ABSTRACT
BACKGROUND
Severe postoperative acute respiratory failure (PARF) is potentially life-threatening. However, risk factors for severe PARF and mortality associated with severe PARF requiring corticosteroids remain unclear. The objectives of this study was to elucidate the occurrence and risk factors of severe PARF and in-hospital mortality after severe PARF.
METHODS
We utilised the Diagnosis Procedure Combination database, a national inpatient database in Japan, to retrospectively extract data on adult patients who underwent thoracic or abdominal surgery under general anaesthesia from April 2012 to March 2013. We performed a multivariable logistic regression analysis for the occurrence of severe PARF, defined by patients who required corticosteroid pulse therapy after surgery.
RESULTS
Among 607,079 patients who met the inclusion criteria, 553,106 underwent abdominal surgery and 53,973 underwent thoracic surgery. A significantly lower proportion of patients underwent corticosteroid pulse therapy in the abdominal than thoracic surgery group (0.2% vs. 1.0%, respectively; p < 0.001). The occurrence of severe PARF requiring corticosteroid pulse therapy was significantly associated with male sex, poor activities of daily living at admission, a longer duration of anaesthesia, thoracic surgery, and preoperative interstitial pneumonia. The mortality in patients who required corticosteroid pulse therapy were 34.2% and 36.7% in the abdominal and thoracic surgery groups, respectively (p = 0.292).
CONCLUSIONS
This large-scale study demonstrated significant risks of the occurrence of severe PARF requiring corticosteroid pulse therapy. Poor clinical outcomes were observed in association with severe PARF.
INTRODUCTION
Acute exacerbation (AE) of interstitial pneumonia (IP) is one of the severe postoperative lung complication (PLC) causing acute respiratory failure and is often as critical as respiratory distress syndrome (ARDS) [1]. These two pathological conditions are usually difficult to distinguish from each other at onset [2]. The mortality rates associated with AE of IP and ARDS are considerably high, and no effective pharmacologic treatments have been established. Although debatable, treatment with a high-dose corticosteroid has been exploited as an initial management technique in patients with severe PLC [3–5].
Some surgical procedures are reportedly associated with the development of PLC. Surgeries involving general anaesthesia may catalyse severe PLC, namely, severe postoperative acute respiratory failure (PARF), particularly AE of IP and ARDS [3, 6–9]. A higher incidence of AE of IP in patients who underwent thoracic than abdominal surgery has also been reported [10]. Several studies have revealed risk factors for PLC in patients undergoing craniocervical surgery [9, 11] and lung surgery [12]. PLC were associated with prolonged intensive care unit and hospital stays in a previous study on craniocervical surgery [9], while another study failed to determine such risks [11]. Chronic obstructive pulmonary disease and smoking are reported risk factors for PLC after lung surgery [12].
However, most previous studies of severe PLC have focused on patients diagnosed with IP before surgery. Little is known about factors affecting the development of severe PLC in patients without IP. Whether the risk of severe PLC in thoracic surgery is higher than that in abdominal surgery remains unclear because of the small sample sizes of previous reports. Additionally, whether the risk factors for severe PLC reported in previous studies can be generalised to all abdominal and thoracic surgeries is unknown. Inclusion of patients with bronchospasm, pneumothorax, atelectasis, or pleural effusion after surgery in PLC of previous studies discriminates PLC from severe PARF. Finally, mortality after high-dose corticosteroid therapy in patients with severe PARF has not been reported.
The present study was performed to clarify the risk factors for the occurrence of severe PARF and the mortality associated with severe PARF in patients undergoing thoracic and abdominal surgery using a nationwide inpatient database in Japan.
METHODS
ETHICAL CONSIDERATIONS
Conduct of the study was approved by the Institutional Review Board of The University of Tokyo with waiver of informed consent owing to the anonymity of the data.
DATABASE
This study was approved by the Institutional Review Board of The University of Tokyo. Exemption of the requirement for patient informed consent was granted because of the anonymous nature of the data.
We retrospectively collected data abstracted from the Japanese Diagnosis Procedure Combination database, which is a nationwide inpatient database in Japan. The database contains administrative claims data and discharge abstract data. The main diagnosis, comorbidities on admission, and complications occurring during hospitalisation are indicated using the International Classification of Disease and Related Health Problems, 10th Revision (ICD-10) codes accompanied by Japanese text data. The database also contains the following data: age, sex, body height and weight, smoking (pack-years), status of disability of activities of daily living based on the Barthel index (an original scale used to measure performance in activities of daily living) [13] on admission, duration of anaesthesia, medications, and discharge status including in-hospital death.
The body mass index (BMI) was calculated and divided into the following categories: <18.5, 18.5–24.9, 25.0–29.9, and ≥30.0 kg/m2. The smoking status was categorised into 0, 1–9, 10–19, 20–39, and ≥40 pack-years. The Barthel index was categorised into 20, 11–19, and 0–10. The duration of anaesthesia was categorised into ≤120, 121–180, 181–240, 241–300, and ≥301 min.
PATIENT SELECTION
We included patients aged ≥20 years who underwent thoracic or abdominal surgery under general anaesthesia from April 2012 to March 2013. We defined patients with severe PARF as those who required postoperative corticosteroid pulse therapy (CP); that is, intravenous high-dose (equivalent to methylprednisolone at ≥250 mg/day) corticosteroid infusion for ≥3 consecutive days. Our attempt was to increase the sensitivity of PARF by defining patients by the use of corticosteroid pulse therapy instead of ICD-10 codes, because the sensitivity of treatment records were higher compared to that of the diagnosis of comorbidities in the previous study of the DPC database, while the specificity of the diagnosis of comorbidities were comparably high as treatment records [14]. We excluded patients who were diagnosed with specific diseases requiring postoperative CP, such as collagen vascular disease (Supplementary Table 1), because these patients may have been treated with CP without lung complications [15]. We defined patients with pre-existing IP as those who had ICD-10 codes for IP (J841, J848, J849, J672, J679, J990, and J991) at admission.
PRIMARY AND SECONDARY OUTCOMES
The primary outcome was the occurrence of severe PARF. The secondary outcome was in-hospital mortality after severe PARF.
