoracotomy. Though studies have demonstrated better clinical outcomes without elevation in PH post -LVRS (5-10), guidelines still suggests that PH is a contraindication for LVRS (4). The results of this study has also demonstrated better clinical and QOL outcomes during in-hospital stay and at oneyear post-surgery in patients with mild to moderate PH. Clinical, functional and QOL outcomes were comparable between patients diagnosed with PH by ECHO only or by RHC only. In our study RHC was performed in patients for whom ECHO measurements could not be obtained due to hyperinflation of the lungs. Poor visualization of the heart and difficulty obtaining clean signals are two important technical reasons for not considering ECHO in patients with hyperinflation and hence ECHO measurements not recommended for diagnosing PH (11, 12). RHC is an invasive procedure and may not be well tolerated in patients with severe emphysema who are generally older and sicker. Hence in our center RHC is performed only if it is difficult to estimate PAP by ECHO and if the patient has other hemodynamic complications requiring an RHC. Not having RHC in all patients is one of the limitations of this study. However, the results shows that patients with ECHO only and RHC only measurements have similar clinical, functional and quality of outcomes. To the best of our knowledge this study is the first to look at one-year clinical outcomes along with in-hospital post-surgery outcomes, functional and QOL outcomes in patients with PH undergoing LVRS for emphysema. Likewise, to our knowledge this is the first study to look at the provider’s perception about using PH as a selection criteria for LVRS. Most of the responders believed that PH should not be a sole criteria for denying LVRS and some believed that severity of PH should be taken into account. One of the limitations is that repeat ECHO/RHC was available only in few of the study patients
(n=31). However clinical, functional and QOL outcomes at one-year follow-up were similar between patients who had repeat ECHO/RHC compared to those who did not have a repeat ECHO/RHC (data not shown). In conclusion, PH within this cohort did not seem to impact the outcomes in patients with emphysema undergoing LVRS. Lung volume reduction surgery may be a potential option for select emphysema patients with PH.
References: 1.
National Emphysema Treatment Trial Research Group. Rationale and design of the national
emphysema treatment trial: A prospective randomized trial of lung volume reduction surgery. . Chest 1999;116(6):1750-1761. 2.
Ginsburg ME, Thomashow BM, Yip CK et al. Lung volume reduction surgery using the nett
selection criteria. Ann Thorac Surg 2011;91(5):1556-1560; discussion 1561. 3.
2018 Lung volume reduction surgery. Available at
https://www.memorialmedical.com/services/lung-volume-reduction-surgery. Accessed 2018 10/26/2018. 4.
2003 Lung volume reduction surgery certification. Available at
https://www.jointcommission.org/assets/1/18/LVRS_final_addendum%20.pdf. Accessed 2018 10/25/2018. 5.
Eberhardt R, Gerovasili V, Kontogianni K et al. Endoscopic lung volume reduction with
endobronchial valves in patients with severe emphysema and established pulmonary hypertension. Respiration 2015;89(1):41-48. 6.
Opitz I, Ulrich S. Pulmonary hypertension in chronic obstructive pulmonary disease and
emphysema patients: Prevalence, therapeutic options and pulmonary circulatory effects of lung volume reduction surgery. J Thorac Dis 2018;10(Suppl 23):S2763-S2774. 7.
Pizarro C, Schueler R, Hammerstingl C, Tuleta I, Nickenig G, Skowasch D. Impact of endoscopic
lung volume reduction on right ventricular myocardial function. PLoS One 2015;10(4):e0121377. 8.
Thurnheer R, Bingisser R, Stammberger U et al. Effect of lung volume reduction surgery on
pulmonary hemodynamics in severe pulmonary emphysema. Eur J Cardiothorac Surg 1998;13(3):253258. 9.
Wei B, D'Amico T, Samad Z, Hasan R, Berry MF. The impact of pulmonary hypertension on
morbidity and mortality following major lung resection. Eur J Cardiothorac Surg 2014;45(6):1028-1033. 10.
