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Preoperative 6-minute walk distance accurately predicts postoperative complications after operations for hepato-pancreato-biliary cancer
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Preoperative 6-minute walk distance accurately predicts postoperative complications after operations for hepato-pancreato-biliary cancer Kazuhiro Hayashi, PT, MSc,a Yukihiro Yokoyama, MD, PhD,b Hiroki Nakajima, PT,a Masato Nagino, MD, PhD,b Takayuki Inoue, PT, PhD,a Motoki Nagaya, PT, MSc,a Keiko Hattori, PT,a Izumi Kadono, MD, MSc,a,c Satoru Ito, MD, PhD,a,d and Yoshihiro Nishida, MD, PhD,a,c Nagoya, Japan
Background. Operation for hepato-pancreato-biliary cancer is among the most invasive open abdominal operations, with a high postoperative morbidity and mortality rate. The purpose of the present study is to investigate whether a preoperative 6-minute walk distance can predict major postoperative complications after operation for hepato-pancreato-biliary diseases. Methods. A total of 81 participants who underwent pancreaticoduodenectomy, major hepatectomy with extrahepatic bile duct resection, or hepatopancreatoduodenectomy were included. The 6-minute walk distance was performed within 1 week before operation. Patients were categorized into 2 groups based on surgical complications: Clavien-Dindo grade <3 and Clavien-Dindo grade $3. Clinical differences between the 2 groups were analyzed. Multivariate logistic regression analysis was performed to identify risk factors for postoperative complications that were categorized as Clavien-Dindo grade $3. Results. The multiple logistic regression model revealed a significant correlation between major postoperative complications and preoperative low 6-minute walk distance, low body mass index, and major blood loss. In patients with 6-minute walk distance <400 m (1,312 feet), the Clavien-Dindo grade was considerably greater than patients with $400 m. Conclusion. The 6-minute walk distance is useful in identifying patients with a greater chance of developing major postoperative complications after surgery for hepato-pancreato-biliary cancer. (Surgery 2016;j:j-j.) From the Department of Rehabilitation,a Nagoya University Hospital, Nagoya, Japan; Division of Surgical Oncology,b Department of Surgery, Department of Orthopaedic Surgery,c and Department of Respiratory Medicine,d Nagoya University Graduate School of Medicine, Nagoya, Japan
OPEN ABDOMINAL OPERATION for the treatment of gastrointestinal cancer carries a high rate of postoperative complications. Operation for hepatopancreato-biliary disease, especially, is one of the most invasive, with a high postoperative morbidity and mortality rate.1,2 In this type of operation, a The authors certify that no affiliation or financial involvement exists between them and any organization with a direct interest in the subject matter or materials discussed in the article. Accepted for publication August 3, 2016. Reprint requests: Kazuhiro Hayashi, PT, MSc, Department of Rehabilitation, Nagoya University Hospital, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan. E-mail: hayashi.k@ med.nagoya-u.ac.jp. 0039-6060/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2016.08.002
precise preoperative risk assessment for postoperative complications is critical for determining the operative indication and planning a perioperative patient management strategy. Previous reports indicated that the postoperative complications after operation for gastrointestinal cancer can be predicted by preoperative skeletal muscle mass.3-5 However, skeletal muscle mass may not correlate linearly with functional exercise capacity. In addition, to the assessment of skeletal muscle mass, it may be important to assess the functional exercise capacity in each patient to predict the risk of postoperative complications accurately. The 6-minute walk test is a simple, safe, and inexpensive test that can be used in evaluating the functional exercise capacity of patients.6 The 6-minute walk distance (6MWD) has been used to assess patients’ condition with cardiopulmonary SURGERY 1
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Table I. Patient characteristics and univariate analysis of potential prediction of postoperative complications Clavien-Dindo grade <3 (n = 48) Male, n (%) Median (range) age, y Median (range) height, cm Median (range) body weight, kg Median (range) BMI, kg/m2 Comorbidities, n (%) Hypertension Diabetes mellitus Dyslipidemia Chronic kidney disease Cardiopulmonary disorder Preoperative cholangitis Neoadjuvant chemotherapy Charlson comorbidity index (0/1/2) Median (range) 6MWD, m Preoperative laboratory values Median (range) albumin, g/dL Median (range) AST, IU/L Median (range) ALT, IU/L Median (range) TB, mg/dL Median (range) TLC, mm3 Median (range) PT-INR Median (range) WBC, mg/dL Median (range) CRP, mg/dL Median (range) PNI PD/HEBRD/HPD Treated disease, n (%) Pancreatic cancer Biliary tract cancer Ampullary cancer Other malignancies Benign disease Median (range) operative time, min Median (range) blood loss, mL Median (range) postoperative hospital stay, d
31 67 162 57.8 21.4
(64) (38–82) (141–185) (40.5–94.5) (16.4–37.8)
Clavien-Dindo grade S3 (n = 33) 21 69 164 57.1 20.9
(63) (45–88) (139–176) (34.0–67.6) (15.2–24.9)
.930 .577 .882 .290 .093
21 (43) 14 (29) 6 (12) 4 (8) 5 (10) 7 (14) 4 (8) 31/14/3 492 (372–620)
(51) (15) (12) (6) (12) (27) (3) 23/8/2 465 (276–636)
.491 .144 .959 .701 .810 .159 .330 .881 .041
3.7 (1.7–4.6) 27 (14–194) 35 (10–267) 0.8 (0.3–2.9) 1.3 (0.6–3.1) 0.98 (0.85–1.35) 5.4 (2.7–9.1) 0.26 (0.01–7.48) 45.5 (23.5–53.5) 14/27/7
3.5 36 38 0.9 1.2 0.99 5.9 0.18 42.5
.049 .157 .693 .717 .213 .554 .078 .211 .032 .378 .467
9 33 3 2 1 565 1,140 23
(18) (68) (6) (4) (2) (339–900) (273–3,376) (10–72)
17 5 4 2 4 9 1
P value
2 25 3 1 2 628 1,323 43
(2.0–4.5) (13–822) (9–714) (0.3–3.2) (0.6–3.4) (0.86–1.18) (3.5–8.5) (0.03–1.57) (23.0–62.0) 6/19/8 (6) (75) (9) (3) (6) (322–1,012) (209–12,428) (19–121)
.087 .141 <.001
ALT, Alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CRP, C-reactive protein; PT-INR, international normalized ratio of prothrombin time; TB, total bilirubin; TLC, total lymphocyte count; WBC, white blood cell counts.
diseases.7 It also has been used to predict the complications after thoracotomy and sternotomy.8 However, only a limited number of studies have determined the clinical value of the 6MWD in predicting complications after laparotomy.9 The purpose of the present study was to investigate whether the 6MWD can be a useful tool in predicting the incidence of major postoperative complications in patients who underwent hepato-pancreato-biliary surgeries such as pancreatoduodenectomy (PD), major hepatectomy with extrahepatic bile duct resection (HEBDR), or hepatopancreatoduodenectomy (HPD), which are the most invasive abdominal operations.