STATISTICAL ANALYSIS
We used the chi-square test to compare proportions between abdominal surgery and thoracic surgery and to compare proportions between those who developed severe PARF and those who died after severe PARF development. We performed a multivariable logistic regression analysis for the occurrence of severe PARF with adjustment for Patient backgrounds, while adjusting for within-hospital clustering with a generalised estimation equation. In the multivariable model, we excluded patients who had missing values for age and pack-years of cigarette smoking, because the fraction of patients was extremely small. We employed missing indicator approach in the regression model for BMI and Barthel index, both of which had moderate size missingness. We further conducted multiple imputation analysis and complete case analysis as sensitivity analyses to show the robustness of our results. For multiple imputation method to acquire imputation estimates and standard errors, 20 imputed datasets were created, by using multivariate imputation by chained equations technique, which were then combined by fitting into Rubin’s rule [16]. “The variables used to create data sets were the followings: development of PARF, age, sex, pre-existing interstitial pneumonia, surgical region of the body.”
In order to assess the plausibility of the definition of CP to capture PARF, we conducted sensitivity analyses using two more definitions of CP: intravenous high-dose (equivalent to methylprednisolone at ≥250 mg/day) corticosteroid infusion for ≥4 consecutive days and intravenous high-dose (equivalent to methylprednisolone at ≥500 mg/day) corticosteroid infusion for ≥3 consecutive days. The threshold value for significance was p < 0.05. All statistical analyses were performed using SPSS version 22.0 (IBM SPSS Inc., Armonk, NY, USA).
RESULTS
PATIENT CHARACTERISTICS
The baseline characteristics of patients assessed in this study are shown in Table 1. Among 607,079 patients who met the inclusion criteria, 53,973 patients underwent thoracic surgery, and 553,106 patients underwent abdominal surgery (Fig. 1). The mean age was 59.8 (standard deviation [SD], 19.5) in the thoracic surgery group and 56.4 years (SD, 21.8) in the abdominal surgery group. The proportion of males was 65.9% and 48.8% in thoracic and abdominal surgery groups, respectively. The mean BMI was 22.1 kg/m2 (SD, 3.7) and 22.4 kg/m2 (SD, 4.1), and the mean Barthel index was 19.2 (SD, 3.2) and 18.4 (SD, 4.8) in the thoracic and abdominal surgery groups, respectively. The median anaesthesia time was 224 min (interquartile range [IQR], 153–310 min) and 170 min (IQR, 153–310 min) for thoracic and abdominal surgery, respectively. The number of patients who were diagnosed with IP before surgery was 1,965 (3.6%) in the thoracic surgery group and 629 (0.1%) in the abdominal surgery group.
Table 1
Baseline characteristics
|
Total
(n = 607,079) |
Abdominal surgery
(n = 553,106) |
Thoracic surgery
(n = 53,973) |
p |
| n |
(%) |
n |
(%) |
n |
(%) |
| Age in years, mean [SD] |
56.7 |
[21.7] |
56.4 |
[21.8] |
59.8 |
[19.5] |
<0.001 |
| ≤59 |
268,895 |
(44.3) |
250,604 |
(45.3) |
18,291 |
(33.9) |
|
| 60–69 |
132,005 |
(21.7) |
116,879 |
(21.1) |
15,126 |
(28.0) |
|
| 70–79 |
137,999 |
(22.7) |
122,090 |
(22.1) |
15,909 |
(29.5) |
|
| ≥80 |
68,179 |
(11.2) |
63,532 |
(11.5) |
4,647 |
(8.6) |
|
| Missing data |
1 |
|
1 |
|
|
|
|
| Sex |
|
|
|
|
|
|
<0.001 |
| Male |
305,267 |
(50.3) |
269,699 |
(48.8) |
35,568 |
(65.9) |
|
| Female |
301,812 |
(49.7) |
283,407 |
(51.2) |
18,405 |
(34.1) |
|
| BMI in kg/m2, mean [SD] |
22.4 |
[4.1] |
22.4 |
[4.1] |
22.1 |
[3.7] |
<0.001 |
| <18.5 |
93,766 |
(15.4) |
85,188 |
(15.4) |
8,578 |
(15.9) |
|
| 18.5–24.9 |
365,931 |
(60.3) |
331,820 |
(60.0) |
34,111 |
(63.2) |
|
| 25.0–29.9 |
109,605 |
(18.1) |
100,455 |
(18.2) |
9,150 |
(17.0) |
|
| ≥30.0 |
22,879 |
(3.8) |
21,600 |
(3.9) |
1,279 |
(2.4) |
|
| Missing data |
14,898 |
|
14,043 |
|
855 |
|
|
| Barthel index, mean [SD] |
18.5 |
[4.6] |
18.4 |
[4.8] |
19.2 |
[3.2] |
<0.001 |
| 20 |
478,965 |
(78.9) |
432,599 |
(78.2) |
46,366 |
(85.9) |
|
| 11–19 |
32,961 |
(5.4) |
29,819 |
(5.4) |
3,142 |
(5.8) |
|
| 0–10 |
40,459 |
(6.7) |
38,652 |
(7.0) |
1,807 |
(3.3) |
|
| Missing data |
54,694 |
|
52,036 |
|
2,658 |
|
|
| Smoking (pack-years) |
|
|
|
|
|
|
0.267 |
| 0 |
372,328 |
(61.3) |
348,106 |
(62.9) |
24,222 |
(44.9) |
|
| 1–9 |
28,255 |
(4.7) |
25,192 |
(4.6) |
3,063 |
(5.7) |
|
| 10–19 |
28,771 |
(4.7) |
26,017 |
(4.7) |
2,754 |
(5.1) |
|
| 20–39 |
52,525 |
(8.7) |
45,928 |
(8.3) |
6,597 |
(12.2) |
|
| ≥40 |
125,184 |
(20.6) |
107,848 |
(19.5) |
17,336 |
(32.1) |
|
| Missing data |
16 |
|
15 |
|
1 |
|
|
| Duration of anaesthesia in min, median [IQR] |
175 |
[114–277] |
170 |
[110–272] |
224 |
[153–310] |
<0.001 |
| ≤120 |
173,075 |
(28.5) |
166,633 |
(30.1) |
6,442 |
(11.9) |
|
| 121–180 |
143,102 |
(23.6) |
130,382 |
(23.6) |
12,720 |
(23.6) |
|
| 181–240 |
95,425 |
(15.7) |
84,635 |
(15.3) |
10,790 |
(20.0) |
|
| 241–300 |
68,096 |
(11.2) |
58,723 |
(10.6) |
9,373 |
(17.4) |
|
| ≥301 |
127,326 |
(21.0) |
112,678 |
(20.4) |
14,648 |
(27.1) |
|
| Missing data |
55 |
|
55 |
|
|
|
|
| Pre-existing IP |
|
|
|
|
|
|
<0.001 |
| No |
604,485 |
(99.6) |
552,477 |
(99.9) |
52,008 |
(96.4) |
|
| Yes |
2,594 |
(0.4) |
629 |
(0.1) |
1,965 |
(3.6) |
|
SD, standard deviation; BMI, body mass index; IQR, interquartile range; IP, interstitial pneumonia
Fig. 1 Flow diagram of patient seletion.
