Analysis of risk factors of postoperative complication for non-small cell lung cancer

Background The relationship between risk factors of common postoperative complications after pulmonary resection, such as air leakage, atelectasis, and arrhythmia, and patient characteristics, including nutritional status or perioperative factors, has not been sufficiently elucidated. Methods One thousand one hundred thirty-nine non-small cell lung cancer patients who underwent pulmonary resection were retrospectively analyzed for risk factors of common postoperative complications. Results In a multivariate analysis, male sex (P = 0.01), age ≥ 65 years (P < 0.01), coexistence of chronic obstructive pulmonary disease (COPD) (P < 0.01), upper lobe (P < 0.01), surgery time ≥ 155 min (P < 0.01), and presence of lymphatic invasion (P = 0.01) were significant factors for postoperative complication. Male sex (P < 0.01), age ≥ 65 years (P = 0.02), body mass index (BMI) < 21.68 (P < 0.01), coexistence of COPD (P = 0.02), and surgery time ≥ 155 min (P = 0.01) were significant factors for severe postoperative complication. Male sex (P = 0.01), BMI < 21.68 (P < 0.01), thoracoscopic surgery (P < 0.01), and surgery time ≥ 155 min (P < 0.01) were significant risk factors for postoperative air leakage. Coexistence of COPD (P = 0.01) and coexistence of asthma (P < 0.01) were significant risk factors for postoperative atelectasis. Prognostic nutrition index (PNI) < 45.52 (P < 0.01), lobectomy or extended resection more than lobectomy (P = 0.01), and surgery time ≥ 155 min (P < 0.01) were significant risk factors for postoperative arrhythmia. Conclusion Low BMI, thoracoscopic surgery, and longer surgery time were significant risk factors for postoperative air leakage. Coexistence of COPD and coexistence of asthma were significant risk factors for postoperative atelectasis. PNI, surgery time, and surgical procedure were revealed as risk factors of postoperative arrhythmia. Patients with these factors should be monitored for postoperative complication. Trial registration The Institutional Review Board of Kanazawa Medical University approved the protocol of this retrospective study (approval number: I392), and written informed consent was obtained from all patients.


Background
The incidence of postoperative complications associated with pulmonary resection for non-small cell lung cancer (NSCLC) was reported to be 9-37% [1][2][3].Furthermore, the incidence of postoperative complications associated with lobectomy was 10-50% and was higher in older patients [4].Several postoperative complications might occur after pulmonary resection, and air leakage, pneumonia, atelectasis, and arrhythmia are considered common complications.In these reports, the incidence of postoperative pulmonary complications after pulmonary resection was 6-30%.Age, smoking history, and chronic obstructive pulmonary disease (COPD) are considered significant risk factors for postoperative pulmonary complications [5][6][7][8][9].
In our previous study, we reported that the coexistence of asthma, neutrophil-to-lymphocyte ratio (NLR), and pulmonary lobe were significant risk factors for postoperative complications [10].Recently, low body mass index (BMI) and nutritional status, such as prognostic nutrition index (PNI), have been demonstrated as risk factors of postoperative pulmonary complications [11][12][13].Furthermore, Charlson comorbidity index (CCI), surgical procedure, and surgery time were showed as risk factors of postoperative complications [14].However, the relationship between risk factors of common postoperative complications, such as air leakage, atelectasis, and arrhythmia, after pulmonary resection and patient characteristics, including nutritional status, or perioperative factors have not been adequately elucidated.
In the present study, we retrospectively analyzed the risk factors of postoperative complications in NSCLC patients who underwent pulmonary resection, including risk factors of common postoperative complications.

Patients
One thousand one hundred thirty-nine NSCLC patients who underwent pulmonary resection at Kanazawa Medical University between January 2002 and December 2021 were enrolled in this retrospective study.
Data collected were sex, age, smoking history, BMI, comorbidity, CCI, carcinoembryonic antigen (CEA) levels, PNI, NLR, cancer inflammation prognostic index (CIPI), and pulmonary lobe involvement in lung cancer.Smoking history was assessed using the Brinkman Index, which is calculated by multiplying the number of cigarettes smoked per day by the number of years the subject has been smoking [15].CCI was calculated by score according to the comorbidity grade [16].Furthermore, comorbidity was divided into six categories: atrial fibrillation, pectoris angina, interstitial lung disease (ILD), COPD, asthma, and diabetes mellitus.PNI was calculated by combining serum albumin levels with the total peripheral lymphocyte count in peripheral blood [17].NLR was defined as the ratio of neutrophil-to-lymphocyte count, and CIPI was calculated as CEA (ng/ml) × NLR [18,19].