METHODS Participants. A total of 81 participants who underwent open abdominal operations for hepato-pancreato-biliary diseases between April 2014 and November 2015 at Nagoya University Hospital were enrolled in this study. Among the 81 patients, 20 underwent PD, 46 underwent HEBDR, and 15 underwent HPD (Table I). Most of the patients (n = 78, 96%) underwent operation due to hepato-pancreato-biliary malignancies. Operations were performed by 5 well-experienced staff hepato-pancreato-biliary surgeons. All patients were provided similar pre- and postoperative rehabilitation, which included mobilization, ambulation,
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Table II. List of postoperative complications with Clavien-Dindo grade $3 Postoperative complications Intra-abdominal abscess Bile leakage grade B or C Pancreatic fistula grade B or C Bacteremia Liver failure grade B or C Cholangitis Wound infection Ascites Hemorrhage Pleural effusion Delayed gastric emptying Pneumonia
n (%) 15 13 13 11 6 3 3 3 2 2 1 1
(19) (16) (16) (14) (7) (4) (4) (4) (2) (2) (1) (1)
Note: Multiple complications were observed in some patients.
breathing exercise, and muscle strength exercise according to the institutional protocol. When the patients had jaundice, an appropriate biliary drainage by endoscopic nasobiliary drainage, endoscopic biliary stent, or percutaneous transhepatic biliary drainage was performed. No specific nutritional therapy was performed before operation in any patient. This study was approved by the Ethics Committee of Nagoya University Hospital (no. 413). Information about the patients was collected through a review of electronic medical records. Evaluation of the 6MWD. Functional exercise capacity was measured using the 6MWD within 1 week before operation (median, 2 days before operation; range, 1–6 days before operation). The evaluation of 6MWD was performed prospectively in consecutive patients who underwent open abdominal operations for hepato-pancreato-biliary diseases. 6MWD was not measured within any period after operation. The 6-minute walk test was performed by following a standardized procedure described by the American Thoracic Society Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories.10 Briefly, patients were instructed to walk the predetermined course at their own pace for 6 minutes. Standardized encouragement was given for patients in every minute during the test. At 6 minutes, patients were instructed to stop walking and the distance walked was measured. 6MWD was measured by the physical therapists in the department of rehabilitation, and surgeons were blinded as to the results of 6MWD. Data collection. Demographic data including age, sex, height, body weight, body mass index, presence of preoperative cholangitis, and other comorbidities were recorded. The Charlson
comorbidity index was used to score comorbid conditions uniformly.11 Intraoperative data such as operative procedure, operation time, and intraoperative blood loss also were recorded. Preoperative serum levels of albumin, aspartate aminotransferase, alanine aminotransferase, total bilirubin, total lymphocyte count, international normalized ratio of prothrombin time, white blood cell counts, and C-reactive protein were measured and recorded. The prognostic nutritional index (PNI), an indicator of nutritional status, was assessed by the following equation: PNI = 10 3 serum albumin (mg/dL) + 0.005 3 total lymphocyte count.12 The incidence of in-hospital complications was classified according to the Clavien-Dindo score.13 Briefly, patients were classified as grade 0 if they had no postoperative complications. Patients were classified as grade 1 if there was any deviation from the normal postoperative course, without the need for pharmacologic treatment or surgical, endoscopic, or radiologic interventions. Patients were classified as grade 2 if they required pharmacologic treatment with drugs other than such allowed for grade 1 complications. Patients were classified as grade 3 if they required surgical, endoscopic, or radiologic intervention. Patients were classified as grade 4 if they required admission to the intensive care unit. Postoperative mortality was defined as a grade 5 complication. Liver failure and bile leakage were defined according to the definition of the International Study Group of Liver Surgery.14,15 Postoperative pancreatic fistula and delayed gastric emptying were defined according to the definition of the International Study Group of Pancreatic Surgery.16,17 Postoperative surgical site infections including intra-abdominal abscess and wound infection also were recorded. Cholangitis patients fulfilled the following criteria: a sustained fever that required treatment with antibiotics, increased serum hepatobiliary enzymes, and isolation of bacteria from bile cultures with no focused infections other than cholangitis.18 The diagnosis of pneumonia required radiologic evidence of consolidation with leukocytosis. Bacteremia was diagnosed when a blood culture grew an isolate of organisms with no contamination of the skin flora. Clinically significant ascites or pleural effusion requiring drainage also was recorded. Statistical analysis. All continuous variables were expressed as median (range). Patients were categorized into the following 2 groups: patients with Clavien-Dindo grade <3 complications and those with Clavien-Dindo grade $3 complications. Differences between the 2 groups were analyzed using
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Table III. Binary logistic regression analysis for the risk of major postoperative complications with Clavien-Dindo grade $3 95% CI Odds ratio Lower limit Upper limit P value 6MWD BMI Blood loss
1.537 1.471 1.199
1.066 1.040 1.019
2.218 2.081 1.408
.021 .029 .029
Ten preoperative and intraoperative variables with P < .200 (ie, BMI, diabetes mellitus, preoperative cholangitis, 6MWD, albumin, aspartate aminotransferase, white blood cell counts, prognostic nutritional index, operative time, and blood loss) were entered into the binary logistic regression models. Odds ratio is for the occurrence of major postoperative complications with Clavien-Dindo grade $3 in each decrement of 50 m in 6MWD, each decrement of 2 kg/m2 in BMI, or each increment of 200 mL in intraoperative blood loss. BMI, Body mass index; CI, confidence interval.