Table 2 shows the proportions of patients with severe PARF in each category and the proportions of in-hospital death among patients with severe PARF in each category. The proportions of patients with severe PARF were higher in patients with an age of ≥60 years, male sex, BMI of <18.5 kg/m2, Barthel index of ≤10, smoking history of ≥40 pack-years, longer duration of anaesthesia, comorbid IP at admission, and thoracic surgery. There was no difference in the in-hospital mortality rate between patients with severe PARF who underwent thoracic surgery and abdominal surgery (36.7% vs. 34.2%, respectively).
Table 2
Proportions of patients with PARFs in each category and proportions of in-hospital death among patients with PARFs
|
n |
PARFs |
(%) |
p* |
Death |
(%) |
p† |
| Total |
607,079 |
1,884 |
(0.31) |
|
658 |
(34.9) |
|
| Age in years |
|
|
|
<0.01 |
|
|
<0.01 |
| ≤59 |
268,895 |
558 |
(0.21) |
|
87 |
(15.6) |
|
| 60–69 |
132,005 |
475 |
(0.36) |
|
160 |
(33.7) |
|
| 70–79 |
137,999 |
552 |
(0.40) |
|
243 |
(44.0) |
|
| ≥80 |
68,179 |
299 |
(0.44) |
|
168 |
(56.2) |
|
| Sex |
|
|
|
<0.01 |
|
|
<0.01 |
| Male |
305,267 |
1,321 |
(0.43) |
|
511 |
(38.7) |
|
| Female |
301,812 |
563 |
(0.19) |
|
147 |
(26.1) |
|
| BMI in kg/m2, mean [SD] |
|
|
|
<0.01 |
|
|
0.152 |
| <18.5 |
93,766 |
367 |
(0.39) |
|
125 |
(34.1) |
|
| 18.5–24.9 |
365,931 |
1,039 |
(0.28) |
|
367 |
(35.3) |
|
| 25.0–29.9 |
109,605 |
312 |
(0.28) |
|
97 |
(31.1) |
|
| ≥30.0 |
22,879 |
61 |
(0.27) |
|
22 |
(36.1) |
|
| Missing data |
14,898 |
105 |
(0.70) |
|
47 |
(44.8) |
|
| Barthel index, mean [SD] |
|
|
|
<0.01 |
|
|
<0.01 |
| 20 |
478,965 |
1,138 |
(0.24) |
|
361 |
(31.7) |
|
| 11–19 |
32,961 |
157 |
(0.48) |
|
63 |
(40.1) |
|
| 0–10 |
40,459 |
380 |
(0.94) |
|
162 |
(42.6) |
|
| Missing data |
54,694 |
209 |
(0.38) |
|
72 |
(34.4) |
|
| Smoking (pack-years) |
|
|
|
<0.01 |
|
|
0.490 |
| 0 |
372,328 |
849 |
(0.23) |
|
282 |
(33.2) |
|
| 1–9 |
28,255 |
66 |
(0.23) |
|
21 |
(31.8) |
|
| 10–19 |
28,771 |
78 |
(0.27) |
|
31 |
(39.7) |
|
| 20–39 |
52,525 |
195 |
(0.37) |
|
67 |
(34.4) |
|
| ≥40 |
125,184 |
696 |
(0.56) |
|
257 |
(36.9) |
|
| Anaesthesia time in min, median [IQR] |
|
|
|
<0.01 |
|
|
0.916 |
| ≤120 |
173,075 |
175 |
(0.10) |
|
64 |
(36.6) |
|
| 121–180 |
143,102 |
259 |
(0.18) |
|
85 |
(32.8) |
|
| 181–240 |
95,425 |
222 |
(0.23) |
|
75 |
(33.8) |
|
| 241–300 |
68,096 |
190 |
(0.28) |
|
68 |
(35.8) |
|
| ≥301 |
127,326 |
1,038 |
(0.82) |
|
366 |
(35.3) |
|
| Pre-existing IP |
|
|
|
<0.01 |
|
|
0.21 |
| No |
604,485 |
1,696 |
(0.28) |
|
578 |
(34.1) |
|
| Yes |
2,594 |
188 |
(7.25) |
|
80 |
(42.6) |
|
| Surgical region of the body |
|
|
|
<0.01 |
|
|
0.292 |
| Thoracic surgery |
53,973 |
550 |
(1.02) |
|
202 |
(36.7) |
|
| Abdominal surgery |
553,106 |
1,334 |
(0.24) |
|
456 |
(34.2) |
|
PARFs, postoperative acute respiratory failure; SD, standard deviation; BMI, body mass index; IQR, interquartile range; IP, interstitial pneumonia, * denotes P-values derived from chi-squared tests for the probability of the development of PARF in patients who underwent surgery. † denotes P-values derived from chi-squared tests for the mortality in patients with PARF.
