Ventilatory efficiency is superior to peak oxygen uptake for prediction of lung resection cardiovascular complications.

INTRODUCTION: Ventilatory efficiency (VE/VCO2 slope) has been shown superior to peak oxygen consumption (VO2) for prediction of post-operative pulmonary complications in patients undergoing thoracotomy. VE/VCO2 slope is determined by ventilatory drive and ventilation/perfusion mismatch whereas VO2 is related to cardiac output and arteriovenous oxygen difference. We hypothesized pre-operative VO2 predicts post-operative cardiovascular complications in patients undergoing lung resection.
METHODS: Lung resection candidates from a published study were evaluated by post-hoc analysis. All of the patients underwent preoperative cardiopulmonary exercise testing. Post-operative cardiovascular complications were assessed during the first 30 post-operative days or hospital stay. One-way analysis of variance or the Kruskal-Wallis test, and multivariate logistic regression were used for statistical analysis and data summarized as median (IQR).
RESULTS: Of 353 subjects, 30 (9%) developed pulmonary complications only (excluded from further analysis), while 78 subjects (22%) developed cardiovascular complications and were divided into two groups for analysis: cardiovascular only (n = 49) and cardiovascular with pulmonary complications (n = 29). Compared to patients without complications (n = 245), peak VO2 was significantly lower in the cardiovascular with pulmonary complications group [19.9 ml/kg/min (16.5-25) vs. 16.3 ml/kg/min (15-20.3); P<0.01] but not in the cardiovascular only complications group [19.9 ml/kg/min (16.5-25) vs 19.0 ml/kg/min (16-23.1); P = 0.18]. In contrast, VE/VCO2 slope was significantly higher in both cardiovascular only [29 (25-33) vs. 31 (27-37); P = 0.05] and cardiovascular with pulmonary complication groups [29 (25-33) vs. 37 (34-42); P<0.01)]. Logistic regression analysis showed VE/VCO2 slope [OR = 1.06; 95%CI (1.01-1.11); P = 0.01; AUC = 0.74], but not peak VO2 to be independently associated with post-operative cardiovascular complications.
CONCLUSION: VE/VCO2 slope is superior to peak VO2 for prediction of post-operative cardiovascular complications in lung resection candidates.

Introduction

Peak oxygen consumption (VO2) is recommended by both American and European guidelines for pre-operative risk stratification of lung resection candidates [1,2]. However, over the last decade, several studies have shown peak VO2 to be a poor predictor of post-operative pulmonary complications [3] and inferior to ventilatory efficiency (VE/VCO2 slope) [4,5].

By the alveolar gas equation ventilatory efficiency is defined as VE/VCO2 = 863 / (PaCO2 x (1—VD /VT)) [6]. Therefore, VE/VCO2 is increased by lower PaCO2 (hyperventilation) or increase of the VD /VT ratio (ventilation/perfusion mismatch or ineffective breathing pattern with rapid and shallow breathing) which may explain its superior prediction of post-operative pulmonary complications [6].

In contrast, determinants of VO2 include cardiac output [7] and arteriovenous oxygen difference. Peak VO2 is considered a cardiovascular fitness parameter [8] and was shown to be a major risk factor for post-operative cardiovascular complications [9]. Hence, an association with cardiovascular complications might be expected.

We hypothesized peak exercise VO2 predicts post-operative cardiovascular complications in patients undergoing thoracic surgery. Accordingly, the aim of this study was to compare pre-operative peak exercise VO2 and VE/VCO2 slope in the prediction of post-operative cardiovascular complications in patients after lung resection surgery.

Methods

Subject selection

Subjects included were consecutive patients who underwent lung resection surgery. Inclusion criteria were age ≥18 years and ability to undergo cardiopulmonary exercise testing (CPET). Exclusion criteria were contraindication for lung resection because of inoperability or low peak predicted post-operative VO2 [VO2<10ml/kg/min or <35% predicted together with predicted post-operative forced expiratory volume at one second (FEV1) <30% and diffusing capacity for carbon monoxide (DLCO) <30% 2)] and development of pulmonary complications only.

Study design

This is a post-hoc analysis of a previously published prospective multicenter study which evaluated pre-operative rest ventilatory parameters as predictors of post-operative pulmonary complications in lung resection candidates [10]. All of the included patients underwent preoperative CPET and pulmonary function tests. Post-operative cardiovascular complications were prospectively accessed from the first 30 post-operative days or from the hospital stay. The study was conducted in accordance with the declaration of Helsinki. All participants provided written informed consent and the study was approved by the local Ethics Committee of St. Anne’s University Hospital in Brno (reference No. 19JS/2017, date of approval April 12, 2017; reference No. 2G/2018, date of approval March 21st, 2018) and by the local Ethics Committee of the University Hospital Brno (reference No. 150617/EK, date of approval June 19th, 2017). The study was registered at ClinicalTrials.gov (NCT03498352) and the manuscript adheres to the applicable STROBE guidelines.

Cardiopulmonary exercise testing

Exercise capacity was assessed by CPET as described previously [10]. Subjects underwent preoperative CPET (symptom-limited) using a bicycle ergometer (Ergoline, Ergometrics 800®, Bitz, Germany). Expired gas analysis was done with the use of a PowerCube-Ergo® cardiopulmonary exercise system (Ganshorn Medizin Electronic GmbH, Niederlauer, Germany). Arterial blood gas analysis was done twice (at rest and peak exercise) using the ABL90 Flex Plus® (Radiometer Medical ApS, Denmark) device. The CPET protocol included a warm-up phase without resistance (60 seconds) followed by a linearly increasing (15 W/min) ramp protocol. Measured parameters included VO2, carbon dioxide output (VCO2), breathing frequency (fb), tidal volume (VT), minute ventilation (VE) and PETCO2. The derived CPET parameters included dead space to tidal volume ratio (VD/VT), respiratory exchange ratio (RER) and VE/VCO2 slope.

Pulmonary function tests

Spirometry was performed using the ZAN100 device (nSpire Health, Inc., USA) and DLCO using the PowerCube Diffusion+ device (Ganshorn Medizin Electronic GmbH, Germany). Analyzed parameters include forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and FEV1/FVC ratio and were reported as percent (%) of predicted value.

Cardiovascular complications

Cardiovascular complications were defined as previously recommended [11] and prospectively assessed from the first 30 post-operative days or from the hospital stay including arrhythmias (atrial fibrillation, supraventricular tachycardia–duration ≥ 10 seconds [12]); hypotension (catecholamine administration or parenteral fluids >200ml/h); heart failure (recently elevated serum brain natriuretic peptide and/or administration of inotropes); pulmonary edema (chest X-ray + clinical signs); pulmonary embolism (CT-angiography or highly suspicious right heart echocardiography signs); myocardial infarction/minimal myocardial lesion (coronary angiography or new ECG signs with serum positive troponin), stroke (newly developed neurological deficit with CT signs of brain infarction of ischemic or hemorrhagic etiology [13]) and cardiopulmonary resuscitation.

