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Clinical risk factors of delayed gastric emptying in patients after pancreaticoduodenectomy: A systematic review and meta-analysis
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EJSO 39 (2013) 213e223
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Clinical risk factors of delayed gastric emptying in patients after pancreaticoduodenectomy: A systematic review and meta-analysis* H. Qu a, G.R. Sun a, S.Q. Zhou b, Q.S. He a,* a
Department of General Surgery, Shandong University Qilu Hospital, No. 107 of the West Cultural Road, Jinan 250012, Shandong, China b Department of Internal Medicine, Jinan Central Hospital, Shandong, China Accepted 7 December 2012 Available online 5 January 2013
Abstract Background: The clinical risk factors of delayed gastric emptying (DGE) in patients after pancreaticoduodenectomy (PD) remains controversial. Herein, we conducted a systematic review to quantify the associations between clinical risk factors and DGE in patients after conventional PD or pylorus preserving pancreaticoduodenectomy (PPPD). Methods: A systematic search of electronic databases (PubMed, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2012 was performed. Cohort, caseecontrol studies, and randomized controlled trials that examined clinical risk factors of DGE were included. Results: Eighteen studies met final inclusion criteria (total n ¼ 3579). From the pooled analyses, preoperative diabetes (OR 1.49, 95% CI, 1.03e2.17), pancreatic fistulas (OR 2.66, 95% CI, 1.65e4.28), and postoperative complications (OR 4.71, 95% CI, 2.61e8.50) were significantly associated with increased risk of DGE; while patients with preoperative biliary drainage (OR 0.68, 95% CI, 0.48e0.97) and antecolic reconstruction (OR 0.17, 95% CI, 0.07e0.41) had decreased risk of DGE development. Gender, malignant pathology, preoperative jaundice, intra-operative transfusion, PD vs. PPPD and early enteral feeding were not significantly associated with DGE development (all P > 0.05). Conclusions: Our findings demonstrate that preoperative diabetes, pancreatic fistulas, and postoperative complications were clinical risk factors predictive for DGE. Antecolic reconstruction and preoperative biliary drainage result in a reduction in DGE. Knowledge of these risk factors may assist in identification and appropriate referral of patients at risk of DGE. Ó 2012 Elsevier Ltd. All rights reserved. Keywords: Pancreaticoduodenectomy; Complication; Delayed gastric emptying; Risk factors
Introduction Pancreatic cancer is a deadly disease worldwide.1 Although surgical resection provides the only chance of cure, most patients present with advanced disease that precludes complete resection and contributes to the poor outcome.2 Patients with pancreatic cancer can anticipate a median survival of <12 months and a 5-year survival of <5%.3e6 However, the decrease in peri-operative mortality rates in patients undergoing pancreatic operations in experienced centers, as well as the increasing interest of the * Meeting Presentation: Neither this paper nor any part of its content has been submitted for presentation in meeting(s). * Corresponding author. Tel.: þ86 0531 82166331. E-mail address: [email protected] (Q.S. He).
0748-7983/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejso.2012.12.010
surgical community regarding not only patients quality of life but also matters of cost/benefit, led scientists to focus on specific morbidity parameters associated with PD, including DGE.7e9 DGE is one of the most troublesome postoperative complications following PD. It prolongs the hospital stay, increasing costs and compromising quality of life.10 In the last two decades, DGE has come on the front scene as the leading cause of postoperative complications following pancreatic surgery. Numerous prior studies have analyzed the clinical risk factors associated with DGE in patients undergoing PD.7,9e25 However, the results of these studies were not consistent and the sample sizes were relatively modest. We perform a systematic review to evaluate the risk factors predictive for DGE in patients undergoing conventional PD or pylorus preserving pancreatoduodenectomy (PPPD).