Table 3 shows the results of the multivariable logistic regression analysis for the occurrence of severe PARF. A higher probability of severe PARF was significantly associated with male sex, a BMI of <18.5 kg/m2, a lower Barthel index, a smoking history of ≥40 pack-years, a longer duration of anaesthesia, comorbid IP at admission, and thoracic surgery. Results from multiple imputation methods and complete case analyses were similar to that of missing indicator approach. (Supplementary Table 2 and 3) In our sensitivity analyses using two different definitions for PARF, the odds ratios (95% confidence interval, P-value) for thoracic surgery were 2.30 (1.82–2.91, <0.001) and 2.84 (2.37–3.42, P<0.001) for “corticosteroid infusion for ≥4 consecutive days” and “high-dose (equivalent to methylprednisolone at ≥500 mg/day)”, respectively. (Supplementary Table 4 and 5)
Table 3
Multivariable logistic regression analysis for the occurrence of PARFs
|
Adjusted odds ratio |
95% confidence interval |
p |
| Age in years |
|
|
|
| ≤59 |
Reference |
|
|
| 60–69 |
0.96 |
0.78–1.19 |
0.715 |
| 70–79 |
0.98 |
0.77–1.24 |
0.843 |
| ≥80 |
1.12 |
0.88–1.41 |
0.356 |
| Sex |
|
|
|
| Male |
Reference |
|
|
| Female |
0.67 |
0.59–0.75 |
<0.001 |
| BMI in kg/m2 |
|
|
|
| <18.5 |
1.38 |
1.19–1.60 |
<0.001 |
| 18.5–24.9 |
Reference |
|
|
| 25.0–29.9 |
0.96 |
0.85–1.08 |
0.488 |
| ≥30.0 |
1.10 |
0.82–1.46 |
0.526 |
| Missing data |
1.88 |
1.47–2.40 |
<0.001 |
| Barthel index |
|
|
|
| 20 |
Reference |
|
|
| 11–19 |
2.11 |
1.72–2.58 |
<0.001 |
| 0–10 |
4.79 |
4.00–5.73 |
<0.001 |
| Missing data |
2.18 |
1.71–2.79 |
<0.001 |
| Pack-years |
|
|
|
| 0 |
Reference |
|
|
| 1–9 |
1.06 |
0.82–1.37 |
0.643 |
| 10–19 |
1.04 |
0.80–1.33 |
0.786 |
| 20–39 |
1.09 |
0.92–1.30 |
0.320 |
| ≥40 |
1.41 |
1.20–1.66 |
<0.001 |
| Anaesthesia time in min |
|
|
|
| ≤120 |
Reference |
|
|
| 121–180 |
1.68 |
1.34–2.09 |
<0.001 |
| 181–240 |
2.14 |
1.63–2.81 |
<0.001 |
| 241–300 |
2.60 |
2.02–3.37 |
<0.001 |
| ≥301 |
7.83 |
6.14–9.99 |
<0.001 |
| Pre-existing IP |
|
|
|
| No |
Reference |
|
|
| Yes |
12.93 |
10.50–15.93 |
<0.001 |
| Surgical region of the body |
|
|
|
| Thoracic surgery |
2.70 |
2.29–3.18 |
<0.001 |
| Abdominal surgery |
Reference |
|
|
PARFs, postoperative acute respiratory failure; SD, standard deviation; BMI, body mass index; IP, interstitial pneumonia
DISCUSSION
The present nationwide study showed that significant risks of PARF included male sex, a BMI of <18.5 kg/m2, a lower Barthel index, a smoking history of ≥40 pack-years, a longer duration of anaesthesia, comorbid IP, and thoracic surgery. Sensitivity analyses with two different approaches for missingness, namely multiple imputation method and complete case analysis, and two different definitions of PARF, namely “corticosteroid infusion for ≥4 consecutive days” and “high-dose (equivalent to methylprednisolone at ≥500 mg/day)”, supported our results from the primary analysis. In-hospital mortality in patients with severe PARF was not significantly different between thoracic and abdominal surgery.
The overall proportion of severe PARF was 0.3% in the present study. This is much lower than the proportions of PLC reported in previous studies of craniocervical surgery and lung surgery because those studies included moderate pulmonary complications such as pneumonia and atelectasis [9, 11, 12]. Severe PARF focused on severe postoperative complications. Pathological conditions for which corticosteroid pulse therapy may be of value were also included in severe PARF in this study. That is, diseases with similar manifest were included, including ARDS, fat embolism, pneumocystis pneumonia, drug induced pneumonia, and severe viral or bacterial pneumonia. Therefore, the results of our study may not be comparable to previously reported risk scores such as ARISCAT score [17]. Meanwhile, the proportion of severe PARF among patients with IP in the present study was 7.3%, which is comparable with postoperative lung complications in a previous small study [10]. We therefore believe that the definition of PARF in this study have successfully captured the patients of interest.
Our study showed a higher proportion of severe PARF after thoracic surgery than abdominal surgery. This is in agreement with a previous small study of patients with interstitial lung disease [10]. Direct manipulation of the lung may trigger severe PARF in patients undergoing thoracic surgery. Pre-existing IP was the strongest risk factor among all explanatory variables tested in the present study. Our study showed that thoracic surgery had a higher risk of severe PARF even in patients including those without a preoperative diagnosis of IP. Furthermore, we demonstrated that cigarette smoking and the duration of anaesthesia were dose-dependent risk factors for severe PARF after adjustment for baseline characteristics.
The mortality rate after severe PARF in our study was 34.9%, while that after AE of IP following lung resection in previous studies ranged from 33% to 100% [1]. Because severe PARF can have devastating consequences, understanding the precise risk of severe PARF may be important for physician’s planning for surgery and patient’s decision making, particularly when they have alternative choices. Interestingly, women had a lower incidence of and lower mortality rate associated with PARF than did men. This association has not been clearly demonstrated in previous studies because of small sample sizes. One study suggested a similar trend, but it was not statistically significant [18].