Pulmonary complications

Pulmonary complications were assessed as previously described by our group [10] and others [4,14] and included pneumonia; atelectasis; respiratory failure requiring mechanical ventilation; adult respiratory distress syndrome and tracheostomy. ICU length of stay (LOS), hospital LOS and 30-day mortality were also monitored. Surgical Mortality Probability Model (S-MPM), an ASA (American Society of Anesthesiologists) physical status adjusted for surgery risk class and emergency status [15], was used to allow patient’s co-morbidities comparison.

Statistics

The Shapiro-Wilk test was used to evaluate normality. One-way analysis of variance or the Kruskal–Wallis test by ranks followed by either post-hoc Tukey HSD test or Mann–Whitney U test (as appropriate) were used to test for differences among the groups. Chi-square test was used to compare categorical variables. Univariate logistic regression was done for parameters significantly different between groups. The Spearman rank test was performed to evaluate parameters with significant correlation. Parameters with correlation coefficients <±0.5 were used for multivariate stepwise logistic and linear regression. A multivariate stepwise logistic regression model was constructed to analyze which parameters were independently associated with the development of cardiovascular complications, ICU readmission and 30-day mortality. To evaluate model performance receiver operating characteristic (ROC) analyses were performed. Multivariate stepwise linear regression analyses (using same parameters as for multivariate logistic regression) were performed to evaluate the association of peak VO2 and VE/VCO2 slope with hospital and ICU LOS. Data are summarized as mean ± SD or median (IQR) as appropriate; P values <0.05 were considered statistically significant. Statistica software 12.0 (StatSoft Inc., Prague, Czech Republic) and IBM SPSS Statistics 25.0 (IBM Corp, USA) were used for analysis.

Results

Data from 353 lung resection surgery candidates from our previous study [10] were analyzed. Thirty patients (9%) developed pulmonary complications only and were excluded; 78 patients (22%) developed cardiovascular complications and 245 patients (69%) had no complications. Comparison of patients with and without cardiovascular complications is shown in S1 Table. Out of the 78 patients with cardiovascular complications, 49 patients developed cardiovascular complications only and 29 patients developed cardiovascular with pulmonary complications. Cardiovascular and pulmonary complications often coexist [16], and despite prospective assessment of complications, we were not able to fully distinguish which complications were primary and which were secondary. To mitigate this, we divided our cardiovascular complications subjects into 2 groups–cardiovascular only and cardiovascular with pulmonary complications (frequency of cardiovascular complications was nearly the same in both groups Table 1) and analyzed them separately.

Table 1

Cardiovascular complications: Type and frequency (n = 78).

	Cardiovascular only (n = 49)	With pulmonary (n = 29)	P
Lung edema n (%)	0	2 (7)	0.14
Pulmonary embolism n (%)	3 (6)	1 (3)	1.00
Arrhythmia n (%)	26 (53)	21 (72)	0.10
Hypotension n (%)	26 (53)	19 (66)	0.35
Heart failure n (%)	0	2 (7)	0.14
Acute myocardial infarction n (%)	0	0	1.00
Cardiopulmonary resuscitation n (%)	0	3 (10)	0.05
Ischemic stroke n (%)	0	2 (7)	0.14

Subject and surgery characteristics are shown in Table 2. Subjects in both the post-operative cardiovascular complications groups were significantly older and had higher S-MPM and comorbidities. Hospital and ICU LOS was significantly longer and frequency of ICU readmissions higher in both cardiovascular complication groups. The 30-day mortality was significantly higher in the cardiovascular with pulmonary complications group.

Table 2

Subject characteristics and surgery comparison.

parameter	Without complications (n = 245)	Cardiovascular complications (n = 78)			ANOVA P
		Cardiovascular only(n = 49)	With pulmonary (n = 29)
Male n (%)	135 (55)	26 (53)	20 (69)		0.33
Age (years)	65 (55–70)	67 (63–74)*	70 (65–73)**		<0.01
BMI (kg/m2)	28.2 (24.4–31.5)	27.4 (23.8–29.9)	29.1 (25.3–32)		0.64
S-MPM	4 (4–6)	6 (4–6)**	6 (6–6)**		<0.01
Hypertension n (%)	114 (47)	32 (65)*	24 (83)**		<0.01
Ischemic heart disease n (%)	17 (7)	7 (14)	5 (17)		0.07
COPD/asthma n (%)	37 (15)	7 (14)§§	15 (52)**		<0.01
Diabetes mellitus n (%)	31 (13)	10 (20)	8 (28)		0.06
Stroke n (%)	10 (4)	6 (12)*	5 (17)*		<0.01
Surgery
Thoracotomy n (%)	123 (50)	28 (57)		22 (76)**	0.03
Lobectomy n (%)	106 (43)	29 (64)*§		24 (83)**	<0.01
Bilobectomy n (%)	6 (15)	3 (1)		0	0.23
Pneumonectomy n (%)	5 (2)	5 (10)**		1 (3)	0.02
Wedge resection n (%)	128 (52)	12 (24)**		4 (14)**	<0.01
Post-operative Outcome
Hospital LOS (days)	6 (5–8)	8 (7–12)**§§		16 (12–26)**	<0.01
ICU LOS (days)	3 (2–4)	5 (4–7)**§§		10 (8–13)**	<0.01
ICU readmission n (%)	1 (0.4)	2 (4)*§§		8 (28)**	<0.01
30-day mortality n (%)	2 (1)	0§§		5 (17)**	<0.01

* = P<0.05

** = P<0.01 vs without complications group.

§ = P<0.05

§§ = P<0.01 vs cardiovascular with pulmonary group.

BMI = body mass index; COPD = Chronic obstructive pulmonary disease; ICU = intensive care unit; LOS = length of stay; PPC = post-operative pulmonary complications; S-MPM = Surgical Mortality Probability Model.

Results of pulmonary function tests and arterial blood gases are summarized in Table 3. FEV1%, FVC%, FEV1/FVC% and DLCO% and rest PaO2 were significantly lower in the cardiovascular with pulmonary complications group. FEV1/FVC% was also lower in the cardiovascular complications only group.

Table 3

Pulmonary function tests and arterial blood gases comparison.

parameter	Without complications (n = 245)		Cardiovascular complications (n = 78)		ANOVA P
			Cardiovascular only(n = 49)	With pulmonary (n = 29)
Pulmonary Function Tests
FEV1 (%predicted)		94 ± 18	87 ± 19	82 ± 20**	<0.01
FVC (%predicted)		95 ± 16	92 ± 18	87 ± 18*	0.02
FEV1/FVC (%)		82 (76–87)	79 (70–85)*	77 (68–84)*	0.01
DLCO (%predicted)		84 ± 21	79 ± 26	71 ± 23**	0.01
Rest Arterial Blood Gases
PaO2 (mmHg)		79 ± 9	76 ± 8	74 ± 7*	0.01
PaCO2 (mmHg)		36 (33–38)	35 (33–38)	35 (32–36)	0.12
pH		7.45 (7.43–7.46)	7.44 (7.43–7.46)	7.44 (7.42–7.46)	0.45
Peak Exercise Arterial Blood Gases
PaO2 (mmHg)		86 (79–92)	86 (77–92)	78 (74–89)	0.13
PaCO2 (mmHg)		36 ± 5	35 ± 4	35 ± 5	0.23
pH		7.37 (7.33–7.39)	7.36 (7.34–7.39)	7.37 (7.33–7.41)	0.49

* = P<0.05

** = P<0.01 vs without complications group.

§ = P<0.05

§§ = P<0.01 vs cardiovascular with pulmonary group.