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Methods The methods for this meta-analysis are in accordance with “Meta-Analysis of Observational Studies in Epidemiology: A Proposal for Reporting”.26 Selection of risk factors We performed a systematic review and meta-analysis of a selection of risk factors for development of DGE after PD or PPPD. Initially, we scrutinized in detail the literature on DGE to identify all possible risk factors. The initial search yielded 11 possible risk factors. Search strategy We conducted a systematic search of publications listed in the electronic databases (Medline via PubMed, EMBASE, OVID, Web of Science, the Cochrane Library) from 1970 to 2012. For the first search, text key words were “pancreaticoduodenectomy” or “pylorus-preserving pancreaticoduodenectomy” or “whipple” or ‘‘pancreatic surgery’’ or ‘‘pancreatic resection’’ and excluded “infant,” “newborn,” and “fetus”. The results of this search were combined with a subsequent search using terms “delayed gastric emptying” or “complications”. Language restrictions were not applied, but our search was limited to human studies. The ‘‘related articles’’ function was used to broaden the search, and all abstracts, studies, and citations scanned were reviewed. The list of articles was reviewed independently by two authors. The references from articles were also searched by hand. Study selection Cohort, caseecontrol studies, and randomized controlled trials were included if they investigated which clinical and peri-operative factors directly influencing the occurrence of DGE after conventional PD or PPPD. The potential variables assessed including patient baseline characteristics (e.g., age, gender and disease history), perioperative clinical and laboratory data, operative methods and postoperative complications. After obtaining full reports of candidate studies, the same reviewers independently assessed eligibility. Differences in data between the two reviewers were resolved by reviewing corresponding articles, and the final set was agreed on by consensus. If the publications did not contain the full information necessary for meta-analysis, we obtained the missing information directly from the authors. Data extraction For each study, the following data were extracted: first author’s last name, publication year, study design, sample size, patient characteristics and definition of DGE. Initially,
we scrutinized in detail the literature on PD to identify all possible risk factors for DGE. The initial search yielded 22 possible risk factors. Following review by an expert panel (GRS, SQZ and QSH), 11 factors that were considered to be easily measured in routine clinical practice and had been analyzed in at least 3 studies were selected for the full systematic review. These factors assessed including gender, malignancy, preoperative diabetes, preoperative jaundice, preoperative biliary drainage, PPPD vs. PD, intra-operative blood transfusion, antecolic vs. retrocolic route for duodenojejunostomy, pancreatic fistulas, postoperative (non-DGE) complications, and early enteral feeding. In this meta-analysis, we compared the risk of developing DGE in patients with and without the above factors. Study quality assessment The assessment of quality characteristics used the following criteria: 1. The Jadad score was introduced to evaluate the quality of randomized controlled trials (RCTs).27 Trials scored one point for each area addressed in the study design (randomization, blinding, concealment of allocation, reporting of withdrawals, and generation of random numbers) with a possible score of between 0 and 5 (highest level of quality). “Good” was defined as a Jadad score 4; “fair,” a Jadad score of 3; and “poor,” defined as a Jadad score <3. 2. The NewcastleeOttawa Scale was used to assess the quality of observational studies based on the following nine questions: (1) representativeness of the exposed cohort; (2) selection of the non-exposed cohort; (3) ascertainment of exposure; (4) demonstration that the outcome was not present at outset of study; (5) comparability; (6) assessment of outcome; (7) length of follow-up sufficient; (8) Adequacy of participant follow-up; (9) total stars. Maximum score on this scale is a total of 9.28 “Good” was defined as a total score of 7e9; “fair,” a total score of 4e6; and “poor,” defined as a total score of 4.
Statistical analyses We used REVMAN software (version 5.0; Cochrane Collaboration, Oxford, United Kingdom) and Stata software (version 11.0; Stata Corporation, College Station, TX) to pool data for all outcomes. Random effects (DerSimonian and Laird method) model was conducted to estimate the association between the 11 clinical factors and development of DGE. The odds ratios (ORs) and 95% confidence interval (CI) were calculated for each study. As the definitions of DGE may be a potential source of heterogeneity. In order to analyze the heterogeneity associated with
H. Qu et al. / EJSO 39 (2013) 213e223
different definitions of DGE, we performed subgroup analyses by comparing summary results obtained from subsets of studies grouped by ISGPS or other definitions. Statistical heterogeneity was evaluated with the Cochran’s c2 and the I2 statistics, which assess the appropriateness of pooling the individual study results. The I2 value provides an estimate of the amount of variance across studies resulting from heterogeneity rather than chance. P value was considered statistically significant at <0.05. Results Study selection Our initial search yielded 274 potential literature citations. Of these, 242 were excluded after scanning titles and abstracts, leaving 32 citations for full text assessment. Of these, 18 studies met the inclusion criteria and were used for this meta-analysis.19,21,29e44 The remaining studies were excluded largely because they did not provide DGE data according to the risk factors we evaluated; or had no control data; or reported the risk factors in an unusable format that were not comparable to the other studies (Fig. 1).