∼399
400∼449
450∼499
500∼549
550∼
Fig 1. The 6-minute walk distance and the incidence of major complication with Clavien-Dindo grade $3.
the v2 test for the categorical variables and the Mann-Whitney U test for the continuous variables, respectively. Potential risk factors for ClavienDindo grade $3, as determined by univariate analysis (with P < .200), were explored with multivariate logistic regression analysis to determine if they were independent risk factors for high-grade complications. Postoperative survival was calculated by means of the Kaplan-Meier method, and differences in the survival curves were compared with the log-rank test. The data were analyzed using SPSS (version 20.0 for Microsoft Windows; SPSS, Chicago, IL). RESULTS There was no postoperative in-hospital or within 90 days mortality in analyzed patients. The number of patients with Clavien-Dindo grades 0, 1, 2, 3, 4,
and 5 were 16 (20%), 4 (5%), 28 (35%), 31 (38%), 2 (2%), and 0 (0%), respectively. Postoperative complications with Clavien-Dindo grade $3 occurred in 33 patients (40%; Table I). The number of patients with various postoperative complications categorized in the Clavien-Dindo grade $3 is listed in Table II. Among 15 incidences of intra-abdominal abscess, 9 incidences (60%) were associated with pancreatic and/or biliary leakage. Differences in the pre-, intra-, and postoperative variables between the patients with Clavien-Dindo grade <3 and those with Clavien-Dindo grade $3 are shown in Table I. Sex, age, and preoperative comorbidities were not significantly different between the 2 groups. Preoperative 6MWD, serum albumin, and PNI in the group with Clavien-Dindo grade $3 were significantly lower than the group with Clavien-Dindo grade <3. Postoperative hospital stay in the group with Clavien-Dindo grade $3 was significantly longer than the group with Clavien-Dindo grade <3. The various preoperative and intraoperative risk factors that have a potential association with the incidence of major postoperative complications (Clavien-Dindo grade $3) were included in the multivariate logistic regression analysis. The analyzed risk factors included body mass index, diabetes mellitus, preoperative cholangitis, 6MWD, albumin, aspartate aminotransferase, white blood cell counts, PNI, operation time, and intraoperative blood loss (all with P < .200 in the univariate analysis). A preoperative low 6MWD, low body mass index, and significant blood loss were identified as independent risk factors for major postoperative complications (Table III). The odds ratio was 1.53 (95% confidential interval, 1.06–2.21, P = .021) for the occurrence of major postoperative complications with Clavien-Dindo grade $3 in each decrement of 50 m in 6MWD. In patients with 6MWD <400 m (1,312 feet), the incidence rate of Clavien-Dindo grade $3 was considerably greater than patients with 6MWD $400 m (Fig 1). The patients with 6MWD <400 m were associated with greater age, lower height, female sex, and poor PNI, compared with those with 6MWD $400 m (Table IV). Finally, we analyzed the long-term survival in patients who underwent 6MWD test. The median (range) follow-up period was 353 days (30–808 days). The overall survival was significantly worse in patients with 6MWD <400 m compared with those with 6MWD $400 m (1-year survival rate, 65% vs 94%; P = .045; Fig 2, A). The overall survival also was significantly worse in patients with Clavien-Dindo grade $3 complication
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Table IV. Patient characteristics according to the preoperative 6MWD 6MWD $400 m (n = 70) Male, n (%) Median (range) age (y) Median (range) height (cm) Median (range) body weight (kg) Median (range) BMI (kg/m2) Comorbidities, n (%) Hypertension Diabetes mellitus Dyslipidemia Chronic kidney disease Cardiopulmonary disorder Preoperative cholangitis Neoadjuvant chemotherapy Charlson Comorbidity Index (0/1/2) Preoperative laboratory values Median (range) Albumin (g/dL) Median (range) AST (IU/L) Median (range) ALT (IU/L) Median (range) TB (mg/dL) Median (range) TLC (mm3) Median (range) PT-INR Median (range) WBC (mg/dL) Median (range) CRP (mg/dL) Median (range) PNI PD/HEBRD/HPD Treated disease, n (%) Pancreatic cancer Biliary tract cancer Ampullary cancer Other malignancies Benign disease Clavien-Dindo grade $3, n (%) Median (range) Operative time (min) Median (range) Blood loss (mL) Median (range) postoperative hospital stay (d)
49 66 164 57.8 21.1 31 18 7 6 8 15 4
(70) (38–82) (146–185) (38.7–94.5) (16.0–37.8) (44) (25) (10) (8) (7) (21) (5) 45/20/5
3.7 (1.7–4.6) 29 (13–822) 38 (10–714) 0.8 (0.3–3.2) 1.3 (0.6–3.4) 0.98 (0.85–1.35) 5.6 (2.7–9.1) 0.20 (0.01–6.81) 44.5 (23.0–62.0) 17/40/13 11 49 4 3 3 24 572 1,146 28
(15) (70) (5) (4) (4) (34) (322–1,012) (273–12,428) (10–121)
6MWD <400 m (n = 11) 3 76 151 54.5 21.1 7 1 3 0 1 1 1
(27) (65–88) (139–168) (34.0–62.5) (15.2–30.4) (63) (9) (27) (0) (9) (9) (9) 9/2/0
3.5 38 34 0.9 1.0 1.02 5.9 0.25 4.0
(2.9–3.8) (15–74) (9–128) (0.5–2.1) (0.6–2.7) (0.95–1.11) (3.6–7.1) (0.03–7.48) (33.5–49.5) 3/6/2
0 9 2 0 0 9 580 812 45
(0) (81) (18) (0) (0) (81) (373–677) (209–2,394) (17–92)
P value .006 <.001 .003 .172 .890 .232 .226 .105 .313 .339 .665 .449 .044 .381 .301 .442 .309 .307 .907 .558 .050 .977 .303
.003 .984 .416 .004
ALT, Alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CRP, C-reactive protein; PT-INR, international normalized ratio of prothrombin time; TB, total bilirubin; TLC, total lymphocyte count; WBC, white blood cell counts.
compared with others (1-year survival rate, 82% vs 95%; P = .033; Fig 2, B). DISCUSSION The present study indicates that major postoperative complications (Clavien-Dindo grade $3) after hepato-pancreato-biliary surgeries were predicted by low preoperative 6MWD. In patients with 6MWD <400 m, the incidence rate of ClavienDindo grade $3 complication was significantly greater (81%) compared with those with 6 MWD $400 m (34%). Interestingly, the long-term survival also was substantially worse in patients with 6MWD <400 m (1-year survival rate, 65%) compared with those with 6MWD $400 m (1-year survival rate 94%). These results indicate that the 6MWD is a
useful screening tool to identify the high-risk patients in hepato-pancreato-biliary operations. The 6MWD has been used to assess the functional recovery after cardiac,19,20 pulmonary,21 and orthopedic operations.22 However, the predictive value of the 6MWD for the incidence of postoperative complications has been studied in only a limited number of reports.23,24 Of note, only a few reports25 have evaluated the predictive value of the 6MWD for postoperative complications after abdominal operations. This study is the first to analyze the association between 6MWD results and postoperative complications in patients who underwent hepato-pancreatobiliary operations, which are the most invasive abdominal operations.