DLCO = diffusing lung capacity for carbon monoxide; FEV1 = forced expiratory volume in one second; FVC = forced vital capacity; PaCO2 = arterial partial pressure of carbon dioxide; PaO2 = arterial partial pressure of oxygen.

Rest and exercise ventilatory parameters for all groups are summarized in Table 4. At rest, PETCO2 was significantly lower in both cardiovascular complication groups. At peak exercise, VO2, VCO2, RER and VT were significantly lower and fb significantly higher in the cardiovascular with pulmonary complications group. Peak exercise PETCO2 was lower and VE/VCO2 slope higher in both cardiovascular complication groups.

Table 4

Cardiopulmonary exercise testing comparison.

parameter	Without complications (n = 245)	Cardiovascular complications (n = 78)		ANOVA P
		Cardiovascular onlyonly (n = 49)	With pulmonary (n = 29)
Rest Ventilation and Gas Exchange
VO2 (ml/kg/min)	4.2 (3.5–5.0)	4.2 (3.1–4.6)	4.1 (3.4–5.2)	0.51
VCO2 (ml/min)	0.25 ± 0.10	0.22 ± 0.08	0.22 ± 0.10	0.04
VE (l/min)	10 ± 4	9 ± 3	10 ± 5	0.47
VT (ml)	0.57 (0.40–0.74)	0.57 (0.43–0.71)	0.45 (0.31–0.65)	0.19
fb (bpm)	18 (15–21)	17 (14–21)§§	20 (18–23)*	0.01
VD/VT	0.29 (0.23–0.34)	0.30 (0.24–0.34)	0.29 (0.23–0.34)	0.77
PETCO2 (mmHg)	30 (27–32)	28 (24–31)*§	26 (23–28)**	<0.01
Peak Exercise Ventilation and Gas Exchange
VO2 (ml/kg/min)	19.9 (16.5–25)	19.0 (16–23.1)	16.3 (15–20.3)**	0.01
VCO2 (ml/min)	1.67 (1.30–2.10)	1.56 (1.23–1.95)	1.32 (1.03–1.71)**	<0.01
RER	1.05 (0.92–1.14)	0.99 (0.88–1.12)	0.97 (0.82–1.05)**	0.01
VE (l/min)	54 (44–68)	53 (41–65)	48 (43–61)	0.31
VT (ml)	1.75 (1.37–2.11)	1.74 (1.27–2.14)	1.42 (1.08–1.85)**	0.01
fb (bpm)	32 (28–36)	33 (30–37)	35 (32–41)**	0.01
VD/VT	0.21 ± 0.07	0.22 ± 0.06	0.24 ± 0.06	0.12
PETCO2 (mmHg)	36 ± 5	33 ± 6*§	30 ± 5**	<0.01
VE/VCO2 slope	29 (25–33)	31 (27–37)*§§	37 (34–42)**	<0.01

* = P<0.05

** = P<0.01 vs without complications group.

§ = P<0.05

§§ = P<0.01 vs cardiovascular with pulmonary group.

fb = breathing frequency; PETCO2 = partial pressure of end-tidal carbon dioxide; PPC = post-operative pulmonary complications; RER = respiratory exchange ratio; VCO2 = carbon dioxide output; VD = dead space volume; VE = minute ventilation; VE/VCO2 = ventilatory efficiency; VO2 = oxygen consumption; VT = tidal volume.

Univariate logistic regression demonstrated VE/VCO2 slope to be significantly associated with cardiovascular complications (OR = 1.10; 95%CI 1.06–1.15; P<0.01; AUC = 0.67) and ICU readmissions (OR = 0.92; 95% CI 0.85–0.99; P = 0.02; AUC = 0.71). Patients with VE/VCO2 slope ≥34.8 had significantly higher probability (17.4% vs. 46.1%) for post-operative cardiovascular complications with OR 4.1 (95% CI 2.3–7.1; P<0.01). However, VE/VCO2 slope association with 30-day mortality was not significant (OR = 0.93; 95%CI 0.85–1.01; P = 0.08; AUC = 0.68). While peak VO2 was significantly associated with cardiovascular complications (OR = 0.93; 95% CI 0.89–0.98; P<0.01; AUC = 0.60), it was not associated with ICU readmissions (OR = 1.05; 95% CI 0.95–1.16; P = 0.36; AUC = 0.56) or 30-day mortality (OR = 1.11; 0.97–1.28; P = 0.14; AUC = 0.61).

Multivariate logistic regression showed VE/VCO2 slope, age, and wedge resection, but not peak VO2 to be independently associated with post-operative cardiovascular complications (Table 5) with AUC 0.75 (Fig 1). VE/VCO2 slope also remained significantly associated with ICU readmissions (OR = 0.92; 95% CI 0.86–0.99; P = 0.03; AUC = 0.70).

Table 5

Logistic regression analysis.

	univariate			multivariate stepwise
	OR	95 CI	p	OR	95 CI	P
Age	1.05	1.02–1.08	<0.01	1.04	1.01–1.07	0.02
S-MPM	1.63	1.29–2.07	<0.01	NS
Thoracotomy No (%)	1.77	1.05–3.00	0.03	NS
Lobectomy No (%)	2.78	1.62–4.76	<0.01	NS
Wedge resection No (%)	0.24	0.13–0.43	<0.01	0.28	0.15–0.53	<0.01
FEV1/FVC	0.97	0.94–0.99	<0.01	NS
DLCO	0.98	0.97–1.00	0.01	NS
peak VO2	0.93	0.89–0.98	<0.01	NS
VE/VCO2 slope	1.10	1.06–1.15	<0.01	1.06	1.01–1.11	0.01

DLCO = diffusing lung capacity for carbon monoxide; FEV1 = forced expiratory volume in one second; FVC = forced vital capacity; PETCO2 = partial pressure of end-tidal carbon dioxide; S-MPM = Surgical Mortality Probability Model; VE/VCO2 = ventilatory efficiency; VO2 = oxygen consumption.

Fig 1

Receiver operating characteristic curve of VE/VCO2 slope and post-operative cardiovascular complications.

Multivariate logistic regression model [AUC = 0.747 (0.687; 0.807)].

Both peak VO2 and VE/VCO2 significantly correlated with ICU LOS (rho = -0.13, P = 0.02; rho = 0.38, P<0.01, respectively) and hospital LOS (rho = -0.13, P = 0.02; rho = 0.34, P<0.01, respectively). Multiple stepwise regression analysis showed VE/VCO2 slope, but not peak VO2 to be significantly associated with ICU LOS (b = 0.13, F = 9, P<0.01) and hospital LOS (b = 0.19, F9.7, P<0.01).