215
Characteristics of the trials Baseline characteristics of the studies included are shown in Table 1. The 18 included studies consisted of 14 prospective19,29e37,41e44 and 4 retrospective studies.21,38e40 Two of the prospective studies (the studies by Kurahara et al.37 and Tani et al.43) were RCTs, and others were prospective observational study. The study population included 3579 patients underwent either PD or PPPD. Demographic features of study populations were similar across the studies, and the average age of the patients ranged from 49 to 67 years. The percent of malignant disease ranged from 51% to 99% across the 18 studies. The definitions of DGE were different among the studies. In the 11 studies published before 2007,19,21,29e32,38,39,41e43 the need for a nasogastric tube beyond the 10th postoperative day (DGE10GT) or failure to tolerate a regular diet after the 14th postoperative day (DGE14) was the most commonly used definitions. Other definitions for DGE included the inability to tolerate a regular diet after the 10th postoperative day (DGE10)30,31 and the need for nasogastric tube for more than 7 days postoperative (DGE7GT).19 The International Study Group of Pancreatic Surgery (ISGPS) consensus definition of DGE
Figure 1. QUOROM (Quality Of Reporting Of Meta-analyses) statement flow diagram.
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Table 1 Characteristics of selected studies. Author
Year
Study design
Sample size
Mean age, y
Male, %
Malignancy, %
Intervention
Definition of DGE*
Quality assessmenty
Henegouwen et al.41
1997
Prospective
200
61
50
88
PPPD/PD
Fair
Horstmann et al.19
1999
Prospective
51
59
73
76
PPPD
Fabre et al.29 Martignoni et al.42
1999 2000
Prospective Prospective
88 64
61 64
70 53
81 87
PD PPPD/PD
Park YC et al.21
2003
Retrospective
150
58
60
86
PPPD
Riediger et al.30
2003
Prospective
204
58
63
51
PPPD
Sugiyama et al.38 Hartel et al.31
2004 2005
Retrospective Retrospective
30 200
61 63
63 44
83 73
PPPD PPPD
Bu et al.39 Tani et al.43
2006 2006
Retrospective Prospective
186 40
55 65
59 52
99 80
PPPD PPPD
Lermite et al.32 Nikfarjam et al.33 Park JS et al.40 Hashimoto and Traverso 35 Malleo et al.36 Welsch et al.34 Sakamoto et al.44 Kurahara et al.37
2007 2009 2009 2010
Prospective Prospective Retrospective Prospective
131 151 129 507
60 67 62 61
66 54 60 53
66 60 91 51
PD PPPD/PD PPPD/PD PPPD/PD
DGE14 or DGE10GT DGE14 or DGE7GT DGE10GT DGE14 or DGE10GT DGE14 or DGE10GT DGE10 or 14 or DGE10GT DGE10GT DGE10 or DGE10GT DGE10GT DGE14 or DGE10GT DGE10GT ISPGS ISPGS ISPGS
Good Good Good Good
2010 2010 2011 2011
Prospective Prospective Prospective Prospective
260 755 387 46
49 64 NA 65
57 56 60 70
78 NA 52 NA
PPPD PPPD/PD PPPD/PD PD
ISPGS ISPGS ISPGS ISPGS
Good Good Good Fair
Poor Poor Fair Fair Fair Poor Good Fair Fair
*Definitions of DGE. DGE10, the inability to tolerate a regular diet after the 10th postoperative day. DGE14, failure to tolerate a regular diet after the 14th postoperative day. DGE7GT, the need for nasogastric decompression for more than 7 postoperative days. DGE10GT, the need for a nasogastric tube beyond the10th postoperative day. ISGPS, the different grades of DGE were defined according to the requirement for a nasogastric tube in the postoperative period or inability to tolerate unlimited solid oral intake. Grade A was either 4e7 days with a nasogastric tube or reinsertion after postoperative day 3, or inability to tolerate solid oral intake by postoperative day 7. Grade B was 8e14 days with a nasogastric tube, or reinsertion after 7 day, or inability to tolerate solid oral intake by postoperative day 14. Grade C was more than 14 days with a nasogastric tube, or reinsertion after 14 days, or inability to tolerate solid oral intake by day 21. y Study quality was assessed using Jadad Score for the 2 randomized controlled trials (the studies by Kurahara et al.37 and Tani et al.43) with a possible score of between 0 and 5 (highest level of quality), and “Good” was defined as a Jadad score 4; “fair,” a Jadad score of 3; and “poor,” defined as a Jadad score <3. And the Newcastlee Ottawa Scale (NOS) was used to assess the quality of other 16 observational studies. Maximum score on this scale is a total of 9. “Good” was defined as a total score of 7e9; “fair,” a total score of 4e6; and “poor,” defined as a total score of 4.
