j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e7
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Recombinant soluble thrombomodulin for postoperative disseminated intravascular coagulation Daisuke Hashimoto, MD, PhD,a Akira Chikamoto, MD,a Nobutomo Miyanari, MD, PhD,b Chitoshi Ohara, MD, PhD,c Masafumi Kuramoto, MD, PhD,d Kei Horino, MD, PhD,e Hisami Ohshima, MD,f and Hideo Baba, MD, PhDa,* a Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan b Department of Surgery, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan c Department of Surgery, Kumamoto Saishunso National Hospital, Koshi, Japan d Department of Surgery, Kumamoto Social Insurance General Hospital, Yatsushiro, Japan e Department of Surgery, Kumamoto Rosai Hospital, Yatsushiro, Japan f Department of Surgery, Arao Municipal Hospital, Arao, Japan
article info
abstract
Article history:
Background: Thrombomodulin is a thrombin receptor on the endothelial cell surface that
Received 22 October 2014
plays an important role in the regulation of intravascular coagulation. The purpose of this
Received in revised form
study was to evaluate the efficacy and safety of treatment with recombinant human sol-
10 March 2015
uble thrombomodulin (rhTM) for patients with septic-disseminated intravascular coagu-
Accepted 14 April 2015
lation (DIC) associated with gastroenterological surgery.
Available online xxx
Materials and methods: From April 2011eSeptember 2013, 201 patients with DIC associated with gastroenterological surgery were treated in 16 institutions in Kumamoto, Japan. The patients
Keywords:
were diagnosed according to the Japanese Association for Acute Medicine DIC scoring system.
Disseminated intravascular
The clinical course, mortality rate at 28 d, and adverse events were evaluated retrospectively.
coagulation
Results: Forty-five patients were excluded because they did not meet the Japanese Asso-
Thrombomodulin
ciation for Acute Medicine DIC criteria or had an insufficient duration of drug adminis-
Gastroenterological operation
tration. Thus, 156 patients were analyzed. Of these patients, 107 received rhTM at the
Complication
discretion of the attending surgeon and 49 did not. The most common reason for surgery in both groups was peritonitis due to perforation of the colon. Within 7 d, the platelet count, prothrombin timeeinternational normalized ratio, DIC score, neutrophil count, and C-reactive protein level significantly improved in the rhTM group compared with those in the control. Treatment with rhTM was significantly associated with reduced inhospital mortality at 28 d. The incidence of adverse events did not differ between the two groups. Conclusions: Therapy with rhTM may be associated with reduced inhospital mortality in patients with septic DIC associated with gastroenterological surgery without increasing adverse events. ª 2015 Elsevier Inc. All rights reserved.
* Corresponding author. Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto 860 8556, Japan. Tel.: þ81 96 373 5213; fax: þ81 96 371 4378. E-mail address: [email protected] (H. Baba). 0022-4804/$ e see front matter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2015.04.048
2
1.
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e7
Introduction
Disseminated intravascular coagulation (DIC) frequently complicates hematologic malignancies and infections such as sepsis [1,2]. Sepsis-induced DIC is a life-threatening condition characterized by systemic activation of blood coagulation, which generates intravascular fibrin and leads to multiple organ dysfunction syndrome or even death [3,4]. Emergency gastroenterological surgery for conditions such as perforation of diverticulitis, ulceration, or tumors is associated with high morbidity and mortality rates, and postoperative sepsis and DIC often develop in such patients [5,6]. Although these operations are necessary to improve the condition of the patient, such emergency procedures are very invasive. Additionally, after the performance of elective gastroenterological operations, severe postoperative complications such as intra-abdominal abscess formation, anastomotic leakage, pneumonia, and acute respiratory distress syndrome may occur, and each of these conditions may be associated with the development of DIC [7,8]. Furthermore, these gastroenterological operations frequently lead to systemic inflammation such as that seen in systemic inflammatory response syndrome. Thus, the patient’s response to treatment for surgeryrelated DIC may differ from that for DIC unrelated to a prior operation. Guidelines for the diagnosis and treatment of DIC were recently published in Britain [9], Japan [10], and Italy [11]. Treatment for surgery-related DIC is complicated for a surgeon; however, it has been not discussed enough in these guidelines. In addition, some differences in the recommendations for various anticoagulant therapies exist among these guidelines. Recombinant human soluble thrombomodulin (rhTM) is a novel biological agent [12,13]. Two randomized clinical trials involving patients with DIC due to hematologic malignancy or infection showed that rhTM therapy more effectively improves DIC and alleviates bleeding symptoms than does heparin therapy [14,15]. Similarly, another retrospective cohort study indicated that rhTM therapy may be associated with reduced inhospital mortality in mechanically ventilated adults with sepsisinduced DIC [16]. However, the effects of rhTM on DIC associated with gastroenterological surgery have not been thoroughly evaluated, whereas these patients’ condition and effect of treatment may differ from patients with DIC, which is not associated with operation. Additionally, the potentially increased risk of bleeding as an adverse event of rhTM has never been discussed in the treatment for DIC, which has developed after gastroenterological surgery. Thus, it may be necessary to distinguish the optimal therapeutic strategies between DIC that is and is not associated with gastroenterological surgery. To support our hypothesis that rhTM is effective for DIC after elective or emergency gastroenterological surgery without increasing adverse events such as bleeding, we conducted this retrospective multicenter study.
2.
Material and methods
2.1.