We believe that our approach to the evaluation of severe PARF requiring CP is reasonable and may have an advantage in readily integrating our findings into clinical practice. AE of idiopathic pulmonary fibrosis (IPF) or idiopathic IP is often difficult to distinguish from ARDS by symptoms, laboratory testing, and diagnostic imaging at the time of onset. In fact, AE of IPF and ARDS are pathologically comparable in the sense that the primary pathological feature in the lungs is diffuse alveolar damage [19, 20]. Both AE of IPF/IP and ARDS have been reported to occur after surgery with general anaesthesia [9, 19, 21]. Furthermore, without high resolution computed tomography before surgery, it may be difficult to diagnose pre-existing IP. In fact, only 10 to 33% of all the AE-IP cases diagnosed by attending physicians fulfilled criteria on central adjudication in previous clinical trials [22]. CP has been widely used in clinical practice for patients with acute and subacute interstitial lung diseases such as drug-induced IP, acute eosinophilic pneumonia, acute exacerbations of idiopathic IP including IPF, and acute hypersensitivity pneumonitis [19, 22–24], without clear evidence. Although evidence is weak, various international societies (American Thoracic Society, European Respiratory Society, Japan Respiratory Society, and Latin American Thoracic Association) recommend corticosteroids for most patients with AE of IPF. In patients with ARDS, however, relatively low-dose corticosteroid therapy (methylprednisolone at 2 mg/kg for 14 days followed by tapering) is recommended [25, 26] rather than high-dose corticosteroid therapy such as CP followed by daily prednisolone at 1 mg/kg as a maintenance dose. Nevertheless, when we confront severe PARF in clinical practice, CP is considered a reasonable therapeutic strategy because the mortality rate for AE of IPF reportedly reaches ≥50% [10, 27, 28].
There are some limitations in our study. First, the database we used does not contain laboratory data, imaging findings, or physiological examination results. Thus, the severity as well as response to CP of the PARF could not be precisely adjusted for, although extracting patients who underwent CP as those with severe PARF may have helped to equalise the patients with severe PARF. We therefore did not perform multivariable regression analysis to further evaluate independent risks for in-hospital mortality. Second, the diagnosis of pre-existing IP relies on ICD-10 codes recorded by the attending physicians. It is conceivable that pre-existing IP was not confirmed by specialists such as pulmonologists, especially in patients undergoing abdominal surgery. In addition, patients whose pre-existing IP were not recognized nor registered by the attending physician were considered as not having pre-existing IP. Moreover, if we take previous reports into consideration, claiming for higher incidence of AE of IPF [29] and reportedly higher incidence of drug induced pneumonia in molecular target drugs [30–32] in Japanese ethnicity, using a database which was comprised of only Japanese ethnicity may be the third limitation of this study. This ethnic disparity may also indirectly account for corticosteroid pulse therapy being more common therapy in Japan. However, whether vulnerability to surgical stress or general anesthesia accompanied by mechanical ventilation may differ between ethnicities remain uncertain. The forth limitation was the consequence of the defining PARF by the use of CP. Our definition may have increased the sensitivity of PARF, whereas the specificity of the disease may have been compromised. However, considering the relatively low sensitivity of the ICD-10 codes for comorbidities, in general, in the DPC data base, we believed that the advantage of our definition of PARF outrun the disadvantage.
Summarizing the above, the present study using a nationwide inpatient database showed that male sex, a BMI of <18.5 kg/m2, a lower Barthel index, a smoking history of ≥40 pack-years, a longer duration of anaesthesia, comorbid IP, and thoracic surgery were significantly associated with severe PARF. This study provides important information on the postoperative risks, thereby supporting clinical decision-making.
ACKNOWLEDGMENTS
This work was supported by grants from the Ministry of Health, Labour and Welfare, Japan (H29-Policy-Designated-009 and H29-ICT-Genral-004); Ministry of Education, Culture, Sports, Science and Technology, Japan (17H04141); and the Japan Agency for Medical Research and Development (AMED).
ABBREVIATIONS