was used in all the 7 studies published from 2009 to 2011.33e37,40,44 Fifteen of the 18 studies were of high methodological quality (good or fair) (Table 1).
Gender Ten studies investigated the influence of gender on the occurrence of DGE.21,29e37 These studies included 1522 male and 1174 female patients. The proportion of males was 60% in patients with DGE compared with 56% in patients without. Findings from this analysis suggested there was no significant association between gender and development of DGE (OR, 1.46; 95% CI, 0.85e2.50; P ¼ 0.17). Statistical heterogeneity among the studies was significant (I2 ¼ 84%; P < 0.001) (Figure was not shown).
Malignancy Ten studies evaluated the effect of pathology on DGE.21,30e32,35,36,40e42,44 1479 patients with malignant pathology and 746 patients with benign pathology. Malignancy was diagnosed in 72% of the DGE patients compared with 65% of those without. The pooled analysis of these studies showed a non-significant association between malignancy pathology and DGE (OR, 1.05; 95% CI, 0.74 to 1.49; P ¼ 0.79). No significant statistical heterogeneity was observed among the studies (I2 ¼ 42%; P < 0.08) (Figure was not shown). Preoperative diabetes From the 8 studies examining diabetes, preoperative diabetes tends to increase the risk for DGE.21,30,32,33,41,42,44
H. Qu et al. / EJSO 39 (2013) 213e223
217
Figure 2-1. Pooled odds ratio for DGE by preoperative diabetes (presence or absence).
The relative risk for DGE was 1.49 (95% CI 1.03e2.17, P ¼ 0.03) in patients with diabetes. The c2 test for heterogeneity was non-significant (I2 ¼ 30%; P ¼ 0.20) (Fig. 2-1). Preoperative biliary drainage Five studies reported the influence of preoperative biliary drainage (1061 patients).21,30,31,34 DGE was found in 12% of patients with preoperative biliary drainage compared to 17% of patients without. Analysis of these studies showed a significant benefit in preoperative biliary drainage (OR, 0.68; 95% CI, 0.48 to 0.97; P ¼ 0.03) (Fig. 2-2).
decreased risk of DGE (OR, 0.17; 95% CI, 0.09 to 0.33; P < 0.001) (Fig. 2-3). PPPD versus PD Seven studies compared the impact of PD and PPPD on development of DGE were included (1600 PD and 464 PPPD).33e35,40e42,44 There was a non-significant trend toward lower incidence of DGE in the PD group. The OR obtained through analysis of these studies was 1.25 (95% CI 0.97e1.62; P ¼ 0.08). No statistically significant heterogeneity was observed between studies (I2 ¼ 10%; P ¼ 0.35) (Fig. 2-4). 1000 mL",1,1,2,0>1000 mL", "pdflink",1,1,0>Intraoperative transfusions/blood loss >1000 mL
Preoperative jaundice In the 4 studies that reported the effect of preoperative jaundice.21,32,35,40 Analysis showed patients with and without preoperative jaundice had similar incidence of DGE (OR, 1.36; 95% CI, 0.59 to 3.17; P ¼ 0.47) (Figure was not shown). Antecolic vs. retrocolic reconstruction Seven studies evaluated if antecolic or retrocolic duodenojejunostomy was associated with the lower incidence of DGE (871 patients).21,31,33,36e38,43 DGE occurred in 10% of patients with the antecolic route for reconstruction versus 22% with the retrocolic route. From the pooled analysis, an antecolic reconstruction was significantly associated with
There were 8 studies that evaluated the influence of intra-operative transfusions or blood loss >1000 mL (2351 patients).21,30,31,33e36,44 No significant difference was observed in the risk for DGE in patients with and without intra-operative transfusion, while there was a trend toward a higher incidence of DGE in patients received intra-operative transfusion/with blood loss >1000 mL (OR, 1.46; 95% CI, 0.94 to 2.29; P ¼ 0.10) (Fig. 2-5). Pancreatic fistulas Six studies reported the effect of postoperative pancreatic fistulas on DGE development.33,35,36,39,40,44
Figure 2-2. Pooled odds ratio for DGE by preoperative biliary drainage (presence or absence).