Discussion

A major finding of this post-hoc analysis of a previously reported surgical cohort was that peak exercise VO2 did not predict post-operative cardiovascular complications, ICU readmissions, mortality, and hospital and ICU LOS in lung resection candidates. However, in contrast VE/VCO2 slope predicted post-operative cardiovascular complications, ICU readmissions, and hospital and ICU LOS.

The incidence of post-operative cardiovascular complications was 22%, similar to previous reports [17,18]. The most frequent cardiovascular complication was supraventricular arrhythmia (60%) in agreement with previous studies of post-lung resection surgery [18,19]. The second most common complication was post-operative hypotension (58%), which is also frequent [20]. Although these complications may be considered mild, post-operative arrhythmias are associated with longer hospital LOS, intensive care unit admissions, resource utilization and costs of care [17,21] and post-operative hypotension may be associated with myocardial injury [20]. Indeed, in our cohort, ICU readmissions were greater and hospital and ICU LOS were significantly longer in both cardiovascular complication groups. Severe complications (except of hypotension and arrhythmia) were relatively rare (16%) and developed in only 10 patients.

Compared to patients without post-operative complications, patients who developed cardiovascular complications (with or without pulmonary complications) were significantly older, had more comorbidities and lower pre-operative FEV1/FVC%. Lobectomy was more frequent and wedge resection less frequent in these patients, in concordance with previous studies [17,18]. In our study, patients with a combination of cardiovascular and pulmonary complications had previously established risk factors for post-operative pulmonary complications including thoracotomy, lower FEV1%, FVC%, DLCO% and PaO2 [22,23]. The 30-day mortality was also higher in this group of patients.

During pre-operative exercise, patients with post-operative cardiovascular complications (with or without pulmonary complications) exhibited significantly higher VE/VCO2 slope. In contrast, peak VO2 was significantly lower only in the cardiovascular with pulmonary complications group. VE/VCO2 slope is determined by ventilatory control impairment [6] suggesting it may be a parameter which is predictive of post-operative pulmonary complications. Indeed, several studies have previously shown its superiority to peak VO2 [4,5,10,14,24,25]. However, the main determinant of peak VO2 is cardiac output [7], which has been shown to be a major risk factor for post-operative cardiovascular complications [9].

Peak VO2 is considered a parameter for assessment of cardiovascular fitness [8]. Hence, an association with cardiovascular complications might be expected. However, in this study, although the peak VO2 was significantly associated with cardiovascular complications by univariate analysis, multivariate logistic regression showed that only VE/VCO2 slope, type of surgical procedure and age were independently associated with cardiovascular complications. This is in agreement with prior studies in chronic heart failure patients where VE/VCO2 slope has also been found superior to peak VO2 in the prediction of cardiovascular events [26-28]. The observed association of VE/VCO2 slope and cardiovascular complications might be explained by an inverse association of VE/VCO2 slope with cardiac output and positive association with capillary wedge pressure [29]. Moreover, unlike peak VO2, VE/VCO2 slope is independent of patient effort and peripheral skeletal muscle function enabling acquisition during submaximal exercise (VE/VCO2 has been validated across different RER [30]) which may be beneficial for assessment of functionally limited lung surgery candidates.

Our findings may have clinical implications. First, peak VO2 is part of risk stratification algorithms in both American and European guidelines [1,2]. However, multiple studies have previously shown its poor prognostic utility [3-5,10]. In contrast, VE/VCO2 slope has been shown to be significantly better in the prediction of pulmonary [4,5,10,14,24,25] and now also cardiovascular complications. Accordingly, we suggest that lung resection candidate risk stratification algorithms consider routine inclusion of VE/VCO2 slope. Second, pre-operative risk stratification may allow pre-operative patient optimization as VE/VCO2 slope may be a therapeutic target [31] and promote better perioperative planning [17].

This study has several limitations. First, according to published ERS/ESTS guidelines [2], subjects with peak predicted post-operative VO2<10ml/kg/min were excluded, which may diminish the predictive value of peak VO2. However, only 6 subjects from our study cohort were excluded for this reason. Second, chronic medication data were unavailable. However, chronic medication is usually associated with the underlying diseases and our logistic regression analysis was adjusted for those. Third, PaO2 was significantly lower in patients with cardiovascular and pulmonary complications at rest. As VO2 is determined not only by cardiac output but also arteriovenous oxygen difference, this may have contributed to the observed VO2 differences (although these were observed only at peak exercise). Therefore, we cannot exclude, that peak VO2 may be a relevant prognostic factor in this subgroup of severely ill patients.

Conclusion

Peak VO2 is a poor predictor of post-operative cardiovascular complications. In contrast, the VE/VCO2 slope predicted post-operative cardiovascular complications, ICU readmissions and both hospital and ICU LOS. Our observations suggest consideration of routine inclusion of VE/VCO2 slope for pre-operative risk stratification in lung resection candidates.

Comparison of patients with and without cardiovascular complications.

Comparison of patients with and without cardiovascular complications.

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16 Jun 2022

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Reviewer #1: Congratulations, you made a great job! Your study is very important for clinical practice and scientific knowledge.

However, some corrections must be taking in count:

ABSTRACT

introduction -> The first sentence is almost a conclusion sentence. I suggest you rewrite or exclude.

methods -> You should mention the evaluation method (Subjects underwent preoperative CPET). You mentioned Friedman’s test in the abstract, but not in the body text.

INTRODUCTION

The first two paragraphs are very precise, however the introduction is too short. Please include one more paragraph.

The aim of the study do no match the title, discussion and conclusions. Please rewrite the aim. Your results and discussions are very clear: Ventilatory efficiency is superior to peak oxygen uptake for prediction of lung resection cardiovascular complications. However, your aim was "to compare pre-operative cardiopulmonary exercise testing parameters in patients who developed post-operative cardiovascular complications with patients who did not after lung resection surgery". Actually you did it, however your discussion and conclusion were made based in two variables (VO2 and VE/VCO2 slope) for complications prediction. In my opinion, the aim of your study was to analyze/compare these two variables for complications prediction.

METHODS

Include a "Study desing" topic. You should include in this new topic the preoperative evaluation method (Subjects underwent preoperative CPET) and some sentences/paragraphs should be moved from "subject selection" to study desing topic:

"This is a post-hoc analysis of a previously published prospective multicenter study which evaluated pre-operative rest ventilatory parameters as predictors of post-operative pulmonary complications in lung resection candidates" -> lines 67-69

"The study was conducted in accordance with the declaration of Helsinki. All participants provided written informed consent and the study was approved by the local Ethics Committee of St. Anne’s University Hospital in Brno (reference No. 19JS/2017, date of approval April 12, 2017; reference No. 2G/2018, date of approval March 21st, 2018) and by the local Ethics Committee of the University Hospital Brno (reference No. 150617/EK, date of approval June 19th, 2017). The study was registered at ClinicalTrials.gov (NCT03498352) and the manuscript adheres to the applicable STROBE guidelines." -> lines 76-82.

You mentioned Friedman’s test in the abstract, but not in the body text methods.