Patients
This investigation was a retrospective study of patients who were admitted to 16 tertiary referral hospitals in Japan after developing septic DIC associated with gastroenterological surgery. All patients who were included in this study were Japanese. These patients were treated with or without rhTM from April 2010eJuly 2013. Patients who fulfilled the criteria of the Japanese Association for Acute Medicine (JAAM) DIC scoring system [17] (DIC score of 4) were included in the investigation, and those who did not fulfill these criteria (DIC score of 3) were excluded (Fig. 1). No predefined protocol regarding the definite indications for rhTM treatment was used in this retrospective study. For patients with severe sepsis with DIC, rhTM was used at the clinical decision of the attending surgeon. rhTM was principally administered intravenously at a dose of 0.06 mg/kg per day and continued as necessary. In previous prospective studies, rhTM was continued for 6 d [14,15]. Because this is a retrospective study, the duration of rhTM therapy was determined by the attending surgeon. To make clear the therapeutic effect of rhTM on DIC, patients who received rhTM for 2 d were excluded from the investigation because this duration was possibly too short to evaluate (Fig. 1). Finally, the patients were assigned to one of two groups: those treated with rhTM (rhTM group) and those treated without rhTM (control group; Fig. 1). The patients’ characteristics, comorbidities, coexisting complications, clinical course, and mortality rate at 28-d from all causes and adverse events were evaluated. Administration of antithrombin concentrate or heparin and/or low-molecular weight heparin (LMWH) was not routinely performed, but these agents were administered to some patients at the discretion of the attending surgeon, based on the individual patient’s condition. Any treatment for DIC, including rhTM, antithrombin concentrate, and heparin and/or LMWH, was not added to the study population before the determination by
Fig. 1 e Patient flow diagram DIC [ disseminated intravascular coagulation.
3
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e7
the JAAM criteria. The study protocol was approved by the Institutional Review Board of Kumamoto University Hospital.
Table 1 e Patients’ baseline characteristics. Characteristics
2.2.
Data collection
The patients’ baseline characteristics and variables were collected in a prospective electronic database. In addition to the DIC score, we also evaluated the sequential organ failure assessment (SOFA) score, 28-d mortality from all causes and adverse events based on the common terminology criteria for adverse events version 4.0. According to previous studies [14e16], parameters were recorded on the day of rhTM administration and on days 3 and 7 after the study entry.
2.3.
Statistical analysis
Descriptive statistics are presented as the median (range) or number (percentage), as appropriate. Data were analyzed using SAS software (release 9.1; SAS Institute, Inc, Cary, NC). Parameters were compared between patient subgroups using the ManneWhitney U tests or chi-squared test. Survival rates were calculated using the KaplaneMeier method, and statistical significance was determined by the log-rank test. Differences were considered statistically significant at P < 0.05.
3.
Results
3.1.
Baseline characteristics
During the study period, 201 consecutive patients were diagnosed septic DIC associated with gastroenterological surgery. These patients were diagnosed as DIC based on clinical signs by the attending surgeon; however, 37 who did not fulfill the JAAM DIC criteria were excluded from the investigation. Of the excluded patients who did not fulfill the JAAM DIC criteria, 16 received rhTM and 21 did not. Of the 164 patients who fulfilled the JAAM DIC criteria, 115 received rhTM and 49 did not (Fig. 1). Eight patients were also excluded because of the short duration of their rhTM
Control group (without rhTM; n ¼ 49)
Male: female (n) 32: 17 Age (y) 75 (58e91) Comorbidities, n (%) Diabetes 13 (26.5) Ischemic 6 (12.2) heart disease Hemodialysis 2 (4.1) Liver cirrhosis 2 (4.1) Use of steroids 4 (8.2) Coexisting complications, n (%) Respiratory failure 25 (51.0) Circulatory failure 22 (44.9) Bacteremia 17 (34.7) Coagulation 5.8 (0.5e10.8) Platelet (104/mL) PT-INR 1.41 (1.02e3.08) FDP (mg/mL) 25.7 (4.1e147.2) AT-III (%) 53.0 (17.6e77) Inflammation 9.3 (0.8e34.3) WBC (103/mL) Neutrophil (%) 92 (55e97) CRP (mg/dL) 16.9 (1.8e36.4) SOFA score 9 (6e18) JAAM DIC score 5 (4e8) Duration of rhTM d therapy (d) Therapeutic intervention, n (%) Heparin/LMWH 5 (10.2) Antithrombin 22 (44.9) RBC 18 (36.7) FFP 26 (53.1)
rhTM group (n ¼ 107)
P value
65: 42 76 (20e103)
0.585 0.310
22 (20.6) 10 (9.3)
0.407 0.691
7 (6.5) 6 (5.6) 5 (4.7)
0.809 0.992 0.385
58 (54.2) 51 (47.7) 45 (42.1)
0.711 0.748 0.383
6.1 1.36 26.3 51.1
(0.6e11.9) (0.95e3.56) (4.6e220.8) (15.7e91)
0.230 0.450 0.376 0.302
9.2 90 18.6 10 5 6
(0.3e38.0) (25e99) (0e38.9) (6e18) (4e8) (3e14)
0.239 0.489 0.257 0.411 0.482 d
(1.9) (36.4) (45.8) (41.1)
0.055 0.315 0.289 0.164
2 39 49 44
AT-III ¼ antithrombin-III; FDP ¼ fibrin degradation products; FFP ¼ fresh-frozen plasma; RBC ¼ red blood cell.