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Figure 2-3. Pooled odds ratio for DGE by duodenojejunostomy route (antecolic vs. retrocolic).
Postoperative pancreatic fistula was defined according to the definition proposed by the International Study Group on Pancreatic Fistula45 (any measurable amount of fluid after postoperative day 3 with an amylase level three or greater times the serum amylase level) in 5 studies,33,35,36,40,44 and the definition was not reported in 1 study.39 The pooled analysis showed the incidence of DGE was 31% in the 324 patients with pancreatic fistulas, compared to 13% in the 1291 patients without. Findings from the meta-analysis show a significant association between postoperative pancreatic fistulas and DGE (OR 2.66; 95% CI 1.65e4.28; P < 0.001) (Fig. 2-6). Postoperative complications Postoperative complications was reported in 11 studies19,21,29e31,33,34,39e42 (1443 patients) (Table 2). DGE was significantly more frequent among patients with postoperative complications (39% vs. 16%). The OR obtained through analysis of these 11 studies was 4.71 (95% CI 2.61e8.50; P < 0.001) (Fig. 2-7). Early enteral feeding Estimates from three studies contributed to this analysis.30,32,42 Analysis of these studies showed no significant difference was observed in the incidence of DGE in patients
with and without early enteral feeding (OR, 1.05; 95% CI, 0.07e15.91; P ¼ 0.97) (Fig. 2-8). Subgroup analysis according to the definitions for DGE In the subgroup meta-analyses, we compared the associations between above risk factors and DGE in subsets of studies grouped by ISGPS or other definitions (Table 3). The results showed that no matter what definition was use in the original studies, no significant differences were observed in the effects of gender, malignancy, diabetes, biliary drainage, PPPD vs. PD, intra-operative transfusion, reconstruction route, and pancreatic fistulas in DGE development. Discussion Although DGE after PD is a well recognized complication, the pathogenesis appears to be multi-factorial. Our systematic review identified 14 prospective and 4 retrospective studies that addressed the clinical risk factors of DGE. In general, although the trials had some methodological limitations, including different conceptions of DGE, heterogeneity of the included studies and sample sizes were inadequate to completely assess the risk factors of DGE, we can say with confidence that of the 11 risk factors identified in
Figure 2-4. Pooled odds ratio for DGE by PPPD vs. PD.
H. Qu et al. / EJSO 39 (2013) 213e223
219
Figure 2-5. Pooled odds ratio for DGE by intra-operative transfusion (presence or absence).
our systematic review and meta-analysis, postoperative complications, pancreatic fistulas and preoperative diabetes were strongly and consistently associated with DGE. Antecolic reconstruction and preoperative biliary drainage result in a reduction in DGE. PPPD and early enteral feeding were not risk factors of DGE.
may result in gastric motor dysfunction including autonomic neuropathy, enteric neuropathy involving excitatory and inhibitory nerves, acute fluctuations in blood glucose, incretin-based medications used to normalize postprandial blood glucose and psychosomatic factors.21,27
Postoperative complications and pancreatic fistulas
Reconstruction route and biliary drainage
In nearly all previous studies, the presence of postoperative complications was the most significant risk factor for DGE, and our meta-analysis confirmed this tendency.21,30,40,42 The reasons why postoperative complications may lead to DGE are not fully understood. It has been suggested that gastroparesis as a consequence of local inflammation or abscess may be the main cause of DGE.30,42 Pancreatic fistulas was one of the most frequent postoperative complications, and have been shown to be associated with some fatal consequences, such as intraabdominal bleeding and infection. Therefore, DGE could be considered a warning for postoperative complications, especially pancreatic fistulas, and would be justified by abdominal imaging during postoperative periods.