RESULTS

9% of the patients were excluded due to pulmonary complications only, but it was not an exclusion criteria. Please add "pulmonary complications only" as an exclusion criteria.

You mentioned the abbreviation S-MPM (line 143, 144) in the text, but only described it in the table.

DISCUSSION

These data must be in results, not in discussion -> "Patients with VE/VCO2 slope ≥34.8 had significantly higher probability (17.4% vs. 46.1%) for post-operative cardiovascular complications with OR 4.1 (95% CI 2.3-7.1; P<0.01)."

CONCLUSION

Remove the term "In conclusion" at the beginning of the sentence.

Be more specific -> Our observations suggest consideration of routine inclusion of VE/VCO2 slope for pre-operative risk stratification in candidates for LUNG RESECTION.

Reviewer #2: Comments:

First, I would like to congratulate the authors for the research. Post-operative prediction of complications is a useful clinical application of cardiopulmonary exercise testing (CPET).

Regarding the manuscript, I have some considerations:

1. Abstract:

Line 24 (and in Introduction - line 57) the authors stated that “VO2 is related to cardiac output.”

The statement is correct, but incomplete. We must not forget that according to “FICK principle”, oxygen uptake (VO2) is the product of cardiac output and arteriovenous oxygen difference. The importance of arteriovenous oxygen difference cannot be neglected, mainly in patients with pulmonary diseases, which can have hypoxia at rest and during exercise. It’s important to consider that this alteration can impact on VO2 by reducing arterial oxygen content:

Arterial oxygen content = (Hemoglobin x 1.36 x SaO2) + (0.0031 x PaO2).

Then, diseases that can affect arterial oxygen, can also have consequences in arteriovenous oxygen difference and VO2 as well.

2. Introduction:

Lines 60-63: the authors stated that “aim of this study was to compare pre-operative cardiopulmonary exercise testing parameters in patients who developed post-operative cardiovascular complications with patients who did not after lung resection surgery.”

The aim of the study was well stablished. That’s why I did not clearly understood why cardiovascular complications were reported only subdivided in “with” or “without pulmonary complications”. This division is interesting and could have been made, but the overall data for cardiovascular complications should have been reported. Subsequent division would be a subgroup analysis.

3. Methods:

Lines 101-111: The definition of cardiovascular complications were wide, ranging from auto-limited arrhythmias and hypotension to cardiopulmonary resuscitation. Conversely, definition of pulmonary complications was clinically narrower.

Probably this was due to the study design that was focused on Pulmonary complications as a Primary Outcome. Cardiovascular Outcome was previously defined as a Secondary Outcome, as described in clinical trial registry (NCT03498352 - Rest Ventilatory Parameters Predict Morbidity and Mortality in Thoracic Surgery).

Thus, a narrowing of the cardiovascular complication or a creating subdivision in minor versus major complication would have been more informative.

4) Results. Table 1 (page 8) describes the type and frequency of the cardiovascular complications.

Most of the complications were related to arrhythmias and hypotension.

Only 3 of the 49 complications (6%) in the “Cardiovascular only subgroup” were not related to arrhythmias and hypotension, while 10 of 29 complication (34%) in the “With pulmonary subgroup” were not related to arrhythmias and hypotension. Thus, cardiovascular complications in the “with pulmonary subgroup” were clinically more relevant.

Thus, the subdivision of the cardiovascular complications generated heterogeneity of the types of complications in the subgroups, and uncertainty to the analysis, as it can influence the prediction value of CPET.

Including the overall analysis could provide more information of the cardiovascular complications and it’s relation with CPET, reducing the uncertainty generated by the analysis of only the subgroups.

5. Results. Table 2 (pages 8-9) describes subjects characteristic.

Patients with complications were older, and there were differences in the type of surgery and post-operative outcomes.

Regarding subgroups of cardiovascular complications, “with pulmonary subgroup” were older (70 versus 67 years), had a higher BMI (29.1 versus 27.4) and heterogeneity in types of the surgery.

Cardiovascular risk factors and medication use were not reported in the subjects’ characteristics.

Thus, there are several clinical characteristics (reported and non-reported) that could have been related to a higher risk profile in the Cardiovascular with pulmonary complication subgroup and could have reduced the prediction value of CPET.

6. Results. Table 3. Pulmonary function (Page 10-11).

Rest pulmonary function were different among the three subgroups.

PaO2 at rest and at peak exercise were lower in the “with pulmonary” subgroup. Maybe that’s why CPET were clinically different in this subgroup, with significantly lower peak VO2.

PaO2 is related to arterial oxygen content and, consequently, arteriovenous oxygen difference and VO2 (FICK Principle).

Hence, along with all other clinical characteristics, peak VO2 might be a predictor within this subgroup with more relevant cardiovascular complications (the difference is not only the presence of pulmonary complications, as discussed above). The suggestion is to include some considerations in the discussion.

7. Logistic regression analysis (page 13)

There were several variables associated to cardiovascular complication in the univariate model, including age, type of surgery, rest pulmonary functions and CPET.

In multivariate stepwise, only age, wedge resection ant VE/VCO2 slope were significant. It must be considered that age and wedge resection were different in the subgroups of cardiovascular complications (with or without pulmonary).

Wedge resection was the most important factor (OR 0.28). Effect size for VE/VCO2 slope (OR 1.06) and age (1.04) were of much smaller magnitude.

Hence, the type of surgery (Wedge resection) could have reduced the effect size for peak VO2 and maybe that’s why it was not significant in multivariate stepwise (In univariate, the OR was 0.93).

Also, there was a wide definition for cardiovascular complication, and this could have affected the predictive model ability to detect relevant impact of CPET variables.

Suggestions

- Review the logistic regression model, as there may be non-reported clinical characteristics that were not analysed (hypertension, diabetes, medication use).

- The major influence for cardiovascular complication risk was the type of surgery (Wedge resection). A reanalysis of logistic regression model removing these patients, may be interesting to increase the sensibility of the CPET predictive variables in the other types of surgeries.

- Cardiovascular complication definition was too wide. Maybe a subgroup analysis with subdivision in minor versus major cardiovascular complications maybe more clinically relevant.

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Reviewer #1: Yes: Murillo Frazão

Reviewer #2: No

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7 Jul 2022

Reviewer #1:

ABSTRACT

introduction -> The first sentence is almost a conclusion sentence. I suggest you rewrite or exclude.

methods -> You should mention the evaluation method (Subjects underwent preoperative CPET). You mentioned Friedman’s test in the abstract, but not in the body text.

We would like to thank the reviewer for these suggestions. We have slightly rewritten the first sentence, added CPET in the methods and removed Friedman’s test.

“Ventilatory efficiency (VE/VCO2 slope) has been shown superior to peak oxygen consumption (VO2) for prediction of post-operative pulmonary complications in patients undergoing thoracotomy.” Line 21-23

“All of the patients underwent preoperative cardiopulmonary exercise testing.” Line 28

“One-way analysis of variance or the Kruskal–Wallis test, and multivariate logistic regression were used for statistical analysis and data summarized as median (IQR).” Line 30-31

INTRODUCTION

The first two paragraphs are very precise, however the introduction is too short. Please include one more paragraph.