Caviezel C, Aruldas C, Franzen D et al. Lung volume reduction surgery in selected patients with
emphysema and pulmonary hypertension. Eur J Cardiothorac Surg 2018;54(3):565-571.
11.
Fisher MR, Criner GJ, Fishman AP et al. Estimating pulmonary artery pressures by
echocardiography in patients with emphysema. Eur Respir J 2007;30(5):914-921. 12.
Janda S, Shahidi N, Gin K, Swiston J. Diagnostic accuracy of echocardiography for pulmonary
hypertension: A systematic review and meta-analysis. Heart 2011;97(8):612-622. 13.
Brazier J, Roberts J, Tsuchiya A, Busschbach J. A comparison of the eq-5d and sf-6d across
seven patient groups. Health Econ 2004;13(9):873-884. 14.
Dolan P. Modeling valuations for euroqol health states. Med Care 1997;35(11):1095-1108.
Table 1. Questionnaire to understand surgeons opinion about the use of pulmonary artery pressure as an exclusion criteria for LVRS S. no
Question
1
In your opinion, is it justifiable to exclude an otherwise appropriate LVRS candidate from surgery based solely on elevated, preoperative pulmonary artery pressure?
2
In your opinion, is preoperative pulmonary artery pressure a predictor of intra-operative LVRS complications?
3
In your opinion, is preoperative pulmonary artery pressure a predictor of post-operative (in hospital/30 day) outcome in LVRS patients?
4
In your opinion, is preoperative pulmonary artery pressure a predictor of post-operative functional outcome in LVRS patients?
5
Other Remarks
Yes
No
Table 2. Demographic details in patients who underwent lung volume reduction surgery for emphysema with/without pulmonary hypertension
Without PH at baseline (n=68)
With PH at baseline (n=56)
p-value
Age (years), mean (SD)
65 (7.8)
67 (7.8)
0.230
BMI (kg/m2), mean (SD)
24.3 (4.4)
25.2 (4.3)
0.281
Male, n (%)
40 (59%)
35 (63%)
0.816
Race: non-Hispanic White, n (%)
68 (100%)
52 (95%)
0.087
Home oxygen use (≥ 3L/min), n (%)
23 (34%)
18 (32%)
0.995
Smoking ≥ 60 pack-years, n (%)
42 (63%)
33 (60%)
0.907
Pulmonary artery pressure, mean (SD)
28.4 (5.7)
41.3 (5.1)
0. 001
Table 3. In-hospital clinical outcomes in patients who underwent lung volume reduction surgery for emphysema with and without pulmonary hypertension at baseline Without PH at baseline (n=68)
With PH at baseline (n=56)
p-value
Ventilator duration (hours)
0.1 (0.4)
1.8 (13.1)
0.882
Chest tube duration (days)
15.9 (18.8)
10.6 (9.4)
0.033
Post-op intensive care unit stay (days)
6.2 (11.7)
4.1 (6.2)
0.263
Post-op hospital stay (days)
15.7 (13.4)
12.8 (10.0)
0.072
19 (28%)
12 (21%)
0.403
Prolonged Air leak (≥ 14 days), n (%)
Table 4. Percent change from baseline to one-year follow-up in functional and QOL outcomes in patients who underwent lung volume reduction surgery for emphysema with and without pulmonary hypertension Without PH at baseline (n=68)
With PH at baseline (n=56)
p- value
∆ FEV1 % predicted
35.2 (38.9)
50.3 (56.0)
0.293
∆ FVC % predicted
38.7 (42.6)
55.4 (55.2)
0.079
∆ FEV1/FVC % predicted
-0.1 (20.2)
3.7 (25.4)
0.778
∆ TLC % predicted
-3.2 (14.0)
-0.3 (13.8)
0.225
∆ RV % predicted
-23.1 (19.7)
-19.2 (21.7)
0.319
∆ DLCO % predicted
12.6 (24.2)
21.9 (33.0)
0.157
∆ 6MWD
7.0 (33.3)
12.4 (22.0)
0.300
∆ EQ5Da
0.13 (0.23)
0.08 (0.15)
0.542
DLCO- Diffusing capacity of the lungs for carbon monoxide, ECHO-Echocardiogram, EQ5D- EuroQol five dimension quality of life questionnaire, FEV- forced expiratory volume, FVC- forced vital capacity, ICU-intensive care unit, PAP- pulmonary arterial pressure, PHpulmonary hypertension, RHC- right heart catheterization, RV- residual volume, 6MWD- six minute walk distance test; a
Absolute change in quality of life utility scores
Figure legend Figure 1. Functional and quality of life outcomes in patients who underwent lung volume reduction surgery for emphysema with and without pulmonary hypertension.