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(%)
A
Percent Survival Probability
100
80
60
40
20 6MWD ≥400 m 6MWD <400 m
0 0
6 12 18 Follow-up months
24
70 11
61 8
2 1
Numbers at risk 6MWD ≥400 m 6MWD <400 m
B
34 4
16 1
(%)
Percent Survival Probability
100
80
60
40
20 Clavien-Dindo < 3 Clavien-Dindo ≥ 3
0 0
6 12 18 Follow-up months
24
48 33
41 28
3 0
Numbers at risk Clavien-Dindo < 3 Clavien-Dindo ≥ 3
27 11
14 3
Fig 2. (A) Kaplan-Meier survival curves for the patients with the 6MWD $400 m and those with 6MWD <400 m. (B) Kaplan-Meier survival curves for the patients with Clavien-Dindo grade <3 and those with Clavien-Dindo grade $3.
Two previous reports studied the predictive value of the 6MWD for postoperative complications after open abdominal operation.8,9 Awdeh et al8 indicated that the 6MWD had a negative correlation with duration of hospital stay. However, in addition to abdominal laparotomy, this study included various other types of major operations, such as thoracotomies and sternotomies. Paisani
et al9 assessed the predictive value of the 6MWD for postoperative complications after upper abdominal operations. However, this study only focused on the incidence of pulmonary complications. The present study specifically studied only patients with hepato-pancreato-biliary diseases undergoing operation. In this disease category, highly invasive and complicated operations such as PD, HEBDR, and HPD are required. The incidence of postoperative complications after these procedures is unexpectedly high.26,27 Therefore, in patients with poor 6MWD results, operative indication and methods of perioperative management should be assessed carefully. Moreover, we recommend an aggressive preoperative physical therapy to improve functional exercise capacity for those with poor 6MWD results. Previous reports have indicated that the postoperative complications after operation for gastrointestinal cancer could be predicted by cardiopulmonary exercise testing.28-30 However, the cardiopulmonary exercise testing used in these studies requires specific equipment, including an electronically braked cycle ergometer with a 12lead electrocardiogram and a metabolic cart with a facemask for gas analyses. Thus, this test is not feasible in every institution. In contrast, the 6MWD is a simple, safe, and inexpensive test that can be performed in all patients without using any equipment. Therefore, we recommend performing the 6MWD preoperatively in patients who are going to undergo a high-risk operation, such as one for hepato-pancreato-biliary diseases. The levels of serum albumin and PNI were substantially lower in patients with Clavien-Dindo grade $3 complications than in patients with Clavien-Dindo grade <3 (Table I). These 2 nutritional factors also were significantly lower in patients with 6MWD <400 m (Table IV). Malnutrition has a negative impact on muscle wasting,31 postoperative recovery including tissue repair,32 and immunologic responses.33 These factors may have an impact on the incidence of postoperative complications. Although we did not measure the muscle strength or total muscle mass in each patient, the nutritional status may affect the functional exercise capacity substantially, which is indicated by a low 6MWD. These results imply the importance of preoperative nutritional therapy for patients who will undergo hepatopancreato-biliary operations. Frailty is a state of vulnerability identified through the assessment of weight loss, gait speed, grip strength, physical activity, and physical exhaustion.34 It has been shown to have a significant
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impact on postoperative complications after operation.35 The long-term survival rates after cancer operation also was shorter in patients with frailty compared with nonfrailty.36 Although frailty is not equivalent to poor functional capacity, the association between frailty and the results of 6MWD should be further clarified in a future study. This study has several limitations. First, we included only a small number of participants from a single medical center. Thus, our observations must be interpreted with caution. A largescale study to investigate the clinical importance of 6MWD on the outcome of highly invasive operations is now ongoing at our institution. Second, the present study included patients who underwent PD, HEBDR, or HPD for hepato-pancreato-biliary malignancies. Although these procedures are all highly invasive, the extent of invasiveness is somewhat variable among these procedures. In conclusion, this study demonstrated that the preoperative 6MWD was useful in predicting major postoperative complications in patients who underwent major operations for hepato-pancreatobiliary diseases, such as PD, HEBDR, and HPD. The 6MWD is an easy, safe, and feasible test that can be used routinely in assessing the risk of postoperative complications in patients who undergo major hepato-pancreato-biliary surgeries. In patients with 6MWD <400 m, operative indication and perioperative patient management should be carefully assessed. This work was supported in part by Grants-in-Aid for Scientific Research (no. 16K21081 to T. Inoue) from the Ministry of Education, Culture, Sports, and Science and Technology of Japan. We sincerely thank all of the patients, collaborating physicians, and other medical staff for their important contributions to this study.
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intensive care unit stay after cardiac surgery in the elderly. Aging Clin Exp Res 2012;24:627-34. Rasekaba T, Lee AL, Naughton MT, Williams TJ, Holland AE. The six-minute walk test: a useful metric for the cardiopulmonary patient. Intern Med J 2009;39: 495-501. Huang YC, Leong CP, Pong YP, Liu TY, Kuo YR. Functional assessment of donor-site morbidity after harvest of a fibula chimeric flap with a sheet of soleus muscle for mandibular composite defect reconstruction. Microsurgery 2012;32:20-5. Keeratichananont W, Thanadetsuntorn C, Keeratichananont S. Value of preoperative 6-minute walk test for predicting postoperative pulmonary complications. Ther Adv Respir Dis 2016;10: 18-25. Nakagawa T, Chiba N, Saito M, Sakaguchi Y, Ishikawa S. Clinical relevance of decreased oxygen saturation during 6-min walk test in preoperative physiologic assessment for lung cancer surgery. Gen Thorac Cardiovasc Surg 2014;62: 620-6. Oliver N, Onofre T, Carlos R, Barbosa J, Godoy E, Pereira E, et al. Ventilatory and metabolic response in the incremental shuttle and 6-min walking tests measured by telemetry in obese patients prior to bariatric surgery. Obes Surg 2015; 25:1658-65. Ebata T, Yokoyama Y, Igami T, Sugawara G, Takahashi Y, Nimura Y, et al. Hepatopancreatoduodenectomy for cholangiocarcinoma: a single-center review of 85 consecutive patients. Ann Surg 2012;256:297-305. Yokoyama Y, Ebata T, Igami T, Sugawara G, Ando M, Nagino M. Predictive power of prothrombin time and serum total bilirubin for postoperative mortality after major hepatectomy with extrahepatic bile duct resection. Surgery 2014;155:504-11.