Antecolic reconstruction and preoperative biliary drainage were the only two factors associated with reduction of DGE in our meta-analysis. Theoretically, an antecolic reconstruction avoids the risk of mechanical outflow obstruction, allows an increased mobility of the stomach, and provides an anatomical barrier from the pancreas, thus minimizing the possible negative effects of an infected collection or a pancreatic fistula.32,37,43 Possible explanation of preoperative biliary drainage in reducing the incidence of DGE was that preoperative hyperbilirubinemia is considered an important risk factor for postoperative complications and death. Hyperbilirubinemia due to obstructive jaundice damages hepatic function, clearance of circulating endotoxins, coagulation system, immune function, and gastrointestinal barrier.21,30,31,35 Some reports have found an influence of jaundice and endotoxemia on intestinal motility in vitro and reported that intestinal motility was lower in the obstructive jaundiced rat, especially when combined with endotoxemia.47e49
Preoperative diabetes Preoperative diabetes was thought to be a risk factor for the development of DGE. Several abnormalities in diabetes
Figure 2-6. Pooled odds ratio for DGE by pancreatic fistulas (presence or absence).
220
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Table 2 Definition of postoperative complications.
PD vs. PPPD
Studies
Postoperative complications definitions in included articles
Hartel et al.31
Pancreatic fistulas, anastomotic leakage, abscess, and hematoma. Pancreatic leakage, intra-abdominal infection, intra-abdominal hemorrhage, liver function failure, bile leakage. Complications were graded according to the severity score suggested by DeOliveira et al.46 Pancreatic fistula, bleeding, intra-abdominal abscess, hepaticojejunostomy leak, wound infection. Pancreatic fistula, bleeding, intra-abdominal abscess, hepaticojejunostomy leak, wound infection. Wound infection, pancreatic leakage, intra-abdominal abscess, pneumonia, bleeding, pancreatitis, biliary leakage, cholangitis, vascular, cardiac Wound infections, intra-abdominal abscesses, bile fistulas, and a pancreatic fistula, sepsis, severe bleeding, peripheral nerve lesion Pancreatic leakage, biliary leakage, hemorrhage, intra-abdominal abscess, relaparotomy Bleeding, pancreatic fistula, wound infection, biliary leak, pulmonary and cardiac complications Bleeding, gastrojejunostomy leakage, burst abdomen, intra-abdominal collection, pancreatic fistula, biliary fistula, thrombosis, wound hematoma Pancreatic fistula, wound infections, postoperative bleeding, intra-abdominal abscess, pneumonia, urinary tract infection, thromboembolic, reoperation
Although PPPD was thought to be risk factor for the development of DGE in some previous studies compared with conventional PD, the majority of recently performed clinical trials and our meta-analysis demonstrated that DGE is not an exclusive characteristic of PPPD and that its incidence is equally distributed between PD and PPPD. The reasons appears to be multi-factorial. Improvement of surgical techniques and increased surgical experience as well as advances in peri-operative and critical care management, were potential contributors in decreased rates of DGE. Perioperative administration of drugs that have been shown to decrease postoperative DGE, like octreotide or erythromycin lactobionate, varies from study to study. The indication for performing PD varies significantly not only between different studies, but also within the same patient cohort. There is therefore a growing need for a multicentre, randomized clinical trial with specific guidelines for perioperative administration of pharmaceutical agents, standard definition of the term DGE, and specific etiology-based performance of pancreatic surgery, to compare the efficiency of the two methods regarding DGE.
Bu et al.39
Welsch et al.34
Park YC et al.21
Park JS et al.40
Riediger et al.30
Martignoni et al.42
Henegouwen et al.41
Horstmann et al.19
Fabre et al.29
Nikfarjam et al.33
70.0 40.4
28.3
57.4
25.0
10.2
27.9
Early enteral feeding 1.16
25.4
27.7
2.8
Early enteral feeding have been demonstrated to be more physiological, better preventive in morphologic and functional alteration of the gut system, and less expensive than parental nutrition.50,51 Whereas several previous studies suggested early enteral feeding was associated with a higher frequency of postoperative complications including DGE.32,42 Our meta-analysis showed early enteral feeding was not a potential contributor to DGE. However, the relatively small sample size and fewer studies included results in wide confidence interval and mandates caution when interpreting this result. Therefore more high-quality and large studies are needed in the future.
Figure 2-7. Pooled odds ratio for DGE by postoperative complications (presence or absence).