S0003-4975(19)31578-4
DOI:
https://doi.org/10.1016/j.athoracsur.2019.09.023
Reference:
ATS 33154
To appear in:
The Annals of Thoracic Surgery
Received Date: 4 April 2019 Revised Date:
26 August 2019
Accepted Date: 6 September 2019
Please cite this article as: Thuppal S, Crabtree T, Markwell S, Colle J, Boley T, Manning B, Nallamothu N, Hazelrigg S, Pulmonary Hypertension: A Contraindication for Lung Volume Reduction Surgery?, The Annals of Thoracic Surgery (2019), doi: https://doi.org/10.1016/j.athoracsur.2019.09.023. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 by The Society of Thoracic Surgeons
Pulmonary Hypertension: A Contraindication for Lung Volume Reduction Surgery? Running Head: LVRS in Pulmonary Hypertension
Sowmyanarayanan Thuppal MD PhD1, Traves Crabtree MD1, Stephen Markwell MA1, Joni Colle RN BSN1, Theresa Boley RN, MSN1, Blaine Manning MD1, Nasaraiah Nallamothu MD1, Stephen Hazelrigg MD1
1
Division of Cardiothoracic Surgery, Department of Surgery, Southern Illinois University School of
Medicine, Springfield, IL 62704
Word Count: 3417 words
Corresponding Author (request for reprints and correspondence): Stephen Hazelrigg, MD 701 N. 1st St Springfield, IL 62794-9679 E-mail: [email protected]
Abstract Background: Historically, pulmonary hypertension (PH) is considered as one of the contraindications for lung volume reduction surgery (LVRS). Newer studies have shown that LVRS is successful in select emphysema patients with PH. Methods: In-hospital and one-year functional and quality of life (QOL) outcomes were studied in patients with PH post-LVRS. PH was defined as pulmonary artery pressure (PAP) > 35 mmHg by right heart catheterization (RHC) where available or else > 35 mmHg by ECHO. Results: Of 124 patients who underwent LVRS, 56 (45%) had PH (mean PAP: 41 mmHg) with 48 mildto-moderate and 8 having severe PH. In-hospital outcomes were similar between patients with and without PH: hours of artificial ventilation (1.8 vs 0.06, p-value-0.882), days in intensive care (4 vs 6, pvalue-0.263), prolonged air leak (12% vs 19%, p-value-0.402), and days of hospital stay (13 vs 16, pvalue-0.072). Lung function improved significantly at one-year follow-up in patients with PH: FEV1% (26 vs 38, p-value-0. 001), FVC% (62 vs 90, p-value-0. 001), RV% (224 vs 174, p-value-0. 001), and DLCO% (36 vs 43, p-value-0. 001), 6MWD test (1104 vs 1232, p-value-0.001), and QOL utility scores (0.67 vs 0.77, p-value-0. 001). There were no differences in in-hospital, baseline, and follow-up functional and QOL outcomes between patients with and without PH. Conclusions: In this small single institutional cohort, patients undergoing LVRS for emphysema with PH had similar outcomes to that of patients without PH. LVRS may be a potential option for select emphysema patients with PH. (Word Count- 240 words)
Lung Volume Reduction Surgery is the preferred treatment for appropriately selected patients with severe emphysema. The National Emphysema Treatment Trial (NETT) concluded that LVRS provides a survival advantage for both predominantly upper-lobe emphysema and patients with low exercise capacity (1). In 2003, the Centers for Medicare and Medicaid Services (CMS) issued National Coverage Determination that provides for Medicare coverage for LVRS (2). Memorial Medical Center (MMC) at Springfield Illinois in conjunction with Southern Illinois University School of Medicine is one of the centers for excellence in LVRS and is one of the first medical centers in Illinois to be accredited by the Joint commission for performing LVRS in the year 2006 (3). Based on the inclusion/exclusion criteria suggested by