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28. Chandrabalan VV, McMillan DC, Carter R, Kinsella J, McKay CJ, Carter CR, et al. Pre-operative cardiopulmonary exercise testing predicts adverse post-operative events and non-progression to adjuvant therapy after major pancreatic surgery. HPB (Oxford) 2013;15:899-907. 29. Ausania F, Snowden CP, Prentis JM, Holmes LR, Jaques BC, White SA, et al. Effects of low cardiopulmonary reserve on pancreatic leak following pancreaticoduodenectomy. Br J Surg 2012;99:1290-4. 30. Junejo MA, Mason JM, Sheen AJ, Moore J, Foster P, Atkinson D, et al. Cardiopulmonary exercise testing for preoperative risk assessment before hepatic resection. Br J Surg 2012;99:1097-104. 31. Smith A. Sarcopenia, malnutrition and nutrient density in older people. Post Reprod Health 2014;20:19-21. 32. Yoshida R, Yagi T, Sadamori H, Matsuda H, Shinoura S, Umeda Y, et al. Branched-chain amino acid-enriched nutrients improve nutritional and metabolic abnormalities in the early post-transplant period after living donor liver transplantation. J Hepatobiliary Pancreat Sci 2012;19:438-48. 33. Reynolds JV, O’Farrelly C, Feighery C, Murchan P, Leonard N, Fulton G, et al. Impaired gut barrier function in malnourished patients. Br J Surg 1996;83:1288-91. 34. Chen X, Mao G, Leng SX. Frailty syndrome: an overview. Clin Interv Aging 2014;9:433-41. 35. Louwers L, Schnickel G, Rubinfeld I. Use of a simplified frailty index to predict Clavien 4 complications and mortality after hepatectomy: analysis of the National Surgical Quality Improvement Project database. Am J Surg 2016;211:1071-6. 36. Fagard K, Leonard S, Deschodt M, Devriendt E, Wolthuis A, Prenen H, et al. The impact of frailty on postoperative outcomes in individuals aged 65 and over undergoing elective surgery for colorectal cancer: a systematic review. J Geriatric Oncol http://dx.doi.org/10.1016/j.jgo.2016.06.001.
Preoperative 6-minute walk distance accurately predicts postoperative complications after operations for hepato-pancreato-biliary cancer Kazuhiro Hayashi, PT, MSc,a Yukihiro Yokoyama, MD, PhD,b Hiroki Nakajima, PT,a Masato Nagino, MD, PhD,b Takayuki Inoue, PT, PhD,a Motoki Nagaya, PT, MSc,a Keiko Hattori, PT,a Izumi Kadono, MD, MSc,a,c Satoru Ito, MD, PhD,a,d and Yoshihiro Nishida, MD, PhD,a,c Nagoya, Japan
Background. Operation for hepato-pancreato-biliary cancer is among the most invasive open abdominal operations, with a high postoperative morbidity and mortality rate. The purpose of the present study is to investigate whether a preoperative 6-minute walk distance can predict major postoperative complications after operation for hepato-pancreato-biliary diseases. Methods. A total of 81 participants who underwent pancreaticoduodenectomy, major hepatectomy with extrahepatic bile duct resection, or hepatopancreatoduodenectomy were included. The 6-minute walk distance was performed within 1 week before operation. Patients were categorized into 2 groups based on surgical complications: Clavien-Dindo grade <3 and Clavien-Dindo grade $3. Clinical differences between the 2 groups were analyzed. Multivariate logistic regression analysis was performed to identify risk factors for postoperative complications that were categorized as Clavien-Dindo grade $3. Results. The multiple logistic regression model revealed a significant correlation between major postoperative complications and preoperative low 6-minute walk distance, low body mass index, and major blood loss. In patients with 6-minute walk distance <400 m (1,312 feet), the Clavien-Dindo grade was considerably greater than patients with $400 m. Conclusion. The 6-minute walk distance is useful in identifying patients with a greater chance of developing major postoperative complications after surgery for hepato-pancreato-biliary cancer. (Surgery 2016;j:j-j.) From the Department of Rehabilitation,a Nagoya University Hospital, Nagoya, Japan; Division of Surgical Oncology,b Department of Surgery, Department of Orthopaedic Surgery,c and Department of Respiratory Medicine,d Nagoya University Graduate School of Medicine, Nagoya, Japan
OPEN ABDOMINAL OPERATION for the treatment of gastrointestinal cancer carries a high rate of postoperative complications. Operation for hepatopancreato-biliary disease, especially, is one of the most invasive, with a high postoperative morbidity and mortality rate.1,2 In this type of operation, a The authors certify that no affiliation or financial involvement exists between them and any organization with a direct interest in the subject matter or materials discussed in the article. Accepted for publication August 3, 2016. Reprint requests: Kazuhiro Hayashi, PT, MSc, Department of Rehabilitation, Nagoya University Hospital, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan. E-mail: hayashi.k@ med.nagoya-u.ac.jp. 0039-6060/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2016.08.002
precise preoperative risk assessment for postoperative complications is critical for determining the operative indication and planning a perioperative patient management strategy. Previous reports indicated that the postoperative complications after operation for gastrointestinal cancer can be predicted by preoperative skeletal muscle mass.3-5 However, skeletal muscle mass may not correlate linearly with functional exercise capacity. In addition, to the assessment of skeletal muscle mass, it may be important to assess the functional exercise capacity in each patient to predict the risk of postoperative complications accurately. The 6-minute walk test is a simple, safe, and inexpensive test that can be used in evaluating the functional exercise capacity of patients.6 The 6-minute walk distance (6MWD) has been used to assess patients’ condition with cardiopulmonary SURGERY 1
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Table I. Patient characteristics and univariate analysis of potential prediction of postoperative complications Clavien-Dindo grade <3 (n = 48) Male, n (%) Median (range) age, y Median (range) height, cm Median (range) body weight, kg Median (range) BMI, kg/m2 Comorbidities, n (%) Hypertension Diabetes mellitus Dyslipidemia Chronic kidney disease Cardiopulmonary disorder Preoperative cholangitis Neoadjuvant chemotherapy Charlson comorbidity index (0/1/2) Median (range) 6MWD, m Preoperative laboratory values Median (range) albumin, g/dL Median (range) AST, IU/L Median (range) ALT, IU/L Median (range) TB, mg/dL Median (range) TLC, mm3 Median (range) PT-INR Median (range) WBC, mg/dL Median (range) CRP, mg/dL Median (range) PNI PD/HEBRD/HPD Treated disease, n (%) Pancreatic cancer Biliary tract cancer Ampullary cancer Other malignancies Benign disease Median (range) operative time, min Median (range) blood loss, mL Median (range) postoperative hospital stay, d
31 67 162 57.8 21.4
(64) (38–82) (141–185) (40.5–94.5) (16.4–37.8)
Clavien-Dindo grade S3 (n = 33) 21 69 164 57.1 20.9
(63) (45–88) (139–176) (34.0–67.6) (15.2–24.9)
.930 .577 .882 .290 .093
21 (43) 14 (29) 6 (12) 4 (8) 5 (10) 7 (14) 4 (8) 31/14/3 492 (372–620)
(51) (15) (12) (6) (12) (27) (3) 23/8/2 465 (276–636)
.491 .144 .959 .701 .810 .159 .330 .881 .041
3.7 (1.7–4.6) 27 (14–194) 35 (10–267) 0.8 (0.3–2.9) 1.3 (0.6–3.1) 0.98 (0.85–1.35) 5.4 (2.7–9.1) 0.26 (0.01–7.48) 45.5 (23.5–53.5) 14/27/7
3.5 36 38 0.9 1.2 0.99 5.9 0.18 42.5
.049 .157 .693 .717 .213 .554 .078 .211 .032 .378 .467
9 33 3 2 1 565 1,140 23
(18) (68) (6) (4) (2) (339–900) (273–3,376) (10–72)
17 5 4 2 4 9 1
P value
2 25 3 1 2 628 1,323 43
(2.0–4.5) (13–822) (9–714) (0.3–3.2) (0.6–3.4) (0.86–1.18) (3.5–8.5) (0.03–1.57) (23.0–62.0) 6/19/8 (6) (75) (9) (3) (6) (322–1,012) (209–12,428) (19–121)
.087 .141 <.001
ALT, Alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CRP, C-reactive protein; PT-INR, international normalized ratio of prothrombin time; TB, total bilirubin; TLC, total lymphocyte count; WBC, white blood cell counts.