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221
Figure 2-8. Pooled odds ratio for DGE by early enteral feeding (presence or absence).
Table 3 Subgroup analysis according to the definitions for DGE. No. of studies
Test for association OR (95% CI)
Male ISPGS Other definitions Malignancy ISPGS Other definitions Preoperative diabetes ISPGS Other definitions Biliary drainage ISPGS Othe definitions Antecolic vs. retrocolic route ISPGS Other definitions PPPD vs. PD ISPGS Othe definitions Transfusion ISPGS Other definitions Pancreatic fistulas ISPGS Other definitions Complications ISPGS Other definitions
Test for subgroup difference I2
P
5 5
1.49 (0.71e3.15) 1.50 (0.59e3.78)
0.18 0.15
4 6
0.92 (0.51e1.67) 0.93 (0.48e1.79)
0.79 0.82
3 5
1.37 (0.87e2.15) 1.54 (0.86e2.76)
0.18 0.15
1 3
0.78 (0.46e1.34) 0.61 (0.38e0.98)
0.37 0.04
3 4
0.26 (0.11e0.64) 0.12 (0.06e0.25)
0.003 <0.001
5 2
1.29 (0.96e1.73) 1.15 (0.69e1.91)
0.009 0.59
5 3
1.26 (0.66e2.41) 1.92 (1.17e3.14)
0.48 0.01
4 2
2.71 (1.82e4.03) 4.88 (0.34e70.2)
<0.001 0.24
3 8
1.75 (1.24e2.46) 7.85 (4.41e13.98)
0.001 <0.001
P
0%
0.99
0%
0.99
0%
0.75
0%
0.55
41%
0.19
0%
0.70
0.6%
Limitation Several limitations of this meta-analysis should be noted. First, the pooled studies differed in inclusion and exclusion criteria, definition of DGE. These may be the major source of heterogeneity. We used a random effects model in an effort to incorporate heterogeneity between trials in our analysis, but recognize that this does not eliminate the fact that heterogeneities were present. Second, the data included in some studies may have been too crude and also subject to measurement error. For example, definition of intraoperative transfusion may encompass a spectrum of conditions including large amount of blood loss; while the amount of blood loss are also determined by subjective judgment of the surgeon and cannot be quantified
0.32
0%
0.67
94%
<0.001
accurately. Several studies reported the intra-operative blood loss >750/1000 ml, we deemed this as intraoperative transfusion. Such potential measurement errors would likely dilute effects in the meta-analysis. Finally, given that a proportion of studies included are retrospective, a possibility of residual confounding by unmeasured factors cannot be eliminated. This provided associative, not causal, evidence and mandates caution when interpreting these results. Conclusion Our analysis provide evidence that postoperative complications, pancreatic fistulas and preoperative diabetes were strongly and consistently associated with DGE.
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Antecolic reconstruction and preoperative biliary drainage result in a reduction in DGE. The evidence does not permit any definite conclusions. Determining the impact these risk factors will require one or more large, well-designed, appropriately powered RCTs. Given the difficulty blinding the personnel involved and the extensive experience many surgeons have with the procedures, an expertise-based design would be the ideal method of exploring this question. Contributions of authors H. Qu and Q.S. He: Designed and performed the studies, and drafted the article. G.R. Sun, S.Q. Zhou: Designed and performed the studies, and revised the article. Conflicts of interest statement None declared.