PARF, postoperative acute respiratory failure; PLC, postoperative lung complications; AE, Acute exacerbation; IP, interstitial pneumonia; IPF, idiopathic pulmonary fibrosis; ARDS, acute respiratory distress syndrome; ICD-10, the International Classification of Disease and Related Health Problems, 10th Revision; BMI, body mass index; CP, corticosteroid pulse therapy; SD, standard deviation; IQR, interquartile range
CONFLICT OF INTEREST
None declared.
Supplementary Table 1
ICD-10 codes used to exclude disease with potential for high dose corticosteroid therapy
| Disease |
ICD-10 codes |
| Erythema |
L539 |
| Drug eruption |
L270 |
| Toxicoderma |
L279 |
| Exudative erythema type poisoning eruption |
L530 |
| Pemphigus |
L101-109 |
| Pemphigoid |
L120-121 129 |
| Epidermolysis bullosa acquisita |
L123 |
| Adult Still’s disease |
M0610 |
| HTLV-1-associated myelopathy |
A858, B973 |
| Myasthenia gravis |
G700 |
| Eaton-Lambert syndrome |
C80 G731 |
| Subacute cerebellar degeneration |
G319 |
| Limbic encephalitis |
C80 G131 |
| Polyneuropathy |
G629 |
| temporal arteritis |
M316 |
| Spinal arachnoiditis |
G039 |
| Acute disseminated encephalomyelitis |
G040 |
| multiple sclerosis |
G35 |
| spastic paraplegia |
G821 |
| Relapsing polychondritis |
M9410 |
| Behcet’s disease |
M352 |
| Idiopathic hypereosinophilic syndrome |
D721 |
| Antiphospholipid antibody syndrome |
D688 |
| Sjogren’s syndrome |
M350 |
| ANCA-associated vasculitis |
M318 |
| Polyarteritis nodosa |
M300 |
| Hypersensitivity vasculitis |
M310 |
| Cryoglobulinemia |
D891 |
| Leukocytoclastic cutaneous vasculitis |
D690 |
| Schoenlein-Henoch purpura |
D690 |
| Scleroderma |
M340 348 349 L940 941 |
| systemic lupus erythematosus |
L930-932 M321 329 |
| rheumatoid arthritis |
M530 M690-M698 |
| Paraquat poisoning |
T603 |
| Fat embolism |
T791 |
| Acute spinal cord injury |
T093 |
| Idiopathic thrombocytopenic purpura |
D693-695 |
| Thrombotic thrombocytopenic purpura |
M311 |
| Hemolytic-uremic syndrome |
D593 |
| Interstitial nephritis |
N10 N119 N12 |
| Nephrotic syndrome |
N049 |
| Purpura nephritis |
N082 |
| IgA nephropathy |
N028 |
| Chronic nephritis |
N039 |
| rapidly progressive glomerulonephritis |
N019 |
| autoimmune hepatitis |
K754 |
| Drug-induced liver injury |
K719 |
| Alcoholic hepatitis |
K701 |
| Fulminant hepatitis |
B199 |
| Crohn’s disease |
K509 |
| Ulcerative colitis |
K519 |
| Aortitis syndrome |
M314 |
| Myocarditis |
I514 |
| Goodpasture’s syndrome |
M310 |
Supplementary Table 2
Multivariable logistic regression analysis for the occurrence of PARFs after multiple imputation
|
Adjusted odds ratio |
95% confidence interval |
p |
| Age in years |
|
|
|
| ≤59 |
Reference |
|
|
| 60–69 |
0.90 |
0.76–1.06 |
0.219 |
| 70–79 |
0.92 |
0.76–1.12 |
0.423 |
| ≥80 |
1.03 |
0.84–1.25 |
0.791 |
| Sex |
|
|
|
| Male |
Reference |
|
|
| Female |
0.70 |
0.64–0.78 |
<0.001 |
| BMI in kg/m2 |
|
|
|
| <18.5 |
1.34 |
1.18–1.53 |
<0.001 |
| 18.5–24.9 |
Reference |
|
|
| 25.0–29.9 |
0.97 |
0.87–1.08 |
0.556 |
| ≥30.0 |
1.09 |
0.85–1.40 |
0.476 |
| Barthel index |
|
|
|
| 20 |
Reference |
|
|
| 11–19 |
2.14 |
1.79–2.57 |
<0.001 |
| 0–10 |
4.65 |
3.95–5.47 |
<0.001 |
| Pack-years |
|
|
|
| 0 |
Reference |
|
|
| 1–9 |
1.06 |
0.86–1.31 |
0.593 |
| 10–19 |
1.03 |
0.83–1.29 |
0.779 |
| 20–39 |
1.08 |
0.93–1.26 |
0.298 |
| ≥40 |
1.43 |
1.25–1.65 |
<0.001 |
| Anaesthesia time in min |
|
|
|
| ≤120 |
Reference |
|
|
| 121–180 |
1.56 |
1.30–1.89 |
<0.001 |
| 181–240 |
1.93 |
1.54–2.42 |
<0.001 |
| 241–300 |
2.31 |
1.85–2.87 |
<0.001 |
| ≥301 |
6.57 |
5.30–8.14 |
<0.001 |
| Pre-existing IP |
|
|
|
| No |
Reference |
|
|
| Yes |
11.87 |
9.67–14.56 |
<0.001 |
| Surgical region of the body |
|
|
|
| Thoracic surgery |
2.54 |
2.18–2.95 |
<0.001 |
| Abdominal surgery |
Reference |
|
|
PARFs, postoperative acute respiratory failure; SD, standard deviation; BMI, body mass index; IP, interstitial pneumonia
Supplementary Table 3
Complete case analysis with a total of 541,227 patients using a multivariable logistic regression model for the occurrence of PARFs
|
Adjusted odds ratio |
95% confidence interval |
p |
| Age in years |
|
|
|
| ≤59 |
Reference |
|
|
| 60–69 |
0.86 |
0.72–1.02 |
0.077 |
| 70–79 |
0.84 |
0.69–1.04 |
0.106 |
| ≥80 |
0.95 |
0.77–1.17 |
0.627 |
| Sex |
|
|
|
| Male |
Reference |
|
|
| Female |
0.66 |
0.59–0.74 |
<0.001 |
| BMI in kg/m2 |
|
|
|
| <18.5 |
1.50 |
1.30–1.73 |
<0.001 |
| 18.5–24.9 |
Reference |
|
|
| 25.0–29.9 |
1.00 |
0.90–1.12 |
0.937 |
| ≥30.0 |
1.12 |
0.86–1.45 |
0.388 |
| Barthel index |
|
|
|
| 20 |
Reference |
|
|
| 11–19 |
2.07 |
1.73–2.48 |
<0.001 |
| 0–10 |
4.59 |
3.85–5.49 |
<0.001 |
| Pack-years |
|
|
|
| 0 |
Reference |
|
|
| 1–9 |
1.05 |
0.84–1.31 |
0.680 |
| 10–19 |
0.91 |
0.72–1.15 |
0.440 |
| 20–39 |
1.03 |
0.89–1.22 |
0.637 |
| ≥40 |
1.38 |
1.19–1.61 |
<0.001 |
| Anaesthesia time in min |
|
|
|
| ≤120 |
Reference |
|
|
| 121–180 |
1.59 |