therapy. Finally, 107 patients were included in the rhTM group and 49 patients were included in the control group (Fig. 1). The baseline characteristics of the study population are shown in Table 1. The patients comprised 32 men and 17
Table 2 e Surgical procedures performed before diagnosis of DIC. Control group (n ¼ 49) Procedure Drainage for perforation of colon Drainage for perforation of upper digestive tract Resection of intestine for strangulated small bowel obstruction Proctectomy and colectomy Pancreaticoduodenectomy Hepatectomy Gastrectomy Esophagectomy Resection of intestine for acute thromboembolic occlusion of the superior mesenteric artery Synectenterotomy
rhTM group (n ¼ 107) n (%)
Procedure
n (%)
19 (38.8) 7 (14.3) 4 (8.2)
Drainage for perforation of colon Drainage for perforation of upper digestive tract Resection of intestine for strangulated small bowel obstruction
36 (33.4) 22 (20.6) 9 (8.4)
3 3 3 2 2 2
(6.1) (6.1) (6.1) (4.1) (4.1) (4.1)
1 (2.0)
Gastrectomy Proctectomy and colectomy Hepatectomy Esophagectomy Synectenterotomy Resection of intestine for acute thromboembolic occlusion of the superior mesenteric artery Pancreaticoduodenectomy Drainage for cholecystitis and/or cholangitis Hemostasis for abdominal injury
8 7 6 4 4 3
(7.5) (6.5) (5.6) (3.7) (3.7) (2.8)
3 (2.8) 3 (2.8) 2 (1.9)
4
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e7
Fig. 2 e Effect of rhTM on DIC parameters. (A) Platelet counts, (B) prothrombin timeeinternational normalized ratios, (C) fibrin degradation products, (D) antithrombin-III level, and (E) JAAM DIC score on days 0, 3, and 7 are indicated in the control group (white bars) and rhTM group (black bars). The control group patients did not receive rhTM. Differences were considered statistically significant at P < 0.05. FDP [ fibrin degradation products; AT-III [ antithrombin-III.
women in the control group and 65 men and 42 women in the rhTM group, with a median age of 75 y (range, 58e91 y) in the control group and 76 y (range, 20e103 y) in the control group (Table 1). Thus, there were no significant differences in age and sex between the two groups. There were also no significant differences in comorbidities (diabetes, ischemic heart disease, hemodialysis, liver cirrhosis, and use of steroids) or coexisting complications (respiratory failure, circulatory failure, and bacteremia; Table 1). The median platelet count was 5.8 (range, 0.5e10.8) 104/mL in the control group and 6.1 (range, 0.6e11.9) 104/mL in the rhTM group, without no significant difference. Other coagulation
parameters, such as the prothrombin timeeinternational normalized ratio (PT-INR), fibrin degradation products, antithrombineIII, and the DIC scores, did not show significant differences between the two groups (Table 1). There were also no significant differences in the baseline characteristics of severity of illness as indicated by the SOFA score, white blood cell (WBC) count, neutrophil count, or C-reactive protein (CRP) level between the two groups (Table 1). The overall median duration of rhTM administration was 6 (range, 3e14) d. There were no significant differences in the use of therapeutic interventions such as heparin and/or LMWH (5 cases [10.2%] in the control group and 2 cases
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e7
5
Fig. 3 e Effect of rhTM on inflammation parameters. (A) WBC counts, (B) neutrophil counts, (C) CRP levels, and (D) SOFA scores on days 0, 3, and 7 are indicated in the control group (white bars) and the rhTM group (black bars). Differences were considered statistically significant at P < 0.05.
[1.9%] in the rhTM group), antithrombin concentrate (22 cases [44.9%] in the control group and 39 cases [36.4%] in the rhTM group), and blood product between the two groups (Table 1). The most common operation performed before diagnosis of DIC in both groups was drainage for perforative peritonitis of the colon secondary to diverticulitis or malignancy (Table 2).
3.2.
Effect of rhTM on DIC parameters
The platelet count on day 7 of treatment was significantly higher in the rhTM group than in the control group, whereas there was no significant difference on day 3 (Fig. 2A). Similarly, the PT-INR was significantly lower in the rhTM group than in the control group on day 7 (Fig. 2B). The fibrin degradation products and antithrombin-III level recovered in both groups without significant differences (Fig. 2C and D). As a result, the JAAM DIC scores on day 7 were significantly better in the rhTM group than in the control group (Fig. 2E).
3.3.
Effect of rhTM on inflammation parameters
There were no significant differences in the WBC counts between the rhTM group and control group (Fig. 3A).
However, the neutrophil count on day 7 and CRP level on days 3 and 7 were significantly lower in the rhTM group than in the control group (Fig. 3B and C). The SOFA scores improved in both groups but were not significantly different (Fig. 3D).
3.4.
Effect of rhTM on mortality
The survival curves of each group as calculated by the KaplaneMeier method are shown in Figure 4. The survival rate at 28 d was 76.6% in the rhTM group and 61.2% in the control group. Treatment with rhTM was significantly associated with reduced 28-d mortality from all causes (P ¼ 0.048).
3.5.
Adverse events associated with DIC treatment
Complications associated with DIC treatment are presented in Table 3. The overall incidence of adverse events was 4.1% in the control group and 3.7% in the rhTM group, and the difference was not statistically significant. In the rhTM group, gastrointestinal bleeding occurred in only one patient (0.9%) and elevations in aspartate aminotransferase and alanine transaminase concentrations occurred in three patients (2.8%). The difference in incidence of each adverse event was not significant between the two groups. No complications
6
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e7
Fig. 4 e Effect of rhTM on mortality. KaplaneMeier analysis was performed in each group during the study period. The control group is indicated by the broken line, and the rhTM group is indicated by the solid line. Differences were considered statistically significant at P < 0.05.
were severe, and all patients in both groups recovered immediately.
4.
Discussion
This multicenter retrospective study demonstrated that rhTM administration significantly improved the platelet count, PT-INR, and DIC score in patients who underwent gastroenterological surgery and subsequently developed severe sepsisinduced DIC. Although many previous studies have shown that rhTM significantly improves sepsis-induced DIC and mortality [14e16], no studies have focused on the efficacy of rhTM treatment in patients with gastroenterological surgeryrelated DIC. In a multicenter retrospective analysis, Yamakawa et al. [16]found that rhTM may reduce inhospital mortality in mechanically ventilated adults with sepsisinduced DIC, and 39% of the patients included in their study underwent emergency operations. However, the authors did not investigate whether rhTM could improve DIC, especially DIC associated with surgery. In the present study, both DIC and 28-d mortality significantly improved with rhTM treatment. Our study emphasized the therapeutic efficacy for rhTM for sepsis-induced DIC that developed after gastroenterological surgery. The anti-inflammatory mechanism of rhTM has also been reported [12,13]. Consistent with these previous studies on inflammation, the present study on DIC showed that the
Table 3 e Adverse events during treatment. Events Gastrointestinal bleeding, n (%) Elevation of AST/ ALT, n (%) Total, n (%)
Control group (n ¼ 49)
rhTM group (n ¼ 107)
P value
1 (2.0)
1 (0.9)
0.844
1 (2.0)
3 (2.8)
0.790
2 (4.1)
4 (3.7)
0.730
ALT ¼ alanine transaminase; AST ¼ aspartate aminotransferase.