We would like to thank the reviewer for this suggestion; we have added one more paragraph in the introduction as follows:

“In contrast, determinants of VO2 include cardiac output (7) and arteriovenous oxygen difference. Peak VO2 is considered a cardiovascular fitness parameter (8) and was shown to be a major risk factor for post-operative cardiovascular complications (9). Hence, an association with cardiovascular complications might be expected.” Line 57-60

The aim of the study do no match the title, discussion and conclusions. Please rewrite the aim. Your results and discussions are very clear: Ventilatory efficiency is superior to peak oxygen uptake for prediction of lung resection cardiovascular complications. However, your aim was "to compare pre-operative cardiopulmonary exercise testing parameters in patients who developed post-operative cardiovascular complications with patients who did not after lung resection surgery". Actually you did it, however your discussion and conclusion were made based in two variables (VO2 and VE/VCO2 slope) for complications prediction. In my opinion, the aim of your study was to analyze/compare these two variables for complications prediction.

We would like to thank the reviewer for this comment. We agree and have rewritten the aim of the study as follows.

“Accordingly, the aim of this study was to compare pre-operative peak exercise VO2 and VE/VCO2 slope in the prediction of post-operative cardiovascular complications in patients after lung resection surgery.” Line 62-64

METHODS

Include a "Study desing" topic. You should include in this new topic the preoperative evaluation method (Subjects underwent preoperative CPET) and some sentences/paragraphs should be moved from "subject selection" to study desing topic:

"This is a post-hoc analysis of a previously published prospective multicenter study which evaluated pre-operative rest ventilatory parameters as predictors of post-operative pulmonary complications in lung resection candidates" -> lines 67-69

"The study was conducted in accordance with the declaration of Helsinki. All participants provided written informed consent and the study was approved by the local Ethics Committee of St. Anne’s University Hospital in Brno (reference No. 19JS/2017, date of approval April 12, 2017; reference No. 2G/2018, date of approval March 21st, 2018) and by the local Ethics Committee of the University Hospital Brno (reference No. 150617/EK, date of approval June 19th, 2017). The study was registered at ClinicalTrials.gov (NCT03498352) and the manuscript adheres to the applicable STROBE guidelines." -> lines 76-82.

We would like to thank the reviewer for this comment. We have added a Study design paragraph as suggested.

“Study design

This is a post-hoc analysis of a previously published prospective multicenter study which evaluated pre-operative rest ventilatory parameters as predictors of post-operative pulmonary complications in lung resection candidates (4). All of the included patients underwent preoperative CPET and pulmonary function tests. Post-operative cardiovascular complications were prospectively accessed from the first 30 post-operative days or from the hospital stay. The study was conducted in accordance with the declaration of Helsinki. All participants provided written informed consent and the study was approved by the local Ethics Committee of St. Anne’s University Hospital in Brno (reference No. 19JS/2017, date of approval April 12, 2017; reference No. 2G/2018, date of approval March 21st, 2018) and by the local Ethics Committee of the University Hospital Brno (reference No. 150617/EK, date of approval June 19th, 2017). The study was registered at ClinicalTrials.gov (NCT03498352) and the manuscript adheres to the applicable STROBE guidelines.” Line 75-87

You mentioned Friedman’s test in the abstract, but not in the body text methods.

We would like to than the reviewer for pointing this out. We have removed Friedman’s test from the abstract.

“One-way analysis of variance or the Kruskal–Wallis test, and multivariate logistic regression were used for statistical analysis and data summarized as median (IQR).” Line 30-31

RESULTS

9% of the patients were excluded due to pulmonary complications only, but it was not an exclusion criteria. Please add "pulmonary complications only" as an exclusion criteria.

We would like to thank the reviewer for this comment. We have modified exclusion criteria.

“Exclusion criteria were contraindication for lung resection because of inoperability or low peak predicted post-operative VO2 [VO2<10ml/kg/min or <35% predicted together with predicted post-operative forced expiratory volume at one second (FEV1) <30% and diffusing capacity for carbon monoxide (DLCO) <30% 2)] and development of pulmonary complications only.” Line 70-74

You mentioned the abbreviation S-MPM (line 143, 144) in the text, but only described it in the table.

We would like to thank the reviewer for pointing this out. We have defined this abbreviation in the text.

“Surgical Mortality Probability Model (S-MPM), an ASA (American Society of Anesthesiologists) physical status adjusted for surgery risk class and emergency status (15), was used to allow patient’s co-morbidities comparison.” Line 121-124

DISCUSSION

These data must be in results, not in discussion -> "Patients with VE/VCO2 slope ≥34.8 had significantly higher probability (17.4% vs. 46.1%) for post-operative cardiovascular complications with OR 4.1 (95% CI 2.3-7.1; P<0.01)."

We would like to thank the reviewer for this comment. We have moved the data to the results section.

“Patients with VE/VCO2 slope ≥34.8 had significantly higher probability (17.4% vs. 46.1%) for post-operative cardiovascular complications with OR 4.1 (95% CI 2.3-7.1; P<0.01).” Line 198-199

CONCLUSION

Remove the term "In conclusion" at the beginning of the sentence.

Be more specific -> Our observations suggest consideration of routine inclusion of VE/VCO2 slope for pre-operative risk stratification in candidates for LUNG RESECTION.

We would like to thank the reviewer for this suggestion. We have rewritten the conclusion.

“Peak VO2 is a poor predictor of post-operative cardiovascular complications. In contrast, the VE/VCO2 slope predicted post-operative cardiovascular complications, ICU readmissions and both hospital and ICU LOS. Our observations suggest consideration of routine inclusion of VE/VCO2 slope for pre-operative risk stratification in lung resection candidates.“ Line 295-299

Reviewer #2:

1. Abstract:

Line 24 (and in Introduction - line 57) the authors stated that “VO2 is related to cardiac output.”

The statement is correct, but incomplete. We must not forget that according to “FICK principle”, oxygen uptake (VO2) is the product of cardiac output and arteriovenous oxygen difference. The importance of arteriovenous oxygen difference cannot be neglected, mainly in patients with pulmonary diseases, which can have hypoxia at rest and during exercise. It’s important to consider that this alteration can impact on VO2 by reducing arterial oxygen content:

Arterial oxygen content = (Hemoglobin x 1.36 x SaO2) + (0.0031 x PaO2).

Then, diseases that can affect arterial oxygen, can also have consequences in arteriovenous oxygen difference and VO2 as well.

We would like to thank the reviewer for this comment. We have added arteriovenous oxygen difference in both abstract and introduction.

“VE/VCO2 slope is determined by ventilatory drive and ventilation/perfusion mismatch whereas VO2 is related to cardiac output and arteriovenous oxygen difference.” Line 23-25

“In contrast, determinants of VO2 include cardiac output (7) and arteriovenous oxygen difference.” Line 57-58

2. Introduction:

Lines 60-63: the authors stated that “aim of this study was to compare pre-operative cardiopulmonary exercise testing parameters in patients who developed post-operative cardiovascular complications with patients who did not after lung resection surgery.”