the joint commission, patients are screened for eligibility to undergo LVRS (4). One of the exclusion criteria recommended by the joint commission is pulmonary hypertension (PH) defined as Peak Systolic Pulmonary Artery Pressure (PAP) ≥ 45 mm Hg or (Denver criterion: ≥ 50 mm Hg) or mean PAP ≥ 35 mm Hg (Denver criterion: ≥ 38 mm Hg). Right heart catheterization (RHC) may be required to rule out pulmonary hypertension if peak systolic PAP on echocardiogram (ECHO) is ≥ 45 mm Hg (4) (LVRS Inclusion and Exclusion Criteria-Supplemental Material). However recent studies have shown that patients undergoing LVRS for emphysema with PH, have improved dyspnea and lung function, along with improvement in pulmonary hemodynamics and PH may not be a contraindication in select emphysema patients (5-10). Surgeons generally prefer RHC instead of ECHO for estimating PAP but it is a more invasive test. Studies have shown that ECHO estimates of PAP correlate very weakly with RHC and the sensitivity and specificity of ECHO are poorer (11, 12). Effect of PH on the outcomes of LVRS in patients with COPD have been studied and the results are inconclusive. The objective of this retrospective data analysis was to study the baseline demographic characteristics, and in-hospital and one-year follow-up clinical and QOL outcomes in patients with and without preexisting pulmonary hypertension. A survey of LVRS surgeons was conducted to understand their perceptions about PH as an exclusion criteria for LVRS.
Patients and Methods Data was collected from all eligible patients who consented and were enrolled in the cardiothoracic surgery database and underwent LVRS at MMC between 2006 and 2016. The study was approved by the Springfield Committee for Research Involving Human Subject, Southern Illinois University School of Medicine. Patients were screened based on the computed tomography (CT) scans and pulmonary function tests. If the patient had a heterogenous hyperinflation then the patients underwent a complete evaluation. Most LVRS patients were older and not eligible for lung transplant. Exclusions for LVRS were based on the NETT trial recommendations ((LVRS Inclusion and Exclusion Criteria-Supplemental Material). Eligible patients were evaluated and discussed in a multi-disciplinary conference prior to surgery. All surgeries were done bilaterally with the intent of removing roughly 30% of the diseased lobe using buttresses for all staple lines. Baseline demographic information including age, gender, race/ethnicity, smoking status, use of supplemental oxygen and body mass index (BMI in kg/m2) were collected. Post-surgery in-hospital outcomes including duration of ventilator use in hours, number of days of chest tube drainage postsurgery, proportion of patients experiencing prolonged air leak (defined as air leak ≥ 14 days) postsurgery, and number of days of ICU stay and in-hospital stay post-surgery were collected and compared between patients with and without PH. Pulmonary function measures including forced expiratory volume (FEV), residual volume (RV), forced vital capacity (FVC), total lung capacity (TLC), diffusing capacity of lungs for carbon monoxide (DLCO), and six-minute walk distance test (6MWD) were collected at baseline pre-surgery and one year post-surgery. Change in lung function at one year follow-up from baseline and change in lung function between patients with and without PH was measured and compared. Quality of life was measured using EQ-5D-3L questionnaires and the mean utility scores (13, 14) were calculated and compared between baseline and one-year follow-up and between patients with and without PH.