diseases.7 It also has been used to predict the complications after thoracotomy and sternotomy.8 However, only a limited number of studies have determined the clinical value of the 6MWD in predicting complications after laparotomy.9 The purpose of the present study was to investigate whether the 6MWD can be a useful tool in predicting the incidence of major postoperative complications in patients who underwent hepato-pancreato-biliary surgeries such as pancreatoduodenectomy (PD), major hepatectomy with extrahepatic bile duct resection (HEBDR), or hepatopancreatoduodenectomy (HPD), which are the most invasive abdominal operations.
METHODS Participants. A total of 81 participants who underwent open abdominal operations for hepato-pancreato-biliary diseases between April 2014 and November 2015 at Nagoya University Hospital were enrolled in this study. Among the 81 patients, 20 underwent PD, 46 underwent HEBDR, and 15 underwent HPD (Table I). Most of the patients (n = 78, 96%) underwent operation due to hepato-pancreato-biliary malignancies. Operations were performed by 5 well-experienced staff hepato-pancreato-biliary surgeons. All patients were provided similar pre- and postoperative rehabilitation, which included mobilization, ambulation,
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Table II. List of postoperative complications with Clavien-Dindo grade $3 Postoperative complications Intra-abdominal abscess Bile leakage grade B or C Pancreatic fistula grade B or C Bacteremia Liver failure grade B or C Cholangitis Wound infection Ascites Hemorrhage Pleural effusion Delayed gastric emptying Pneumonia
n (%) 15 13 13 11 6 3 3 3 2 2 1 1
(19) (16) (16) (14) (7) (4) (4) (4) (2) (2) (1) (1)
Note: Multiple complications were observed in some patients.
breathing exercise, and muscle strength exercise according to the institutional protocol. When the patients had jaundice, an appropriate biliary drainage by endoscopic nasobiliary drainage, endoscopic biliary stent, or percutaneous transhepatic biliary drainage was performed. No specific nutritional therapy was performed before operation in any patient. This study was approved by the Ethics Committee of Nagoya University Hospital (no. 413). Information about the patients was collected through a review of electronic medical records. Evaluation of the 6MWD. Functional exercise capacity was measured using the 6MWD within 1 week before operation (median, 2 days before operation; range, 1–6 days before operation). The evaluation of 6MWD was performed prospectively in consecutive patients who underwent open abdominal operations for hepato-pancreato-biliary diseases. 6MWD was not measured within any period after operation. The 6-minute walk test was performed by following a standardized procedure described by the American Thoracic Society Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories.10 Briefly, patients were instructed to walk the predetermined course at their own pace for 6 minutes. Standardized encouragement was given for patients in every minute during the test. At 6 minutes, patients were instructed to stop walking and the distance walked was measured. 6MWD was measured by the physical therapists in the department of rehabilitation, and surgeons were blinded as to the results of 6MWD. Data collection. Demographic data including age, sex, height, body weight, body mass index, presence of preoperative cholangitis, and other comorbidities were recorded. The Charlson
comorbidity index was used to score comorbid conditions uniformly.11 Intraoperative data such as operative procedure, operation time, and intraoperative blood loss also were recorded. Preoperative serum levels of albumin, aspartate aminotransferase, alanine aminotransferase, total bilirubin, total lymphocyte count, international normalized ratio of prothrombin time, white blood cell counts, and C-reactive protein were measured and recorded. The prognostic nutritional index (PNI), an indicator of nutritional status, was assessed by the following equation: PNI = 10 3 serum albumin (mg/dL) + 0.005 3 total lymphocyte count.12 The incidence of in-hospital complications was classified according to the Clavien-Dindo score.13 Briefly, patients were classified as grade 0 if they had no postoperative complications. Patients were classified as grade 1 if there was any deviation from the normal postoperative course, without the need for pharmacologic treatment or surgical, endoscopic, or radiologic interventions. Patients were classified as grade 2 if they required pharmacologic treatment with drugs other than such allowed for grade 1 complications. Patients were classified as grade 3 if they required surgical, endoscopic, or radiologic intervention. Patients were classified as grade 4 if they required admission to the intensive care unit. Postoperative mortality was defined as a grade 5 complication. Liver failure and bile leakage were defined according to the definition of the International Study Group of Liver Surgery.14,15 Postoperative pancreatic fistula and delayed gastric emptying were defined according to the definition of the International Study Group of Pancreatic Surgery.16,17 Postoperative surgical site infections including intra-abdominal abscess and wound infection also were recorded. Cholangitis patients fulfilled the following criteria: a sustained fever that required treatment with antibiotics, increased serum hepatobiliary enzymes, and isolation of bacteria from bile cultures with no focused infections other than cholangitis.18 The diagnosis of pneumonia required radiologic evidence of consolidation with leukocytosis. Bacteremia was diagnosed when a blood culture grew an isolate of organisms with no contamination of the skin flora. Clinically significant ascites or pleural effusion requiring drainage also was recorded. Statistical analysis. All continuous variables were expressed as median (range). Patients were categorized into the following 2 groups: patients with Clavien-Dindo grade <3 complications and those with Clavien-Dindo grade $3 complications. Differences between the 2 groups were analyzed using
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Table III. Binary logistic regression analysis for the risk of major postoperative complications with Clavien-Dindo grade $3 95% CI Odds ratio Lower limit Upper limit P value 6MWD BMI Blood loss
1.537 1.471 1.199
1.066 1.040 1.019
2.218 2.081 1.408
.021 .029 .029
Ten preoperative and intraoperative variables with P < .200 (ie, BMI, diabetes mellitus, preoperative cholangitis, 6MWD, albumin, aspartate aminotransferase, white blood cell counts, prognostic nutritional index, operative time, and blood loss) were entered into the binary logistic regression models. Odds ratio is for the occurrence of major postoperative complications with Clavien-Dindo grade $3 in each decrement of 50 m in 6MWD, each decrement of 2 kg/m2 in BMI, or each increment of 200 mL in intraoperative blood loss. BMI, Body mass index; CI, confidence interval.