The aim of the study was well stablished. That’s why I did not clearly understood why cardiovascular complications were reported only subdivided in “with” or “without pulmonary complications”. This division is interesting and could have been made, but the overall data for cardiovascular complications should have been reported. Subsequent division would be a subgroup analysis.

We would like to thank the reviewer for this comment. Division to subgroups was done because cardiovascular and pulmonary complications often coexist, and despite prospective assessment of complications, we were not able to fully distinguish which complications were primary and which were secondary. To mitigate this, we divided our cardiovascular complications subjects into 2 groups – cardiovascular only and cardiovascular with pulmonary complications (frequency of cardiovascular complications was nearly the same in both groups Table 1) and analyzed them separately. We commented on this in the manuscript. Moreover, we have now included a Supplement Table 1 comparing no complications vs. cardiovascular complications group (both groups together). Please see Supplement Table 1. We have also modified first paragraph of the results section as follows.

“Thirty patients (9%) developed pulmonary complications only and were excluded; 78 patients (22%) developed cardiovascular complications and 245 patients (69%) had no complications. Comparison of patients with and without cardiovascular complications is shown in Supplement Table 1. Out of the 78 patients with cardiovascular complications, 49 patients developed cardiovascular complications only and 29 patients developed cardiovascular with pulmonary complications. Cardiovascular and pulmonary complications often coexist (16), and despite prospective assessment of complications, we were not able to fully distinguish which complications were primary and which were secondary. To mitigate this, we divided our cardiovascular complications subjects into 2 groups – cardiovascular only and cardiovascular with pulmonary complications (frequency of cardiovascular complications was nearly the same in both groups Table 1) and analyzed them separately.” Line 145-155

3. Methods:

Lines 101-111: The definition of cardiovascular complications were wide, ranging from auto-limited arrhythmias and hypotension to cardiopulmonary resuscitation. Conversely, definition of pulmonary complications was clinically narrower.

Probably this was due to the study design that was focused on Pulmonary complications as a Primary Outcome. Cardiovascular Outcome was previously defined as a Secondary Outcome, as described in clinical trial registry (NCT03498352 - Rest Ventilatory Parameters Predict Morbidity and Mortality in Thoracic Surgery).

Thus, a narrowing of the cardiovascular complication or a creating subdivision in minor versus major complication would have been more informative.

We would like to thank the reviewer for this comment and we understand these concerns. Cardiovascular complications were defined as previously recommended (Bennett-Guerrero E, Welsby I, Dunn TJ, Young LR, Wahl TA, Diers TL, et al. The Use of a Postoperative Morbidity Survey to Evaluate Patients with Prolonged Hospitalization After Routine, Moderate-Risk, Elective Surgery. Anesthesia & Analgesia. 1999 Aug;89(2):514–9.) We agree with the reviewer, that dividing complications into minor and major would be interesting. However, the number of major complications (including pulmonary edema, pulmonary embolism, heart failure, acute myocardial infarction, cardiopulmonary resuscitation and stroke) was low 13 (16%) and presented “only” in 10 patients (13%). Comparison of such a small group would be hard / impossible to interpret. We hope the reviewer will agree. We comment on this in the manuscript.

“The incidence of post-operative cardiovascular complications was 22%, similar to previous reports (17,18). The most frequent cardiovascular complication was supraventricular arrhythmia (60%) in agreement with previous studies of post-lung resection surgery (18,19). The second most common complication was post-operative hypotension (58%), which is also frequent (20). Although these complications may be considered mild, post-operative arrhythmias are associated with longer hospital LOS, intensive care unit admissions, resource utilization and costs of care (17,21) and post-operative hypotension may be associated with myocardial injury (20). Indeed, in our cohort, ICU readmissions were greater and hospital and ICU LOS were significantly longer in both cardiovascular complication groups. Severe complications (except of hypotension and arrhythmia) were relatively rare (16%) and developed in only 10 patients.“ Line 230-240

4) Results. Table 1 (page 8) describes the type and frequency of the cardiovascular complications.

Most of the complications were related to arrhythmias and hypotension.

Only 3 of the 49 complications (6%) in the “Cardiovascular only subgroup” were not related to arrhythmias and hypotension, while 10 of 29 complication (34%) in the “With pulmonary subgroup” were not related to arrhythmias and hypotension. Thus, cardiovascular complications in the “with pulmonary subgroup” were clinically more relevant.

Thus, the subdivision of the cardiovascular complications generated heterogeneity of the types of complications in the subgroups, and uncertainty to the analysis, as it can influence the prediction value of CPET.

Including the overall analysis could provide more information of the cardiovascular complications and it’s relation with CPET, reducing the uncertainty generated by the analysis of only the subgroups.

We would like to thank the reviewer for this comment and we completely agree. However, it may be a misunderstanding. The most important part, the univariate and multivariate logistic regression, was done irrespective of the subdivision. Moreover, as suggested by the reviewer, we have now included a Supplement Table 1 comparing no complications vs. cardiovascular complications group (both groups together). Please see Supplement Table 1.

5. Results. Table 2 (pages 8-9) describes subjects characteristic.

Patients with complications were older, and there were differences in the type of surgery and post-operative outcomes.

Regarding subgroups of cardiovascular complications, “with pulmonary subgroup” were older (70 versus 67 years), had a higher BMI (29.1 versus 27.4) and heterogeneity in types of the surgery.

Cardiovascular risk factors and medication use were not reported in the subjects’ characteristics.

Thus, there are several clinical characteristics (reported and non-reported) that could have been related to a higher risk profile in the Cardiovascular with pulmonary complication subgroup and could have reduced the prediction value of CPET.

We would like to thank the reviewer for this comment. All of the potential confounders (parameters significantly different between groups, and without significant in-between correlation) were included in the multivariate logistic regression model (including age, type of surgery and comorbidities summarized as the S-MPM; please note BMI was not significantly different between groups, and is not different even in the newly included overall (2 groups) comparison - Supplement Table 1). Please see Table 2, Supplement table 1. We comment on logistic regression parameters selection in the statistics section.

“Univariate logistic regression was done for parameters significantly different between groups. The Spearman rank test was performed to evaluate parameters with significant correlation. Parameters with correlation coefficients <±0.5 were used for multivariate stepwise logistic and linear regression.” Line 129-132

In the presented study, cardiovascular risk factors were part of the Surgical Mortality Probability Model (S-MPM), which is basically an ASA physical status adjusted for surgery risk and emergency status. Using this parameter allowed us to control the logistic regression for such a complex confounder as are comorbidities (and not creating an over-fitting model). For the reviewer, we have included frequency of the most common comorbidities in Table 2 (and also in the Supplement Table 1). As you can see, the frequency of comorbidities practically mirrors the S-MPM. We have also added a detailed explanation of components of S-MPM in the methods section.

“Surgical Mortality Probability Model (S-MPM), an ASA (American Society of Anesthesiologists) physical status adjusted for surgery risk class and emergency status (15), was used to allow patient’s co-morbidities comparison.” Line 121-124

We agree with the reviewer, that information about medication would be useful. Unfortunately, we do not have this data readily available. Therefore, we have decided to include this in the limitation section. Moreover, chronic medication is usually bound to the associated disease and our analyses were adjusted for those. We hope the reviewer will agree.