Pulmonary artery pressure (PAP) was measured in all patients at baseline. But follow-up ECHO/RHC measurements were available only in 31 patients and the median duration for repeat ECHO/RHC measurement was 82 days (IQR: 12-461 days). If the mean systolic PAP measured by RHC was greater than 35 mmHg then the patient was considered to have PH. If RHC was not performed, then if the right ventricular systolic pressure (RVSP) measured by ECHO was greater than 35 mmHg then the patient was considered to have PH. If patient had both RHC and ECHO measured then PH was assessed based on RHC value. Any patient with a PAP between 35 mmHg and 45 mmHg were considered to have mild-to-moderate PH while those with PAP ≥ 45 mmHg were considered to have severe PH. A questionnaire including four ‘Yes’ or ‘No’ questions and an open-ended question was administered to cardiothoracic surgeons by email or phone from Joint commission accredited LVRS centers and United Network for Organ Sharing (UNOS) accredited organ transplant centers to understand surgeon’s opinion about the use of pulmonary artery pressure as an exclusion criteria for LVRS (Table 1). Continuous variables are reported as mean (standard deviation) while categorical variables are presented as frequency (%). Wilcoxon rank-sum tests were used to compare groups on continuous measures, while Wilcoxon signed-rank tests were employed to assess changes from baseline to follow-up. Chi-squared tests of independence were used to test for group differences on categorical variables. All statistical analyses were performed using SAS v9.4 (SAS Institute Inc., Cary, NC, USA).
Results Data was collected from 124 patients who underwent LVRS for emphysema. Of which, 56 (45%) patients had elevated PAP (mean (SD) PAP - 41 (5) mm HG) while the remaining 68 (55%) did not have PH (PAP- 28 (6) mm Hg) prior to surgery. Forty-eight patients had mild-to-moderate PH while 8 had severe PH. The mean (SD) age of all participants was 66 (8) years, 60% were men, 98% were nonHispanic White, with a mean (SD) BMI of 25 (5) kg/m2. There were no statistically significant differences in baseline characteristics between participants with and without pulmonary hypertension (Table 2).
There were no significant differences in the post-surgery in-hospital clinical outcomes between patients with and without PH including duration of artificial ventilation (1.8 vs 0.1, p-value: 0.882), number of days in intensive care unit (4 vs 6, p-value: 0.263), proportion of patients with prolonged air leak (12 vs 19, p-value: 0.402), and number of days of hospital stay (13 vs 16, p-value: 0.072). Duration of chest tube drainage in days was significantly lower in patients with PH compared to patients without PH (11 vs 16 days, p-0.033) (Table 3). There were no significant bleeding issues. In patients with PH, there was a significant improvement in lung function parameters from baseline to one-year follow-up post LVRS: FEV1% (26 vs 38, p-value: <0.001), FVC% (62 vs 90, pvalue: <0.001), RV% (224 vs 174, p-value: <0.001), and DLCO% (36 vs 43, p-value: <0.001), 6MWD test (1104 vs 1232, p-value: 0.001), and QOL utility scores (0.67 vs 0.77, p-value: <0.001) (Figure 1). Similar improvements were seen in patients without PH and the magnitude (% change) of improvement at one-year follow-up from baseline was similar between patients with and without PH for FEV1%, FVC%, FEV1/FVC, TLC, RV and DLCO measures, 6MWD test, and QOL utility scores (Table 4). Clinical and QOL outcomes at one-year follow-up were available only for 96 patients. Of the remaining 28 patients, 11 patients died (without PH-5, with PH-6), 17 were lost to follow-up (without PH-9, with PH-8). Of the 11 deaths 6 were in-hospital deaths (respiratory failure-5, gastrointestinal complications-1) while the remaining five were within one-year post discharge (respiratory failure-3, unknown-2). Follow-up ECHO/RHC were available only in 31 patients and the median duration for repeat ECHO/RHC measurement was 82 days (IQR: 12-461 days). Of the 31 patients with follow-up ECHO/RHC, 14 had PH at baseline and 9 of these still had elevated PAP at follow-up, while 17 did not have PH at baseline but 5 of these subsequently developed PH post-LVRS. No significant changes in PAP from baseline to follow-up were noted in those with PH at baseline (mean mm Hg, 41 vs. 39, p=0.519) or in those without PH at baseline (mean mm Hg, 29 vs. 34, p=0.376). Among the 56 patients who had PH, 27 (48%) patients were diagnosed PH solely based on ECHO results, while 23 (41%) were diagnosed using RHC results only. The remaining six (11%) had ECHO followed by RHC. There were no differences in the in-hospital clinical outcomes or changes in