neutrophil count and CRP level were significantly lower after rhTM treatment. The WBC count did not significantly change after rhTM therapy in this study. However, peripheral WBC counts can be influenced by recruitment of WBCs to the focus of infection and afterward recover to a suitable level with the resolution of severe sepsis. Although the SOFA scores decreased as a reflection of improvement in organ dysfunction, there was no statistically significant difference between the two groups. Significance of SOFA score in the treatment of DIC with rhTM should be evaluated in further studies including more patients. Postoperative bleeding is a major complication after gastrointestinal surgery [18,19]. Therefore, the potentially increased risk of bleeding is the greatest concern when rhTM is administered to postoperative patients. In this study, only a mild hemorrhagic complication occurred in one patient who underwent rhTM treatment. This indicates the safety of rhTM administration in patients who have undergone gastroenterological operations. In addition to its retrospective design, there were some limitations in this study. First, more patients who did not receive rhTM were excluded from the study by the JAAM criteria than the patients who received rhTM. The reason of this disproportion was possibly that the diagnosis of DIC was given based on clinical signs by the attending surgeon. Second, the specific type of DIC-associated operations were evaluated. To resolve these problems, further prospective trials including more patients are needed to fully evaluate the effects and safety of rhTM on sepsis-induced DIC associated not only with gastroenterological surgery but also other types of surgery such as cardiovascular and orthopedic procedures.
5.
Conclusions
We found that rhTM may have beneficial effects on the treatment of sepsis-induced DIC and on mortality in patients who have undergone gastroenterological operations, without increasing adverse events such as postoperative bleeding.
Acknowledgment No financial support was received in the performance of this study. The authors thank the following institutions and investigators who participated in this study: Nasu J (Kumamoto Chuo Hospital), Takano S (Tamana Central Hospital), Tanigawa T (Minamata City General Hospital and Medical Center), Yokomizo H (Japanese Red Cross Kumamoto Hospital), Nakahara O (Taragi Municipal Hospital), Takamori H (Saiseikai Kumamoto Hospital), Yamanaka T (Kumamoto Shinto General Hospital), Yokoyama Y (Kumamoto City Hospital), Hirota M (Kumamoto Regional Medical Center), and Matsuzaki H (Amakusa City Ushibuka Hospital). Authors’ contributions: D.H. contributed to the conception and design and writing of the article. A.C. did the analysis and interpretation. N.M., C.O., M.K., K.H., and H.O. did the data collection. H.B. did the critical revision of the article.
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e7
Disclosure The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
references
[1] Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999;341:586. [2] Toh CH, Dennis M. Disseminated intravascular coagulation: old disease, new hope. BMJ 2003;327:974. [3] Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med 2010;38:S26. [4] Esmon CT. The interactions between inflammation and coagulation. Br J Haematol 2005;131:417. [5] Tridente A, Clarke GM, Walden A, et al. Patients with faecal peritonitis admitted to European intensive care units: an epidemiological survey of the GenOSept cohort. Intensive Care Med 2014;40:202. [6] Kim SY, Oh TH, Seo JY, et al. The clinical factors for predicting severe diverticulitis in Korea: a comparison with Western countries. Gut Liver 2012;6:78. [7] Holzheimer RG, Gathof B. Re-operation for complicated secondary peritonitis - how to identify patients at risk for persistent sepsis. Eur J Med Res 2003;8:125. [8] Kiewiet JJ, van Ruler O, Boermeester MA, Reitsma JB. A decision rule to aid selection of patients with abdominal sepsis requiring a relaparotomy. BMC Surg 2013;13:28. [9] Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol 2009;145:24. [10] Wada H, Asakura H, Okamoto K, et al. Expert consensus for the treatment of disseminated intravascular coagulation in Japan. Thromb Res 2010;125:6.
7
[11] Di Nisio M, Baudo F, Cosmi B, et al. Diagnosis and treatment of disseminated intravascular coagulation: guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thromb Res 2012;129:e177. [12] Ito T, Kawahara K, Okamoto K, et al. Proteolytic cleavage of high mobility group box 1 protein by thrombinthrombomodulin complexes. Arterioscler Thromb Vasc Biol 2008;28:1825. [13] Abeyama K, Stern DM, Ito Y, et al. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J Clin Invest 2005;115: 1267. [14] Aikawa N, Shimazaki S, Yamamoto Y, et al. Thrombomodulin alfa in the treatment of infectious patients complicated by disseminated intravascular coagulation: subanalysis from the phase 3 trial. Shock 2011;35:349. [15] Saito H, Maruyama I, Shimazaki S, et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost 2007;5:31. [16] Yamakawa K, Ogura H, Fujimi S, et al. Recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a multicenter propensity score analysis. Intensive Care Med 2013;39:644. [17] Mimuro J, Takahashi H, Kitajima I, et al. Impact of recombinant soluble thrombomodulin (thrombomodulin alfa) on disseminated intravascular coagulation. Thromb Res Suppl 2013;131:436. [18] Kenjo A, Miyata H, Gotoh M, et al. Risk stratification of 7,732 hepatectomy cases in 2011 from the national clinical database for Japan. J Am Coll Surg 2014;218:412. [19] Miyata H, Gotoh M, Hirai I, et al. A pancreaticoduodenectomy risk model derived from 8575 cases from a national single-race population (Japanese) using a web-based data entry system: the 30-day and inhospital mortality rates for pancreaticoduodenectomy. Ann Surg 2014;259:773.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Recombinant soluble thrombomodulin for postoperative disseminated intravascular coagulation Daisuke Hashimoto, MD, PhD,a Akira Chikamoto, MD,a Nobutomo Miyanari, MD, PhD,b Chitoshi Ohara, MD, PhD,c Masafumi Kuramoto, MD, PhD,d Kei Horino, MD, PhD,e Hisami Ohshima, MD,f and Hideo Baba, MD, PhDa,* a Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan b Department of Surgery, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan c Department of Surgery, Kumamoto Saishunso National Hospital, Koshi, Japan d Department of Surgery, Kumamoto Social Insurance General Hospital, Yatsushiro, Japan e Department of Surgery, Kumamoto Rosai Hospital, Yatsushiro, Japan f Department of Surgery, Arao Municipal Hospital, Arao, Japan
article info
abstract
Article history:
Background: Thrombomodulin is a thrombin receptor on the endothelial cell surface that
Received 22 October 2014
plays an important role in the regulation of intravascular coagulation. The purpose of this
Received in revised form
study was to evaluate the efficacy and safety of treatment with recombinant human sol-
10 March 2015
uble thrombomodulin (rhTM) for patients with septic-disseminated intravascular coagu-
Accepted 14 April 2015
lation (DIC) associated with gastroenterological surgery.