∼399
400∼449
450∼499
500∼549
550∼
Fig 1. The 6-minute walk distance and the incidence of major complication with Clavien-Dindo grade $3.
the v2 test for the categorical variables and the Mann-Whitney U test for the continuous variables, respectively. Potential risk factors for ClavienDindo grade $3, as determined by univariate analysis (with P < .200), were explored with multivariate logistic regression analysis to determine if they were independent risk factors for high-grade complications. Postoperative survival was calculated by means of the Kaplan-Meier method, and differences in the survival curves were compared with the log-rank test. The data were analyzed using SPSS (version 20.0 for Microsoft Windows; SPSS, Chicago, IL). RESULTS There was no postoperative in-hospital or within 90 days mortality in analyzed patients. The number of patients with Clavien-Dindo grades 0, 1, 2, 3, 4,
and 5 were 16 (20%), 4 (5%), 28 (35%), 31 (38%), 2 (2%), and 0 (0%), respectively. Postoperative complications with Clavien-Dindo grade $3 occurred in 33 patients (40%; Table I). The number of patients with various postoperative complications categorized in the Clavien-Dindo grade $3 is listed in Table II. Among 15 incidences of intra-abdominal abscess, 9 incidences (60%) were associated with pancreatic and/or biliary leakage. Differences in the pre-, intra-, and postoperative variables between the patients with Clavien-Dindo grade <3 and those with Clavien-Dindo grade $3 are shown in Table I. Sex, age, and preoperative comorbidities were not significantly different between the 2 groups. Preoperative 6MWD, serum albumin, and PNI in the group with Clavien-Dindo grade $3 were significantly lower than the group with Clavien-Dindo grade <3. Postoperative hospital stay in the group with Clavien-Dindo grade $3 was significantly longer than the group with Clavien-Dindo grade <3. The various preoperative and intraoperative risk factors that have a potential association with the incidence of major postoperative complications (Clavien-Dindo grade $3) were included in the multivariate logistic regression analysis. The analyzed risk factors included body mass index, diabetes mellitus, preoperative cholangitis, 6MWD, albumin, aspartate aminotransferase, white blood cell counts, PNI, operation time, and intraoperative blood loss (all with P < .200 in the univariate analysis). A preoperative low 6MWD, low body mass index, and significant blood loss were identified as independent risk factors for major postoperative complications (Table III). The odds ratio was 1.53 (95% confidential interval, 1.06–2.21, P = .021) for the occurrence of major postoperative complications with Clavien-Dindo grade $3 in each decrement of 50 m in 6MWD. In patients with 6MWD <400 m (1,312 feet), the incidence rate of Clavien-Dindo grade $3 was considerably greater than patients with 6MWD $400 m (Fig 1). The patients with 6MWD <400 m were associated with greater age, lower height, female sex, and poor PNI, compared with those with 6MWD $400 m (Table IV). Finally, we analyzed the long-term survival in patients who underwent 6MWD test. The median (range) follow-up period was 353 days (30–808 days). The overall survival was significantly worse in patients with 6MWD <400 m compared with those with 6MWD $400 m (1-year survival rate, 65% vs 94%; P = .045; Fig 2, A). The overall survival also was significantly worse in patients with Clavien-Dindo grade $3 complication
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Table IV. Patient characteristics according to the preoperative 6MWD 6MWD $400 m (n = 70) Male, n (%) Median (range) age (y) Median (range) height (cm) Median (range) body weight (kg) Median (range) BMI (kg/m2) Comorbidities, n (%) Hypertension Diabetes mellitus Dyslipidemia Chronic kidney disease Cardiopulmonary disorder Preoperative cholangitis Neoadjuvant chemotherapy Charlson Comorbidity Index (0/1/2) Preoperative laboratory values Median (range) Albumin (g/dL) Median (range) AST (IU/L) Median (range) ALT (IU/L) Median (range) TB (mg/dL) Median (range) TLC (mm3) Median (range) PT-INR Median (range) WBC (mg/dL) Median (range) CRP (mg/dL) Median (range) PNI PD/HEBRD/HPD Treated disease, n (%) Pancreatic cancer Biliary tract cancer Ampullary cancer Other malignancies Benign disease Clavien-Dindo grade $3, n (%) Median (range) Operative time (min) Median (range) Blood loss (mL) Median (range) postoperative hospital stay (d)
49 66 164 57.8 21.1 31 18 7 6 8 15 4
(70) (38–82) (146–185) (38.7–94.5) (16.0–37.8) (44) (25) (10) (8) (7) (21) (5) 45/20/5
3.7 (1.7–4.6) 29 (13–822) 38 (10–714) 0.8 (0.3–3.2) 1.3 (0.6–3.4) 0.98 (0.85–1.35) 5.6 (2.7–9.1) 0.20 (0.01–6.81) 44.5 (23.0–62.0) 17/40/13 11 49 4 3 3 24 572 1,146 28
(15) (70) (5) (4) (4) (34) (322–1,012) (273–12,428) (10–121)
6MWD <400 m (n = 11) 3 76 151 54.5 21.1 7 1 3 0 1 1 1
(27) (65–88) (139–168) (34.0–62.5) (15.2–30.4) (63) (9) (27) (0) (9) (9) (9) 9/2/0
3.5 38 34 0.9 1.0 1.02 5.9 0.25 4.0
(2.9–3.8) (15–74) (9–128) (0.5–2.1) (0.6–2.7) (0.95–1.11) (3.6–7.1) (0.03–7.48) (33.5–49.5) 3/6/2
0 9 2 0 0 9 580 812 45
(0) (81) (18) (0) (0) (81) (373–677) (209–2,394) (17–92)
P value .006 <.001 .003 .172 .890 .232 .226 .105 .313 .339 .665 .449 .044 .381 .301 .442 .309 .307 .907 .558 .050 .977 .303
.003 .984 .416 .004
ALT, Alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CRP, C-reactive protein; PT-INR, international normalized ratio of prothrombin time; TB, total bilirubin; TLC, total lymphocyte count; WBC, white blood cell counts.