functional measures and QOL at one-year post-surgery in the ECHO only group vs RHC only group (Supplemental Tables 1 and 2). Of the 111 questionnaires sent to LVRS surgeons at six Joint Commission accredited LVRS centers and 48 questionnaires sent to UNOS accredited lung transplant centers, 51 (46%) of the LVRS surgeons responded. Of those responders 50% of the surgeons believed that LVRS should not be denied solely based on PH. Approximately 71% and 42% believed elevated PAP is not a predictor of intraoperative and in-hospital/30 day outcomes respectively. Only 22% believed that elevated PAP will have an effect on functional outcomes post LVRS. Some of the surgeons (16%) believed that the clinical outcomes depend on the severity of PH and hence recommended studying clinical outcomes as a function of PH.
Comment Clinical, functional and QOL outcomes improved significantly in patients with PH and were similar to patients without PH at one-year follow-up post-LVRS. The results of this study demonstrates that at one-year post surgery, patients with and without PH who underwent LVRS for emphysema had improved lung function with improved QOL. Number of deaths at one-year follow-up were similar in both the groups. All patients had a successful thoracoscopic surgery and none of them required a conversion to thoracotomy. Though studies have demonstrated better clinical outcomes without elevation in PH post -LVRS (5-10), guidelines still suggests that PH is a contraindication for LVRS (4). The results of this study has also demonstrated better clinical and QOL outcomes during in-hospital stay and at oneyear post-surgery in patients with mild to moderate PH. Clinical, functional and QOL outcomes were comparable between patients diagnosed with PH by ECHO only or by RHC only. In our study RHC was performed in patients for whom ECHO measurements could not be obtained due to hyperinflation of the lungs. Poor visualization of the heart and difficulty obtaining clean signals are two important technical reasons for not considering ECHO in patients with hyperinflation and hence ECHO measurements not recommended for diagnosing PH (11, 12). RHC is an invasive procedure and may not be well tolerated in patients with severe emphysema who are generally older and sicker. Hence in our center RHC is performed only if it is difficult to estimate PAP by ECHO and if the patient has other hemodynamic complications requiring an RHC. Not having RHC in all patients is one of the limitations of this study. However, the results shows that patients with ECHO only and RHC only measurements have similar clinical, functional and quality of outcomes. To the best of our knowledge this study is the first to look at one-year clinical outcomes along with in-hospital post-surgery outcomes, functional and QOL outcomes in patients with PH undergoing LVRS for emphysema. Likewise, to our knowledge this is the first study to look at the provider’s perception about using PH as a selection criteria for LVRS. Most of the responders believed that PH should not be a sole criteria for denying LVRS and some believed that severity of PH should be taken into account. One of the limitations is that repeat ECHO/RHC was available only in few of the study patients
(n=31). However clinical, functional and QOL outcomes at one-year follow-up were similar between patients who had repeat ECHO/RHC compared to those who did not have a repeat ECHO/RHC (data not shown). In conclusion, PH within this cohort did not seem to impact the outcomes in patients with emphysema undergoing LVRS. Lung volume reduction surgery may be a potential option for select emphysema patients with PH.