Surgical factors
Data collected were surgical approach, surgery time, and surgical procedure.The surgical approach was divided into three categories: robotic-assisted thoracic surgery (RATS), video-assisted thoracic surgery (VATS), and open thoracotomy.We decided to undertake RATS and VATS as the thoracoscopic surgery.The surgical procedure was divided into seven categories: wedge resection, segmentectomy, lobectomy, sleeve lobectomy, lobectomy combined with segmentectomy, lobectomy combined with chest wall resection, bilobectomy, and pneumonectomy.

Pathological factors
Data on lymphatic invasion, vascular invasion, differentiation, histological type, and pathological stage were collected.

Postoperative complications
Postoperative complications were categorized into five grades according to the Clavien-Dindo classification system: grade I, II, IIIa, IIIb, IVa, IVb, and V.The suffix "d" (for "disability") was used to denote any postoperative impairment [20].Severe complications were defined as grade IIIa or more.Furthermore, we also divided postoperative complications into nine categories for the multivariate analysis of risk factors: air leakage, arrhythmia, atelectasis, pneumonia, chylothorax, home oxygen therapy, cerebral infarction, empyema or pleuritis, and surgical site infection.

Statistical analyses
Qualitative variables are expressed as absolute numbers and percentages, and quantitative data are expressed as medians and ranges.The cutoff values for factors associated with postoperative complications were calculated using receiver operating characteristic (ROC) curve analysis, and risk analyses were performed using these cutoff values.The univariate and multivariate analysis of the risk factors for the postoperative complications, including severe postoperative complication and each postoperative complications, were performed by logistic regression analysis Multivariate analysis was performed for the factors that showed significant differences in univariate analysis.All statistical analyses were two-sided and statistical significance was set at P < 0.05.Statistical analyses were performed using JMP software v14 (SAS Institute Inc., Cary, NC, USA).

Patients' characteristics
The clinicopathological characteristics of the 1139 patients are shown in Table 1

Univariate and multivariate analyses
The relationship between patient characteristics and postoperative complications was analyzed (Table 2).

Risk factors of each postoperative complication
The significant risk factors of each postoperative complication by multivariate analysis are shown in Table 4.
Coexistence of COPD (P < 0.01), coexistence of asthma (P < 0.01), and upper lobe (P = 0.04) were significant factors for postoperative atelectasis in the univariate analysis (data not shown).However, coexistence of COPD (P = 0.01) and coexistence of asthma (P < 0.01) were the only significant risk factors for postoperative atelectasis in the multivariate analysis.
While male sex (P < 0.01), Brinkman index ≥ 600 (P < 0.01), coexistence of COPD (P < 0.01), and nonadenocarcinoma (P = 0.03) were significant factors for postoperative pneumonia in the univariate analysis (data not shown), there were no significant risk factors for postoperative pneumonia in the multivariate analysis.
Although we analyzed the risk factors of chylothorax, home oxygen therapy, cerebral infarction, empyema or pleuritis and surgical site infection, significant risk factors could not be identified.

