PONE-D-19-19575

Postoperative delirium after lung resection for primary lung cancer: risk factors, risk scoring system, and prognosis

PLOS ONE

Dear Dr. Hayashi,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Reviewers raised constructive comments. They pointed out the small number of events (postopertaive delirium). You would be better to provide more supportive evidence of you prediction model using advanced statistical methods. 

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Academic Editor

PLOS ONE

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5. Review Comments to the Author

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Reviewer #1: The authors conducted the paper entitled “Postoperative delirium after lung resection for primary lung cancer: risk factors, risk scoring system, and prognosis”.

This retrospective study describes the risk factors of postoperative delirium after pulmonary resection. Postoperative delirium is a serious issue owing to a growing number of pulmonary resection for geriatric and attracts the reader’s interests. However, what the authors mean in this paper lacks persuasion owing to some flaw. I have following comments to make after going through it.

Too many factors (pre-, intra-, postoperative information) were analyzed in this paper. I believe confounding bias existed (ex. smoking, COPD, and Squamous cell carcinoma). I believe factors should be confined depending on the number of cases (only 38 events out of 570 cases). Actually, histologic type should be excluded in this analysis.

Reviewer #2: This paper studied the risk factors of postoperative delirium. With increasing age postoperative complications including delirium are becoming a major concern. Delirium is problematic with regards to medical safety, longer hospital stays, and the need for additional medical attention.

This study established a scoring system for delirium, with the scores indicating the risk of postoperative delirium. The most important point raised in the paper is preventing postoperative delirium. If a patient requiring surgery has a high risk of delirium, what should be carried out prior to surgery?

Although overall survival of the patients who developed delirium was shorter than those who did not, delirium was not related with non-cancer specific death. This finding suggests that delirium is not related to the vulnerability of patients. The conclusion of the paper is therefore incorrect. In addition, DFS and OS was calculated by the Kaplan–Meier method. Cancer-specific survival or non-cancer-specific survival should therefore be calculated using the same method.

The 30-day mortality rate appears to be higher (14 of 570; 2.5%). The annual report of the Japanese Association for Thoracic Surgery (Gen Thorac Cardiovasc Surg 2019; 67:377–411) reported that 30-day mortality rate was 0.4%. This high mortality rate after lung cancer surgery may have affected the results of this study. Please describe the causes of mortality in detail.

Postoperative complications were related with delirium (Table 3). Accordingly, postoperative recovery would affect the development of delirium. However, analyses of the postoperative factors were not sufficient. The enhanced recovery after surgery (ERAS) program is considered to be effective for avoiding postoperative complications. There is no information in the paper about early ambulation and perioperative management.

In the patient demographics, “pulmonary emphysematous change” is obscure and should be changed to pulmonary emphysema or COPD.

In line 229, the authors discussed the relationship between ICU stay and delirium. Did all the patients stay in the ICU? The rate of ICU admissions would be different between institutions. It is not a problem where the patients stay after surgery?

Reviewer #3: This is a single institution, retrospective cohort study that examines 570 patients with a history of primary lung cancer surgery in 2006 and 2017 designed to determine the risk factors related to the onset of postoperative delirium, to construct a clinically useful scoring system, and to investigate the relationship between the onset of delirium and prognosis. You have developed a new scoring system with three variables including old age, cerebrovascular disease history, and squamous cell carcinoma to predict postoperative delirium. And, you have demonstrated that the prognosis of patients with lung cancer who developed delirium after surgery was unfavorable. You have suggested that multidisciplinary approaches to take care of patients who undergo lung cancer surgery are required to improve the survival rate.

1. You should clarify how to define postoperative delirium since your study period looks so long compared with years in cited references.

2. At a glance, old, male, smokers with squamous cell carcinoma seem to have high risk for the development of postoperative dementia. All three variables in your scoring system are unmodifiable factors. I am not sure how much the prediction of postoperative dementia is helpful to improve patient outcomes through multidisciplinary approaches. Please provide your detailed suggestion on its clinical application. Modifiable factors to have potential to be associated with the development of delirium would be more interesting.

3. Since the number of events is only 38, you would be better to use the penalized maximum estimation method, so called Firth regression method, to generate regression coefficients from multivariable analysis. Please describe how to select variables for multivariable analysis among many factors that are significant in univariable analysis. And, perform multicollinearity test to reduce bias.

4. You would be better to provide the quality of the prediction model using several model performance measures, including calibration and decision curve analysis.

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Reviewer #1: No

Reviewer #2: Yes: Satoshi Shiono

Reviewer #3: No

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Postoperative delirium after lung resection for primary lung cancer: risk factors, risk scoring system, and prognosis

PONE-D-19-19575R1

Dear Dr. Hayashi,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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With kind regards,

Hyun-Sung Lee, M.D., Ph.D.

Academic Editor

PLOS ONE

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