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Table 1. Questionnaire to understand surgeons opinion about the use of pulmonary artery pressure as an exclusion criteria for LVRS S. no
Question
1
In your opinion, is it justifiable to exclude an otherwise appropriate LVRS candidate from surgery based solely on elevated, preoperative pulmonary artery pressure?
2
In your opinion, is preoperative pulmonary artery pressure a predictor of intra-operative LVRS complications?
3
In your opinion, is preoperative pulmonary artery pressure a predictor of post-operative (in hospital/30 day) outcome in LVRS patients?
4
In your opinion, is preoperative pulmonary artery pressure a predictor of post-operative functional outcome in LVRS patients?
5
Other Remarks
Yes
No
Table 2. Demographic details in patients who underwent lung volume reduction surgery for emphysema with/without pulmonary hypertension
Without PH at baseline (n=68)
With PH at baseline (n=56)
p-value
Age (years), mean (SD)
65 (7.8)
67 (7.8)
0.230
BMI (kg/m2), mean (SD)
24.3 (4.4)
25.2 (4.3)
0.281
Male, n (%)
40 (59%)
35 (63%)
0.816
Race: non-Hispanic White, n (%)
68 (100%)
52 (95%)
0.087
Home oxygen use (≥ 3L/min), n (%)
23 (34%)
18 (32%)
0.995
Smoking ≥ 60 pack-years, n (%)
42 (63%)
33 (60%)
0.907
Pulmonary artery pressure, mean (SD)
28.4 (5.7)
41.3 (5.1)
0. 001
Table 3. In-hospital clinical outcomes in patients who underwent lung volume reduction surgery for emphysema with and without pulmonary hypertension at baseline Without PH at baseline (n=68)
With PH at baseline (n=56)
p-value
Ventilator duration (hours)
0.1 (0.4)
1.8 (13.1)
0.882
Chest tube duration (days)
15.9 (18.8)
10.6 (9.4)
0.033
Post-op intensive care unit stay (days)
6.2 (11.7)
4.1 (6.2)
0.263
Post-op hospital stay (days)
15.7 (13.4)
12.8 (10.0)
0.072
19 (28%)
12 (21%)
0.403
Prolonged Air leak (≥ 14 days), n (%)
Table 4. Percent change from baseline to one-year follow-up in functional and QOL outcomes in patients who underwent lung volume reduction surgery for emphysema with and without pulmonary hypertension Without PH at baseline (n=68)
With PH at baseline (n=56)
p- value
∆ FEV1 % predicted
35.2 (38.9)
50.3 (56.0)
0.293
∆ FVC % predicted
38.7 (42.6)
55.4 (55.2)
0.079
∆ FEV1/FVC % predicted
-0.1 (20.2)
3.7 (25.4)
0.778
∆ TLC % predicted
-3.2 (14.0)
-0.3 (13.8)
0.225
∆ RV % predicted
-23.1 (19.7)
-19.2 (21.7)
0.319
∆ DLCO % predicted
12.6 (24.2)
21.9 (33.0)
0.157
∆ 6MWD
7.0 (33.3)
12.4 (22.0)
0.300
∆ EQ5Da
0.13 (0.23)
0.08 (0.15)
0.542
DLCO- Diffusing capacity of the lungs for carbon monoxide, ECHO-Echocardiogram, EQ5D- EuroQol five dimension quality of life questionnaire, FEV- forced expiratory volume, FVC- forced vital capacity, ICU-intensive care unit, PAP- pulmonary arterial pressure, PHpulmonary hypertension, RHC- right heart catheterization, RV- residual volume, 6MWD- six minute walk distance test; a
Absolute change in quality of life utility scores
Figure legend Figure 1. Functional and quality of life outcomes in patients who underwent lung volume reduction surgery for emphysema with and without pulmonary hypertension.