Available online xxx
Materials and methods: From April 2011eSeptember 2013, 201 patients with DIC associated with gastroenterological surgery were treated in 16 institutions in Kumamoto, Japan. The patients
Keywords:
were diagnosed according to the Japanese Association for Acute Medicine DIC scoring system.
Disseminated intravascular
The clinical course, mortality rate at 28 d, and adverse events were evaluated retrospectively.
coagulation
Results: Forty-five patients were excluded because they did not meet the Japanese Asso-
Thrombomodulin
ciation for Acute Medicine DIC criteria or had an insufficient duration of drug adminis-
Gastroenterological operation
tration. Thus, 156 patients were analyzed. Of these patients, 107 received rhTM at the
Complication
discretion of the attending surgeon and 49 did not. The most common reason for surgery in both groups was peritonitis due to perforation of the colon. Within 7 d, the platelet count, prothrombin timeeinternational normalized ratio, DIC score, neutrophil count, and C-reactive protein level significantly improved in the rhTM group compared with those in the control. Treatment with rhTM was significantly associated with reduced inhospital mortality at 28 d. The incidence of adverse events did not differ between the two groups. Conclusions: Therapy with rhTM may be associated with reduced inhospital mortality in patients with septic DIC associated with gastroenterological surgery without increasing adverse events. ª 2015 Elsevier Inc. All rights reserved.
* Corresponding author. Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Chuo-ku, Kumamoto 860 8556, Japan. Tel.: þ81 96 373 5213; fax: þ81 96 371 4378. E-mail address: [email protected] (H. Baba). 0022-4804/$ e see front matter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2015.04.048
2
1.
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e7
Introduction
Disseminated intravascular coagulation (DIC) frequently complicates hematologic malignancies and infections such as sepsis [1,2]. Sepsis-induced DIC is a life-threatening condition characterized by systemic activation of blood coagulation, which generates intravascular fibrin and leads to multiple organ dysfunction syndrome or even death [3,4]. Emergency gastroenterological surgery for conditions such as perforation of diverticulitis, ulceration, or tumors is associated with high morbidity and mortality rates, and postoperative sepsis and DIC often develop in such patients [5,6]. Although these operations are necessary to improve the condition of the patient, such emergency procedures are very invasive. Additionally, after the performance of elective gastroenterological operations, severe postoperative complications such as intra-abdominal abscess formation, anastomotic leakage, pneumonia, and acute respiratory distress syndrome may occur, and each of these conditions may be associated with the development of DIC [7,8]. Furthermore, these gastroenterological operations frequently lead to systemic inflammation such as that seen in systemic inflammatory response syndrome. Thus, the patient’s response to treatment for surgeryrelated DIC may differ from that for DIC unrelated to a prior operation. Guidelines for the diagnosis and treatment of DIC were recently published in Britain [9], Japan [10], and Italy [11]. Treatment for surgery-related DIC is complicated for a surgeon; however, it has been not discussed enough in these guidelines. In addition, some differences in the recommendations for various anticoagulant therapies exist among these guidelines. Recombinant human soluble thrombomodulin (rhTM) is a novel biological agent [12,13]. Two randomized clinical trials involving patients with DIC due to hematologic malignancy or infection showed that rhTM therapy more effectively improves DIC and alleviates bleeding symptoms than does heparin therapy [14,15]. Similarly, another retrospective cohort study indicated that rhTM therapy may be associated with reduced inhospital mortality in mechanically ventilated adults with sepsisinduced DIC [16]. However, the effects of rhTM on DIC associated with gastroenterological surgery have not been thoroughly evaluated, whereas these patients’ condition and effect of treatment may differ from patients with DIC, which is not associated with operation. Additionally, the potentially increased risk of bleeding as an adverse event of rhTM has never been discussed in the treatment for DIC, which has developed after gastroenterological surgery. Thus, it may be necessary to distinguish the optimal therapeutic strategies between DIC that is and is not associated with gastroenterological surgery. To support our hypothesis that rhTM is effective for DIC after elective or emergency gastroenterological surgery without increasing adverse events such as bleeding, we conducted this retrospective multicenter study.
2.
Material and methods
2.1.