“Second, chronic medication data were unavailable. However, chronic medication is usually associated with the underlying diseases and our logistic regression analysis was adjusted for those.” Line 284-286

6. Results. Table 3. Pulmonary function (Page 10-11).

Rest pulmonary function were different among the three subgroups.

PaO2 at rest and at peak exercise were lower in the “with pulmonary” subgroup. Maybe that’s why CPET were clinically different in this subgroup, with significantly lower peak VO2.

PaO2 is related to arterial oxygen content and, consequently, arteriovenous oxygen difference and VO2 (FICK Principle).

Hence, along with all other clinical characteristics, peak VO2 might be a predictor within this subgroup with more relevant cardiovascular complications (the difference is not only the presence of pulmonary complications, as discussed above). The suggestion is to include some considerations in the discussion.

We would like to thank the reviewer for this suggestion. We have added a statement in the limitation section. Please note, PaO2 was significantly lower only at rest in the cardiovascular with pulmonary complications group. Whereas VO2 was significantly lower at peak exercise, but not at rest. However, we understand the reviewers point and added a statement in the limitations section.

“Third, PaO2 was significantly lower in patients with cardiovascular and pulmonary complications at rest. As VO2 is determined not only by cardiac output but also arteriovenous oxygen difference, this may have contributed to the observed VO2 differences (although these were observed only at peak exercise). Therefore, we cannot exclude, that peak VO2 may be a relevant prognostic factor in this subgroup of severely ill patients. ” Line 286-291

7. Logistic regression analysis (page 13)

There were several variables associated to cardiovascular complication in the univariate model, including age, type of surgery, rest pulmonary functions and CPET.

In multivariate stepwise, only age, wedge resection ant VE/VCO2 slope were significant. It must be considered that age and wedge resection were different in the subgroups of cardiovascular complications (with or without pulmonary).

Wedge resection was the most important factor (OR 0.28). Effect size for VE/VCO2 slope (OR 1.06) and age (1.04) were of much smaller magnitude.

Hence, the type of surgery (Wedge resection) could have reduced the effect size for peak VO2 and maybe that’s why it was not significant in multivariate stepwise (In univariate, the OR was 0.93).

Also, there was a wide definition for cardiovascular complication, and this could have affected the predictive model ability to detect relevant impact of CPET variables.

Suggestions

- Review the logistic regression model, as there may be non-reported clinical characteristics that were not analysed (hypertension, diabetes, medication use).

We would like to thank the reviewer for this comment. Please note comorbidities were already part of the logistic regression as the S-MPM. Same response as to the comment No. 5 above.

In the presented study, cardiovascular risk factors were part of the Surgical Mortality Probability Model (S-MPM), which is basically an ASA physical status adjusted for surgery risk and emergency status. Using this parameter allowed us to control the logistic regression for such a complex confounder as are comorbidities (and not creating an over-fitting model). For the reviewer, we have included frequency of the most common comorbidities in Table 2 (and also in the Supplement Table 1). As you can see, the frequency of comorbidities practically mirrors the S-MPM. We have also added a detailed explanation of components of S-MPM in the methods section.

“Surgical Mortality Probability Model (S-MPM), an ASA (American Society of Anesthesiologists) physical status adjusted for surgery risk class and emergency status (15), was used to allow patient’s co-morbidities comparison.” Line 121-124

- The major influence for cardiovascular complication risk was the type of surgery (Wedge resection). A reanalysis of logistic regression model removing these patients, may be interesting to increase the sensibility of the CPET predictive variables in the other types of surgeries.

We would like to thank the reviewer for this very interesting comment/suggestion. As suggested, we have removed patients who underwent wedge resection (n=144) and redone the multivariate logistic regression. Removing wedge resection patients decreased the number of patients with cardiovascular complications by 16. Therefore, two variables had to be removed from the logistic regression model (to prevent over-fitting model). We have removed those variables with the weakest association (FEV1/FVC and DLCO). Included variables remained age, lobectomy, thoracotomy, S-MPM, peak VO2 and VE/VCO2 slope. Out of which only VE/VCO2 slope OR=1.06 (95% CI 1.01-1.12); p=0.02 and S-MPM OR=1.46 (95% CI 1.06-1.99); p=0.02 remained significantly associated with the development of cardiovascular complications. Suggesting comorbidities and VE/VCO2 slope are the only independent predictors of cardiovascular complications in this subgroup. Wedge resections are frequent and it is possible this type of procedure will become even more frequent (Hamaji M, Miyahara S, Lee HS, Burt BM. Standardizing the time-honored wedge resection. J Thorac Dis. 2018;10(Suppl 18):S2206–8). Therefore, we have decided not to exclude these patients from our analyses in the manuscript. We hope the reviewer will agree.

- Cardiovascular complication definition was too wide. Maybe a subgroup analysis with subdivision in minor versus major cardiovascular complications maybe more clinically relevant.

We agree with the reviewer, that dividing complications into minor and major would be interesting. However, the number of major complications (including pulmonary edema, pulmonary embolism, heart failure, acute myocardial infarction, cardiopulmonary resuscitation and stroke) was low 13 (16%) and presented “only” in 10 patients (13%). Comparison of such a small group would be hard / impossible to interpret. We hope the reviewer will agree. We comment on this in the manuscript.

“The incidence of post-operative cardiovascular complications was 22%, similar to previous reports (17,18). The most frequent cardiovascular complication was supraventricular arrhythmia (60%) in agreement with previous studies of post-lung resection surgery (18,19). The second most common complication was post-operative hypotension (58%), which is also frequent (20). Although these complications may be considered mild, post-operative arrhythmias are associated with longer hospital LOS, intensive care unit admissions, resource utilization and costs of care (17,21) and post-operative hypotension may be associated with myocardial injury (20). Indeed, in our cohort, ICU readmissions were greater and hospital and ICU LOS were significantly longer in both cardiovascular complication groups. Severe complications (except of hypotension and arrhythmia) were relatively rare (16%) and developed in only 10 patients.“ Line 230-240

Thank you for your consideration. Please direct correspondence to Ivan Cundrle Jr., Department of Anesthesiology and Intensive Care, St. Anne's University Hospital in Brno

Pekarska 53, 656 91 Brno. Phone: +420 543 182 553. E-mail address: Ivan.Cundrle@seznam.cz

Sincerely,

Ivan Cundrle Jr., M.D., Ph.D.

Department of Anesthesiology and Intensive Care

St. Anne's University Hospital in Brno

Pekarska 53, 656 91 Brno

Czech Republic

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

1 Aug 2022

Ventilatory efficiency is superior to peak oxygen uptake for prediction of lung resection cardiovascular complications

PONE-D-22-05505R1

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4 Aug 2022

PONE-D-22-05505R1

Ventilatory efficiency is superior to peak oxygen uptake for prediction of lung resection cardiovascular complications

Dear Dr. Cundrle Jr.:

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