1.28–1.96 |
<0.001 |
| 181–240 |
1.90 |
1.48–2.45 |
<0.001 |
| 241–300 |
2.43 |
1.92–3.08 |
<0.001 |
| ≥301 |
6.88 |
5.48–8.64 |
<0.001 |
| Pre-existing IP |
|
|
|
| No |
Reference |
|
|
| Yes |
12.33 |
9.94–15.30 |
<0.001 |
| Surgical region of the body |
|
|
|
| Thoracic surgery |
2.48 |
2.11–2.92 |
<0.001 |
| Abdominal surgery |
Reference |
|
|
PARFs, postoperative acute respiratory failure; SD, standard deviation; BMI, body mass index; IP, interstitial pneumonia
Supplementary Table 4
Multivariable logistic regression analysis for the occurrence of PARFs defined by “corticosteroid infusion for ≥4 consecutive days”
|
Adjusted odds ratio |
95% confidence interval |
p |
| Age in years |
|
|
|
| ≤59 |
Reference |
|
|
| 60–69 |
0.79 |
0.61–1.03 |
0.063 |
| 70–79 |
0.74 |
0.55–0.99 |
0.039 |
| ≥80 |
0.77 |
0.57–1.03 |
0.076 |
| Sex |
|
|
|
| Male |
Reference |
|
|
| Female |
0.71 |
0.57–0.87 |
0.001 |
| BMI in kg/m2 |
|
|
|
| <18.5 |
1.34 |
1.07–1.67 |
0.01 |
| 18.5–24.9 |
Reference |
|
|
| 25.0–29.9 |
0.99 |
0.82–1.20 |
0.914 |
| ≥30.0 |
1.17 |
0.79–1.72 |
0.438 |
| Missing data |
2.04 |
1.41–2.95 |
<0.001 |
| Barthel index |
|
|
|
| 20 |
Reference |
|
|
| 11–19 |
2.07 |
1.58–2.71 |
<0.001 |
| 0–10 |
5.13 |
4.00–6.58 |
<0.001 |
| Missing data |
1.85 |
1.35–2.57 |
<0.001 |
| Pack-years |
|
|
|
| 0 |
Reference |
|
|
| 1–9 |
1.06 |
0.73–1.54 |
0.748 |
| 10–19 |
1.10 |
0.77–1.56 |
0.608 |
| 20–39 |
0.98 |
0.76–1.25 |
0.847 |
| ≥40 |
1.15 |
0.88–1.49 |
0.305 |
| Anaesthesia time in min |
|
|
|
| ≤120 |
Reference |
|
|
| 121–180 |
1.72 |
1.23–2.40 |
0.002 |
| 181–240 |
2.15 |
1.32–3.51 |
0.002 |
| 241–300 |
2.66 |
1.84–3.85 |
<0.001 |
| ≥301 |
10.42 |
7.57–14.35 |
<0.001 |
| Pre-existing IP |
|
|
|
| No |
Reference |
|
|
| Yes |
15.39 |
11.44–20.70 |
<0.001 |
| Surgical region of the body |
|
|
|
| Thoracic surgery |
2.30 |
1.82–2.91 |
<0.001 |
| Abdominal surgery |
Reference |
|
|
PARFs, postoperative acute respiratory failure; SD, standard deviation; BMI, body mass index; IP, interstitial pneumonia
Supplementary Table 5
Multivariable logistic regression analysis for the occurrence of PARFs defined by “high-dose (equivalent to methylprednisolone at ≥500 mg/day)”
|
Adjusted odds ratio |
95% confidence interval |
p |
| Age in years |
|
|
|
| ≤59 |
Reference |
|
|
| 60–69 |
1.05 |
0.84–1.33 |
0.661 |
| 70–79 |
1.09 |
0.85–1.41 |
0.489 |
| ≥80 |
1.23 |
0.95–1.58 |
0.111 |
| Sex |
|
|
|
| Male |
Reference |
|
|
| Female |
0.61 |
0.53–0.70 |
<0.001 |
| BMI in kg/m2 |
|
|
|
| <18.5 |
1.39 |
1.18–1.63 |
<0.001 |
| 18.5–24.9 |
Reference |
|
|
| 25.0–29.9 |
0.99 |
0.86–1.13 |
0.858 |
| ≥30.0 |
1.11 |
0.82–1.51 |
0.500 |
| Missing data |
1.88 |
1.45–2.44 |
<0.001 |
| Barthel index |
|
|
|
| 20 |
Reference |
|
|
| 11–19 |
2.19 |
1.78–2.71 |
<0.001 |
| 0–10 |
5.14 |
4.23–6.24 |
<0.001 |
| Missing data |
2.23 |
1.69–2.94 |
<0.001 |
| Pack-years |
|
|
|
| 0 |
Reference |
|
|
| 1–9 |
1.06 |
0.79–1.42 |
0.708 |
| 10–19 |
1.15 |
0.88–1.52 |
0.309 |
| 20–39 |
1.10 |
0.90–1.35 |
0.335 |
| ≥40 |
1.40 |
1.18–1.67 |
<0.001 |
| Anaesthesia time in min |
|
|
|
| ≤120 |
Reference |
|
|
| 121–180 |
1.70 |
1.33–2.17 |
<0.001 |
| 181–240 |
2.21 |
1.64–2.98 |
<0.001 |
| 241–300 |
2.61 |
1.97–3.46 |
<0.001 |
| ≥301 |
7.24 |
5.61–9.33 |
<0.001 |
| Pre-existing IP |
|
|
|
| No |
Reference |
|
|
| Yes |
13.18 |
10.52–16.52 |
<0.001 |
| Surgical region of the body |
|
|
|
| Thoracic surgery |
2.84 |
2.37–3.42 |
<0.001 |
| Abdominal surgery |
Reference |
|
|
PARFs, postoperative acute respiratory failure; SD, standard deviation; BMI, body mass index; IP, interstitial pneumonia
REFERENCES
- 1. Watanabe A, Kawaharada N, Higami T. Postoperative Acute exacerbation of IPF after lung resection for primary lung cancer. Pulm Med 2011;2011:960316.
- 2. Ichikado K. High-resolution computed tomography findings of acute respiratory distress syndrome, acute interstitial pneumonia, and acute exacerbation of idiopathic pulmonary fibrosis. Semin Ultrasound CT MR 2014;35:39–46.
- 3. Chida M, Ono S, Hoshikawa Y, Kondo T. Subclinical idiopathic pulmonary fibrosis is also a risk factor of postoperative acute respiratory distress syndrome following thoracic surgery. Eur J Cardiothorac Surg 2008;34:878–881.
- 4. Sakamoto S, Homma S, Mun M, Fujii T, Kurosaki A, Yoshimura K. Acute exacerbation of idiopathic interstitial pneumonia following lung surgery in 3 of 68 consecutive patients: a retrospective study. Intern Med 2011;50:77–85.
- 5. Suzuki H, Sekine Y, Yoshida S, Suzuki M, Shibuya K, Yonemori Y, et al. Risk of acute exacerbation of interstitial pneumonia after pulmonary resection for lung cancer in patients with idiopathic pulmonary fibrosis based on preoperative high-resolution computed tomography. Surgery Today 2011;41:914–921.