Patients
This investigation was a retrospective study of patients who were admitted to 16 tertiary referral hospitals in Japan after developing septic DIC associated with gastroenterological surgery. All patients who were included in this study were Japanese. These patients were treated with or without rhTM from April 2010eJuly 2013. Patients who fulfilled the criteria of the Japanese Association for Acute Medicine (JAAM) DIC scoring system [17] (DIC score of 4) were included in the investigation, and those who did not fulfill these criteria (DIC score of 3) were excluded (Fig. 1). No predefined protocol regarding the definite indications for rhTM treatment was used in this retrospective study. For patients with severe sepsis with DIC, rhTM was used at the clinical decision of the attending surgeon. rhTM was principally administered intravenously at a dose of 0.06 mg/kg per day and continued as necessary. In previous prospective studies, rhTM was continued for 6 d [14,15]. Because this is a retrospective study, the duration of rhTM therapy was determined by the attending surgeon. To make clear the therapeutic effect of rhTM on DIC, patients who received rhTM for 2 d were excluded from the investigation because this duration was possibly too short to evaluate (Fig. 1). Finally, the patients were assigned to one of two groups: those treated with rhTM (rhTM group) and those treated without rhTM (control group; Fig. 1). The patients’ characteristics, comorbidities, coexisting complications, clinical course, and mortality rate at 28-d from all causes and adverse events were evaluated. Administration of antithrombin concentrate or heparin and/or low-molecular weight heparin (LMWH) was not routinely performed, but these agents were administered to some patients at the discretion of the attending surgeon, based on the individual patient’s condition. Any treatment for DIC, including rhTM, antithrombin concentrate, and heparin and/or LMWH, was not added to the study population before the determination by
Fig. 1 e Patient flow diagram DIC [ disseminated intravascular coagulation.
3
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e7
the JAAM criteria. The study protocol was approved by the Institutional Review Board of Kumamoto University Hospital.
Table 1 e Patients’ baseline characteristics. Characteristics
2.2.
Data collection
The patients’ baseline characteristics and variables were collected in a prospective electronic database. In addition to the DIC score, we also evaluated the sequential organ failure assessment (SOFA) score, 28-d mortality from all causes and adverse events based on the common terminology criteria for adverse events version 4.0. According to previous studies [14e16], parameters were recorded on the day of rhTM administration and on days 3 and 7 after the study entry.
2.3.
Statistical analysis
Descriptive statistics are presented as the median (range) or number (percentage), as appropriate. Data were analyzed using SAS software (release 9.1; SAS Institute, Inc, Cary, NC). Parameters were compared between patient subgroups using the ManneWhitney U tests or chi-squared test. Survival rates were calculated using the KaplaneMeier method, and statistical significance was determined by the log-rank test. Differences were considered statistically significant at P < 0.05.
3.
Results
3.1.
Baseline characteristics
During the study period, 201 consecutive patients were diagnosed septic DIC associated with gastroenterological surgery. These patients were diagnosed as DIC based on clinical signs by the attending surgeon; however, 37 who did not fulfill the JAAM DIC criteria were excluded from the investigation. Of the excluded patients who did not fulfill the JAAM DIC criteria, 16 received rhTM and 21 did not. Of the 164 patients who fulfilled the JAAM DIC criteria, 115 received rhTM and 49 did not (Fig. 1). Eight patients were also excluded because of the short duration of their rhTM
Control group (without rhTM; n ¼ 49)
Male: female (n) 32: 17 Age (y) 75 (58e91) Comorbidities, n (%) Diabetes 13 (26.5) Ischemic 6 (12.2) heart disease Hemodialysis 2 (4.1) Liver cirrhosis 2 (4.1) Use of steroids 4 (8.2) Coexisting complications, n (%) Respiratory failure 25 (51.0) Circulatory failure 22 (44.9) Bacteremia 17 (34.7) Coagulation 5.8 (0.5e10.8) Platelet (104/mL) PT-INR 1.41 (1.02e3.08) FDP (mg/mL) 25.7 (4.1e147.2) AT-III (%) 53.0 (17.6e77) Inflammation 9.3 (0.8e34.3) WBC (103/mL) Neutrophil (%) 92 (55e97) CRP (mg/dL) 16.9 (1.8e36.4) SOFA score 9 (6e18) JAAM DIC score 5 (4e8) Duration of rhTM d therapy (d) Therapeutic intervention, n (%) Heparin/LMWH 5 (10.2) Antithrombin 22 (44.9) RBC 18 (36.7) FFP 26 (53.1)
rhTM group (n ¼ 107)
P value
65: 42 76 (20e103)
0.585 0.310
22 (20.6) 10 (9.3)
0.407 0.691
7 (6.5) 6 (5.6) 5 (4.7)
0.809 0.992 0.385
58 (54.2) 51 (47.7) 45 (42.1)
0.711 0.748 0.383
6.1 1.36 26.3 51.1
(0.6e11.9) (0.95e3.56) (4.6e220.8) (15.7e91)
0.230 0.450 0.376 0.302
9.2 90 18.6 10 5 6
(0.3e38.0) (25e99) (0e38.9) (6e18) (4e8) (3e14)
0.239 0.489 0.257 0.411 0.482 d
(1.9) (36.4) (45.8) (41.1)
0.055 0.315 0.289 0.164
2 39 49 44
AT-III ¼ antithrombin-III; FDP ¼ fibrin degradation products; FFP ¼ fresh-frozen plasma; RBC ¼ red blood cell.