compared with others (1-year survival rate, 82% vs 95%; P = .033; Fig 2, B). DISCUSSION The present study indicates that major postoperative complications (Clavien-Dindo grade $3) after hepato-pancreato-biliary surgeries were predicted by low preoperative 6MWD. In patients with 6MWD <400 m, the incidence rate of ClavienDindo grade $3 complication was significantly greater (81%) compared with those with 6 MWD $400 m (34%). Interestingly, the long-term survival also was substantially worse in patients with 6MWD <400 m (1-year survival rate, 65%) compared with those with 6MWD $400 m (1-year survival rate 94%). These results indicate that the 6MWD is a
useful screening tool to identify the high-risk patients in hepato-pancreato-biliary operations. The 6MWD has been used to assess the functional recovery after cardiac,19,20 pulmonary,21 and orthopedic operations.22 However, the predictive value of the 6MWD for the incidence of postoperative complications has been studied in only a limited number of reports.23,24 Of note, only a few reports25 have evaluated the predictive value of the 6MWD for postoperative complications after abdominal operations. This study is the first to analyze the association between 6MWD results and postoperative complications in patients who underwent hepato-pancreatobiliary operations, which are the most invasive abdominal operations.
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(%)
A
Percent Survival Probability
100
80
60
40
20 6MWD ≥400 m 6MWD <400 m
0 0
6 12 18 Follow-up months
24
70 11
61 8
2 1
Numbers at risk 6MWD ≥400 m 6MWD <400 m
B
34 4
16 1
(%)
Percent Survival Probability
100
80
60
40
20 Clavien-Dindo < 3 Clavien-Dindo ≥ 3
0 0
6 12 18 Follow-up months
24
48 33
41 28
3 0
Numbers at risk Clavien-Dindo < 3 Clavien-Dindo ≥ 3
27 11
14 3
Fig 2. (A) Kaplan-Meier survival curves for the patients with the 6MWD $400 m and those with 6MWD <400 m. (B) Kaplan-Meier survival curves for the patients with Clavien-Dindo grade <3 and those with Clavien-Dindo grade $3.
Two previous reports studied the predictive value of the 6MWD for postoperative complications after open abdominal operation.8,9 Awdeh et al8 indicated that the 6MWD had a negative correlation with duration of hospital stay. However, in addition to abdominal laparotomy, this study included various other types of major operations, such as thoracotomies and sternotomies. Paisani
et al9 assessed the predictive value of the 6MWD for postoperative complications after upper abdominal operations. However, this study only focused on the incidence of pulmonary complications. The present study specifically studied only patients with hepato-pancreato-biliary diseases undergoing operation. In this disease category, highly invasive and complicated operations such as PD, HEBDR, and HPD are required. The incidence of postoperative complications after these procedures is unexpectedly high.26,27 Therefore, in patients with poor 6MWD results, operative indication and methods of perioperative management should be assessed carefully. Moreover, we recommend an aggressive preoperative physical therapy to improve functional exercise capacity for those with poor 6MWD results. Previous reports have indicated that the postoperative complications after operation for gastrointestinal cancer could be predicted by cardiopulmonary exercise testing.28-30 However, the cardiopulmonary exercise testing used in these studies requires specific equipment, including an electronically braked cycle ergometer with a 12lead electrocardiogram and a metabolic cart with a facemask for gas analyses. Thus, this test is not feasible in every institution. In contrast, the 6MWD is a simple, safe, and inexpensive test that can be performed in all patients without using any equipment. Therefore, we recommend performing the 6MWD preoperatively in patients who are going to undergo a high-risk operation, such as one for hepato-pancreato-biliary diseases. The levels of serum albumin and PNI were substantially lower in patients with Clavien-Dindo grade $3 complications than in patients with Clavien-Dindo grade <3 (Table I). These 2 nutritional factors also were significantly lower in patients with 6MWD <400 m (Table IV). Malnutrition has a negative impact on muscle wasting,31 postoperative recovery including tissue repair,32 and immunologic responses.33 These factors may have an impact on the incidence of postoperative complications. Although we did not measure the muscle strength or total muscle mass in each patient, the nutritional status may affect the functional exercise capacity substantially, which is indicated by a low 6MWD. These results imply the importance of preoperative nutritional therapy for patients who will undergo hepatopancreato-biliary operations. Frailty is a state of vulnerability identified through the assessment of weight loss, gait speed, grip strength, physical activity, and physical exhaustion.34 It has been shown to have a significant
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impact on postoperative complications after operation.35 The long-term survival rates after cancer operation also was shorter in patients with frailty compared with nonfrailty.36 Although frailty is not equivalent to poor functional capacity, the association between frailty and the results of 6MWD should be further clarified in a future study. This study has several limitations. First, we included only a small number of participants from a single medical center. Thus, our observations must be interpreted with caution. A largescale study to investigate the clinical importance of 6MWD on the outcome of highly invasive operations is now ongoing at our institution. Second, the present study included patients who underwent PD, HEBDR, or HPD for hepato-pancreato-biliary malignancies. Although these procedures are all highly invasive, the extent of invasiveness is somewhat variable among these procedures. In conclusion, this study demonstrated that the preoperative 6MWD was useful in predicting major postoperative complications in patients who underwent major operations for hepato-pancreatobiliary diseases, such as PD, HEBDR, and HPD. The 6MWD is an easy, safe, and feasible test that can be used routinely in assessing the risk of postoperative complications in patients who undergo major hepato-pancreato-biliary surgeries. In patients with 6MWD <400 m, operative indication and perioperative patient management should be carefully assessed. This work was supported in part by Grants-in-Aid for Scientific Research (no. 16K21081 to T. Inoue) from the Ministry of Education, Culture, Sports, and Science and Technology of Japan. We sincerely thank all of the patients, collaborating physicians, and other medical staff for their important contributions to this study.
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