- 6. Kondoh Y, Taniguchi H, Kitaichi M, Yokoi T, Johkoh T, Oishi T, et al. Acute exacerbation of interstitial pneumonia following surgical lung biopsy. Respir Med 2006;100:1753–1759.
- 7. Sugiura H, Takeda A, Hoshi T, Kawabata Y, Sayama K, Jinzaki M, et al. Acute exacerbation of usual interstitial pneumonia after resection of lung cancer. Ann Thorac Surg 2012;93:937–943.
- 8. Kumar P, Goldstraw P, Yamada K, Nicholson AG, Wells AU, Hansell DM, et al. Pulmonary fibrosis and lung cancer: risk and benefit analysis of pulmonary resection. The Journal of Thoracic and Cardiovascular Surgery 2003;125:1321–1327.
- 9. Petrar S, Bartlett C, Hart RD, MacDougall P. Pulmonary complications after major head and neck surgery: A retrospective cohort study. Laryngoscope 2012;122:1057–1061.
- 10. Choi SM, Lee J, Park YS, Cho YJ, Lee CH, Lee SM, et al. Postoperative pulmonary complications after surgery in patients with interstitial lung disease. Respiration 2014;87:287–293.
- 11. Damian D, Esquenazi J, Duvvuri U, Johnson JT, Sakai T. Incidence, outcome, and risk factors for postoperative pulmonary complications in head and neck cancer surgery patients with free flap reconstructions. J Clin Anesth 2016;28:12–18.
- 12. Lugg ST, Agostini PJ, Tikka T, Kerr A, Adams K, Bishay E, et al. Long-term impact of developing a postoperative pulmonary complication after lung surgery. Thorax 2016;71:171–176.
- 13. Mahoney FI, Barthel DW. Functional evaluation: the barthel index. Md State Med J 1965;14:61–65.
- 14. Yamana H, Moriwaki M, Horiguchi H, Kodan M, Fushimi K, Yasunaga H. Validity of diagnoses, procedures, and laboratory data in Japanese administrative data. J Epidemiol 2017;27:476–482.
- 15. Kim TY, Kim SB, Park SK. The efficacy of steroid pulse therapy in patients with IgA nephropathy. Clin Nephrol 2012;78:100–105.
- 16. Aloisio KM, Swanson SA, Micali N, Field A, Horton NJ. Analysis of partially observed clustered data using generalized estimating equations and multiple imputation. Stata J 2014;14:863–883.
- 17. Canet J, Gallart L, Gomar C, Paluzie G, Valles J, Castillo J, et al. Prediction of postoperative pulmonary complications in a population-based surgical cohort. Anesthesiology 2010;113:1338–1350.
- 18. Sato T, Kondo H, Watanabe A, Nakajima J, Niwa H, Horio H, et al. A simple risk scoring system for predicting acute exacerbation of interstitial pneumonia after pulmonary resection in lung cancer patients. Gen Thorac Cardiovasc Surg 2015;63:164–172.
- 19. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183:788–824.
- 20. Travis WD, Costabel U, Hansell DM, King TE, Jr, Lynch DA, Nicholson AG, et al. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013;188:733–748.
- 21. Ghatol A, Ruhl AP, Danoff SK. Exacerbations in idiopathic pulmonary fibrosis triggered by pulmonary and nonpulmonary surgery: a case series and comprehensive review of the literature. Lung 2012;190:373–380.
- 22. Ambrosini V, Cancellieri A, Chilosi M, Zompatori M, Trisolini R, Saragoni L, et al. Acute exacerbation of idiopathic pulmonary fibrosis: report of a series. European Respiratory Journal 2003;22:821–826.
- 23. Collard HR, Ryerson CJ, Corte TJ, Jenkins G, Kondoh Y, Lederer DJ, et al. Acute exacerbation of idiopathic pulmonary fibrosis. An international working group report. Am J Respir Crit Care Med 2016;194:265–275.
- 24. Park IN, Kim DS, Shim TS, Lim CM, Lee SD, Koh Y, et al. Acute exacerbation of interstitial pneumonia other than idiopathic pulmonary fibrosis. Chest 2007;132:214–220.
- 25. Steinberg KP, Hudson LD, Goodman RB, Hough CL, Lanken PN, Hyzy R, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006;354:1671–1684.
- 26. Meduri GU, Golden E, Freire AX, Taylor E, Zaman M, Carson SJ, et al. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest 2007;131:954–963.
- 27. Usui Y, Kaga A, Sakai F, Shiono A, Komiyama K, Hagiwara K, et al. A cohort study of mortality predictors in patients with acute exacerbation of chronic fibrosing interstitial pneumonia. BMJ Open 2013;3.
- 28. Ryerson CJ, Cottin V, Brown KK, Collard HR. Acute exacerbation of idiopathic pulmonary fibrosis: shifting the paradigm. Eur Respir J 2015;46:512–520.
- 29. Natsuizaka M, Chiba H, Kuronuma K, Otsuka M, Kudo K, Mori M, et al. Epidemiologic survey of Japanese patients with idiopathic pulmonary fibrosis and investigation of ethnic differences. American Journal of Respiratory and Critical Care Medicine 2014;190:773–779.
- 30. Akamatsu H, Inoue A, Mitsudomi T, Kobayashi K, Nakagawa K, Mori K, et al. Interstitial lung disease associated with gefitinib in Japanese patients with EGFR-mutated non-small-cell lung cancer: combined analysis of two Phase III trials (NEJ 002 and WJTOG 3405). Jpn J Clin Oncol 2013;43:664–668.
- 31. Nakagawa K, Kudoh S, Ohe Y, Johkoh T, Ando M, Yamazaki N, et al. Postmarketing surveillance study of erlotinib in Japanese patients with non-small-cell lung cancer (NSCLC): an interim analysis of 3488 patients (POLARSTAR). J Thorac Oncol 2012;7:1296–1303.
- 32. Kudoh S, Kato H, Nishiwaki Y, Fukuoka M, Nakata K, Ichinose Y, et al. Interstitial lung disease in Japanese patients with lung cancer: a cohort and nested case-control study. Am J Respir Crit Care Med 2008;177:1348–1357.