therapy. Finally, 107 patients were included in the rhTM group and 49 patients were included in the control group (Fig. 1). The baseline characteristics of the study population are shown in Table 1. The patients comprised 32 men and 17
Table 2 e Surgical procedures performed before diagnosis of DIC. Control group (n ¼ 49) Procedure Drainage for perforation of colon Drainage for perforation of upper digestive tract Resection of intestine for strangulated small bowel obstruction Proctectomy and colectomy Pancreaticoduodenectomy Hepatectomy Gastrectomy Esophagectomy Resection of intestine for acute thromboembolic occlusion of the superior mesenteric artery Synectenterotomy
rhTM group (n ¼ 107) n (%)
Procedure
n (%)
19 (38.8) 7 (14.3) 4 (8.2)
Drainage for perforation of colon Drainage for perforation of upper digestive tract Resection of intestine for strangulated small bowel obstruction
36 (33.4) 22 (20.6) 9 (8.4)
3 3 3 2 2 2
(6.1) (6.1) (6.1) (4.1) (4.1) (4.1)
1 (2.0)
Gastrectomy Proctectomy and colectomy Hepatectomy Esophagectomy Synectenterotomy Resection of intestine for acute thromboembolic occlusion of the superior mesenteric artery Pancreaticoduodenectomy Drainage for cholecystitis and/or cholangitis Hemostasis for abdominal injury
8 7 6 4 4 3
(7.5) (6.5) (5.6) (3.7) (3.7) (2.8)
3 (2.8) 3 (2.8) 2 (1.9)
4
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e7
Fig. 2 e Effect of rhTM on DIC parameters. (A) Platelet counts, (B) prothrombin timeeinternational normalized ratios, (C) fibrin degradation products, (D) antithrombin-III level, and (E) JAAM DIC score on days 0, 3, and 7 are indicated in the control group (white bars) and rhTM group (black bars). The control group patients did not receive rhTM. Differences were considered statistically significant at P < 0.05. FDP [ fibrin degradation products; AT-III [ antithrombin-III.
women in the control group and 65 men and 42 women in the rhTM group, with a median age of 75 y (range, 58e91 y) in the control group and 76 y (range, 20e103 y) in the control group (Table 1). Thus, there were no significant differences in age and sex between the two groups. There were also no significant differences in comorbidities (diabetes, ischemic heart disease, hemodialysis, liver cirrhosis, and use of steroids) or coexisting complications (respiratory failure, circulatory failure, and bacteremia; Table 1). The median platelet count was 5.8 (range, 0.5e10.8) 104/mL in the control group and 6.1 (range, 0.6e11.9) 104/mL in the rhTM group, without no significant difference. Other coagulation
parameters, such as the prothrombin timeeinternational normalized ratio (PT-INR), fibrin degradation products, antithrombineIII, and the DIC scores, did not show significant differences between the two groups (Table 1). There were also no significant differences in the baseline characteristics of severity of illness as indicated by the SOFA score, white blood cell (WBC) count, neutrophil count, or C-reactive protein (CRP) level between the two groups (Table 1). The overall median duration of rhTM administration was 6 (range, 3e14) d. There were no significant differences in the use of therapeutic interventions such as heparin and/or LMWH (5 cases [10.2%] in the control group and 2 cases
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e7
5
Fig. 3 e Effect of rhTM on inflammation parameters. (A) WBC counts, (B) neutrophil counts, (C) CRP levels, and (D) SOFA scores on days 0, 3, and 7 are indicated in the control group (white bars) and the rhTM group (black bars). Differences were considered statistically significant at P < 0.05.
[1.9%] in the rhTM group), antithrombin concentrate (22 cases [44.9%] in the control group and 39 cases [36.4%] in the rhTM group), and blood product between the two groups (Table 1). The most common operation performed before diagnosis of DIC in both groups was drainage for perforative peritonitis of the colon secondary to diverticulitis or malignancy (Table 2).
3.2.
Effect of rhTM on DIC parameters
The platelet count on day 7 of treatment was significantly higher in the rhTM group than in the control group, whereas there was no significant difference on day 3 (Fig. 2A). Similarly, the PT-INR was significantly lower in the rhTM group than in the control group on day 7 (Fig. 2B). The fibrin degradation products and antithrombin-III level recovered in both groups without significant differences (Fig. 2C and D). As a result, the JAAM DIC scores on day 7 were significantly better in the rhTM group than in the control group (Fig. 2E).
3.3.
Effect of rhTM on inflammation parameters
There were no significant differences in the WBC counts between the rhTM group and control group (Fig. 3A).
However, the neutrophil count on day 7 and CRP level on days 3 and 7 were significantly lower in the rhTM group than in the control group (Fig. 3B and C). The SOFA scores improved in both groups but were not significantly different (Fig. 3D).
3.4.
Effect of rhTM on mortality
The survival curves of each group as calculated by the KaplaneMeier method are shown in Figure 4. The survival rate at 28 d was 76.6% in the rhTM group and 61.2% in the control group. Treatment with rhTM was significantly associated with reduced 28-d mortality from all causes (P ¼ 0.048).
3.5.
Adverse events associated with DIC treatment
Complications associated with DIC treatment are presented in Table 3. The overall incidence of adverse events was 4.1% in the control group and 3.7% in the rhTM group, and the difference was not statistically significant. In the rhTM group, gastrointestinal bleeding occurred in only one patient (0.9%) and elevations in aspartate aminotransferase and alanine transaminase concentrations occurred in three patients (2.8%). The difference in incidence of each adverse event was not significant between the two groups. No complications
6
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e7
Fig. 4 e Effect of rhTM on mortality. KaplaneMeier analysis was performed in each group during the study period. The control group is indicated by the broken line, and the rhTM group is indicated by the solid line. Differences were considered statistically significant at P < 0.05.
were severe, and all patients in both groups recovered immediately.
4.
Discussion
This multicenter retrospective study demonstrated that rhTM administration significantly improved the platelet count, PT-INR, and DIC score in patients who underwent gastroenterological surgery and subsequently developed severe sepsisinduced DIC. Although many previous studies have shown that rhTM significantly improves sepsis-induced DIC and mortality [14e16], no studies have focused on the efficacy of rhTM treatment in patients with gastroenterological surgeryrelated DIC. In a multicenter retrospective analysis, Yamakawa et al. [16]found that rhTM may reduce inhospital mortality in mechanically ventilated adults with sepsisinduced DIC, and 39% of the patients included in their study underwent emergency operations. However, the authors did not investigate whether rhTM could improve DIC, especially DIC associated with surgery. In the present study, both DIC and 28-d mortality significantly improved with rhTM treatment. Our study emphasized the therapeutic efficacy for rhTM for sepsis-induced DIC that developed after gastroenterological surgery. The anti-inflammatory mechanism of rhTM has also been reported [12,13]. Consistent with these previous studies on inflammation, the present study on DIC showed that the
Table 3 e Adverse events during treatment. Events Gastrointestinal bleeding, n (%) Elevation of AST/ ALT, n (%) Total, n (%)
Control group (n ¼ 49)
rhTM group (n ¼ 107)
P value
1 (2.0)
1 (0.9)
0.844
1 (2.0)
3 (2.8)
0.790
2 (4.1)
4 (3.7)
0.730
ALT ¼ alanine transaminase; AST ¼ aspartate aminotransferase.