Discussion
We analyzed risk factors of postoperative complication for NSCLC patients who underwent pulmonary resection, including risk factors of common postoperative complications.Male sex, high age, coexistence of COPD, upper lobe, longer surgery time, and presence of lymphatic invasion were significant factors for postoperative complication.Furthermore, male sex, high age, low BMI, coexistence of COPD, and longer surgery time were significant factors for severe postoperative complication.Age, comorbidity, smoking history, surgical approach, and type of surgical procedure have previously been showed as risk factors for postoperative complication in NSCLC patients who have undergone pulmonary resection [4,6,7,14,21,22].In addition, upper lobe location and surgery time were revealed as risk factors for postoperative complication in this study.The pulmonary lobe of the tumor, including the right upper lobe, right lower lobe, and left upper lobe, was a significant risk factor for postoperative complication in our previous study [10].Furthermore, longer surgery time has been reported as a risk factor of postoperative complication for lung cancer patients who underwent pulmonary lobectomy [23].Male sex, high age, coexistence of COPD, and longer surgery time were revealed as risk factors of both postoperative complication and severe postoperative complication in this study; hence, patients with these factors should be especially monitored for postoperative complication, and the effort to shorten the surgery time should be important.
High age and low BMI have been demonstrated as risk factors of postoperative pulmonary complication [12,13].Male sex, low BMI, thoracoscopic surgery, and longer surgery time were significant risk factors for postoperative air leakage, and coexistence of COPD and coexistence of asthma were significant risk factors for postoperative atelectasis, while there was no significant risk factor of postoperative pneumonia identified in this study.In a previous study, male sex and thoracoscopic surgery were revealed as risk factors of postoperative air leakage, and the presence of asthma was showed as a risk factor of postoperative atelectasis or pneumonia [24].
Although risk factors of postoperative pneumonia were not revealed in current study, smoking status tended to be a risk factor of postoperative pneumonia and then the careful follow-up should be necessary.
Although surgical procedure has previously been reported as a risk factor of postoperative arrhythmia [24], PNI and surgery time, in addition to surgical procedure, were revealed as risk factors of postoperative arrhythmia in this study.Nutritional status has not been reported as a risk factor of postoperative arrhythmia for NSCLC patients who have undergone pulmonary resection, and further studies are needed.Longer surgery time might induce autonomic denervation and stress-mediated neurohumoral mechanisms resulting postoperative arrythmia.Surgical procedure, such as lobectomy or extended resection more than lobectomy, might induce a large load to the right heart system and cause arrhythmia by reducing pulmonary vasculature.
The utility of sublobar resection for early-stage NSCLC was recently revealed [25][26][27].Although sublobar resection is associated with less postoperative complications than lobectomy in these reports, there were no significant differences in risk of postoperative complications among surgical procedures in this study.Postoperative complications by surgical procedures might be significant differences in patient populations such as the elderly or with emphysematous lungs, and the future studies should be needed.
Although chylothorax and cerebral infarction are crucial postoperative complications for NSCLC patients who have undergone pulmonary resection, it might be difficult to statistically determine the risk factors of these postoperative complications because of the small numbers of patients with such complications, as in this study.
This study had several limitations.First, it was a retrospective study, and it potentially involved unobserved cofounding and selection biases.Second, the study was performed at a single institution, and the study population was small.The small representation of atrial fibrillation or asthma or interstitial lung disease in this study might be limited the effect to risk on postoperative complications including postoperative severe complications and each postoperative complication.Third, the possibility cannot be ruled out that there were cases that were not included in this study due to insufficient data, resulting in selection bias.

Conclusions
We analyzed risk factors of postoperative complication for NSCLC patients who underwent pulmonary resection, including risk factors of common postoperative complications.Male sex, high age, coexistence of COPD, and longer surgery time were revealed as risk factors of both postoperative complication and severe postoperative complication in this study.For each postoperative complication, male sex, low BMI, thoracoscopic surgery, and longer surgery time were significant risk factors for postoperative air leakage, while coexistence of COPD and coexistence of asthma were significant risk factors for postoperative atelectasis, and PNI, surgery time, and surgical procedure were revealed as risk factors of postoperative arrhythmia.There was no significant risk factor of postoperative pneumonia.Patients with these factors should be carefully monitored for each postoperative complication.

Table 1
Patient characteristics home oxygen therapy in seven, cerebral infarction in six, empyema or pleuritis in six, surgical site infection in six, and broncho-pleural fistula in three.

Table 2
Univariate analysis and multivariate analysis of risk factor for postoperative complication CI; confidence interval, BI; Brinkman index, BMI; body mass index, COPD; chronic obstructive pulmonary disease, PNI; prognostic nutrition index, CIPI; cancerinflammation prognostic index, Lobe or extend; lobectomy or extend resection more than lobectomy, G; grade of differentiation

Table 3
Univariate analysis and multivariate analysis of risk factor for postoperative severe complication CI; confidence interval, BI; Brinkman index, BMI; body mass index, COPD; chronic obstructive pulmonary disease, PNI; prognostic nutrition index, CIPI; cancerinflammation prognostic index, Lobe or extend; lobectomy or extend resection more than lobectomy, G; grade of differentiation

Table 4
Multivariate analysis of risk factors for each postoperative complication CI; confidence interval, BI; Brinkman index, BMI; body mass index, COPD; chronic obstructive pulmonary disease, CIPI; cancer-inflammation prognostic index, PNI; prognostic nutrition index, Lobe or extend; lobectomy or extend resection more than lobectomy, G; grade of differentiation