neutrophil count and CRP level were significantly lower after rhTM treatment. The WBC count did not significantly change after rhTM therapy in this study. However, peripheral WBC counts can be influenced by recruitment of WBCs to the focus of infection and afterward recover to a suitable level with the resolution of severe sepsis. Although the SOFA scores decreased as a reflection of improvement in organ dysfunction, there was no statistically significant difference between the two groups. Significance of SOFA score in the treatment of DIC with rhTM should be evaluated in further studies including more patients. Postoperative bleeding is a major complication after gastrointestinal surgery [18,19]. Therefore, the potentially increased risk of bleeding is the greatest concern when rhTM is administered to postoperative patients. In this study, only a mild hemorrhagic complication occurred in one patient who underwent rhTM treatment. This indicates the safety of rhTM administration in patients who have undergone gastroenterological operations. In addition to its retrospective design, there were some limitations in this study. First, more patients who did not receive rhTM were excluded from the study by the JAAM criteria than the patients who received rhTM. The reason of this disproportion was possibly that the diagnosis of DIC was given based on clinical signs by the attending surgeon. Second, the specific type of DIC-associated operations were evaluated. To resolve these problems, further prospective trials including more patients are needed to fully evaluate the effects and safety of rhTM on sepsis-induced DIC associated not only with gastroenterological surgery but also other types of surgery such as cardiovascular and orthopedic procedures.
5.
Conclusions
We found that rhTM may have beneficial effects on the treatment of sepsis-induced DIC and on mortality in patients who have undergone gastroenterological operations, without increasing adverse events such as postoperative bleeding.
Acknowledgment No financial support was received in the performance of this study. The authors thank the following institutions and investigators who participated in this study: Nasu J (Kumamoto Chuo Hospital), Takano S (Tamana Central Hospital), Tanigawa T (Minamata City General Hospital and Medical Center), Yokomizo H (Japanese Red Cross Kumamoto Hospital), Nakahara O (Taragi Municipal Hospital), Takamori H (Saiseikai Kumamoto Hospital), Yamanaka T (Kumamoto Shinto General Hospital), Yokoyama Y (Kumamoto City Hospital), Hirota M (Kumamoto Regional Medical Center), and Matsuzaki H (Amakusa City Ushibuka Hospital). Authors’ contributions: D.H. contributed to the conception and design and writing of the article. A.C. did the analysis and interpretation. N.M., C.O., M.K., K.H., and H.O. did the data collection. H.B. did the critical revision of the article.
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 5 ) 1 e7
Disclosure The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
references
[1] Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999;341:586. [2] Toh CH, Dennis M. Disseminated intravascular coagulation: old disease, new hope. BMJ 2003;327:974. [3] Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med 2010;38:S26. [4] Esmon CT. The interactions between inflammation and coagulation. Br J Haematol 2005;131:417. [5] Tridente A, Clarke GM, Walden A, et al. Patients with faecal peritonitis admitted to European intensive care units: an epidemiological survey of the GenOSept cohort. Intensive Care Med 2014;40:202. [6] Kim SY, Oh TH, Seo JY, et al. The clinical factors for predicting severe diverticulitis in Korea: a comparison with Western countries. Gut Liver 2012;6:78. [7] Holzheimer RG, Gathof B. Re-operation for complicated secondary peritonitis - how to identify patients at risk for persistent sepsis. Eur J Med Res 2003;8:125. [8] Kiewiet JJ, van Ruler O, Boermeester MA, Reitsma JB. A decision rule to aid selection of patients with abdominal sepsis requiring a relaparotomy. BMC Surg 2013;13:28. [9] Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol 2009;145:24. [10] Wada H, Asakura H, Okamoto K, et al. Expert consensus for the treatment of disseminated intravascular coagulation in Japan. Thromb Res 2010;125:6.
7
[11] Di Nisio M, Baudo F, Cosmi B, et al. Diagnosis and treatment of disseminated intravascular coagulation: guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thromb Res 2012;129:e177. [12] Ito T, Kawahara K, Okamoto K, et al. Proteolytic cleavage of high mobility group box 1 protein by thrombinthrombomodulin complexes. Arterioscler Thromb Vasc Biol 2008;28:1825. [13] Abeyama K, Stern DM, Ito Y, et al. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J Clin Invest 2005;115: 1267. [14] Aikawa N, Shimazaki S, Yamamoto Y, et al. Thrombomodulin alfa in the treatment of infectious patients complicated by disseminated intravascular coagulation: subanalysis from the phase 3 trial. Shock 2011;35:349. [15] Saito H, Maruyama I, Shimazaki S, et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost 2007;5:31. [16] Yamakawa K, Ogura H, Fujimi S, et al. Recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a multicenter propensity score analysis. Intensive Care Med 2013;39:644. [17] Mimuro J, Takahashi H, Kitajima I, et al. Impact of recombinant soluble thrombomodulin (thrombomodulin alfa) on disseminated intravascular coagulation. Thromb Res Suppl 2013;131:436. [18] Kenjo A, Miyata H, Gotoh M, et al. Risk stratification of 7,732 hepatectomy cases in 2011 from the national clinical database for Japan. J Am Coll Surg 2014;218:412. [19] Miyata H, Gotoh M, Hirai I, et al. A pancreaticoduodenectomy risk model derived from 8575 cases from a national single-race population (Japanese) using a web-based data entry system: the 30-day and inhospital mortality rates for pancreaticoduodenectomy. Ann Surg 2014;259:773.