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14. Tanaka M, Sarr MG. Role of the duodenum in the control of canine gastrointestinal motility. Gastroenterology 1988;94:622–9. 15. Tanaka A, Ueno T, Oka M, Suzuki T. Effect of denervation of the pylorus and transection of the duodenum on acetaminophen absorption in rats; possible mechanism for early delayed gastric emptying after pylorus preserving pancreatoduodenectomy. Tohoku J Exp Med 2000;192:239–47. 16. Itani KM, Coleman RE, Meyers WC, Akwari OE. Pylorus-preserving pancreatoduodenectomy. A clinical and physiologic appraisal. Ann Surg 1986;204:655–64. 17. Ueno T, Tanaka A, Hamanaka Y, Tsurumi M, Suzuki T. A proposal mechanism of early delayed gastric emptying after pylorus preserving pancreatoduodenectomy. Hepatogastroenterology 1995;42:269–74. 18. Kim DK, Hindenburg AA, Sharma SK, et al. Is pylorospasm a cause of delayed gastric emptying after pylorus-preserving pancreaticoduodenectomy? Ann Surg Oncol 2005;12:222–7. 19. Horstmann O, Becker H, Post S, Nustede R. Is delayed gastric emptying following pancreaticoduodenectomy related to pylorus preservation? Langenbecks Arch Surg 1999;384:354–9. 20. Horstmann O, Markus PM, Ghadimi MB, Becker H. Pylorus preservation has no impact on delayed gastric emptying after pancreatic head resection. Pancreas 2004;28:69–74. 21. Park YC, Kim SW, Jang JY, Ahn YJ, Park YH. Factors influencing delayed gastric emptying after pylorus-preserving pancreatoduodenectomy. J Am Coll Surg 2003;196:859–65. 22. Akizuki E, Kimura Y, Nobuoka T, et al. Prospective nonrandomized comparison between pylorus-preserving and subtotal stomachpreserving pancreaticoduodenectomy from the perspectives of DGE occurrence and postoperative digestive functions. J Gastrointest Surg 2008 Jul;12:1185–92. 23. Hunt DR, McLean R. Pylorus-preserving pancreatectomy: functional results. Br J Surg 1989;76:173–6. 24. Murakami H, Suzuki H, Nakamura T. Pancreatic fibrosis correlates with delayed gastric emptying after pylorus-preserving pancreaticoduodenectomy with pancreaticogastrostomy. Ann Surg 2002;235:240–5. 25. Braasch JW, Deziel DJ, Rossi RL, Watkins Jr E, Winter PF. Pyloric and gastric preserving pancreatic resection: experience with 87 patients. Ann Surg 1986;204:411–9. 26. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting: Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. J Am Med Assoc 2000;283:2008–12. 27. Moher D, Pham B, Jones A, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet 1998;352:609–13. 28. Wells G, Shea B, O’Connell D, et al. The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomized studies in metaanalysis. Ottawa Health Research Institute (OHRI); 2006. 29. Fabre JM, Jean SB, Francis N, Boccarat G, Lemoine C, Domergue J. Delayed gastric emptying after pancreaticoduodenectomy and pancreaticogastrostomy. Eur J Surg 1999;165:560–5. 30. Riediger H, Makowiec F, Schareck WD, Hopt UT, Adam U. Delayed gastric emptying after pylorus-preserving pancreatoduodenectomy is strongly related to other postoperative complications. J Gastrointest Surg 2003;7:758–65. 31. Hartel M, Wente MN, Hinz U, et al. Effect of antecolic reconstruction on delayed gastric emptying after the pylorus-preserving Whipple procedure. Arch Surg 2005;140:1094–9. 32. Lermite E, Pessaux P, Brehant O, et al. Risk factors of pancreatic fistula and delayed gastric emptying after pancreaticoduodenectomy with pancreaticogastrostomy. J Am Coll Surg 2007;204:588–96. 33. Nikfarjam M, Kimchi ET, Gusani NJ, et al. A reduction in delayed gastric emptying by classic pancreaticoduodenectomy with an antecolic gastrojejunal anastomosis and a retrogastric omental patch. J Gastrointest Surg 2009;13:1674–82. 34. Welsch T, Borm M, Degrate L, Hinz U, B€uchler MW, Wente MN. Evaluation of the International Study Group of Pancreatic Surgery
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43. Tani M, Terasawa H, Kawai M, et al. Improvement of delayed gastric emptying in pylorus-preserving pancreaticoduodenectomy results of a prospective, randomized, controlled trial. Ann Surg 2006;243:316–20. 44. Sakamoto Y, Yamamoto Y, Hata S, et al. Analysis of risk factors for delayed gastric emptying (DGE) after 387 pancreaticoduodenectomies with usage of 70 stapled reconstructions. J Gastrointest Surg 2011;15: 1789–97. 45. Bassi C, Dervenis C, Butturini G, et al. Postoperative pancreatic fistula: an International Study group (ISGPF) definition. Surgery 2005; 138:8–13. 46. DeOliveira ML, Winter JM, Schafer M, et al. Assessment of complications after pancreatic surgery: a novel grading system applied to 633 patients undergoing pancreaticoduodenectomy. Ann Surg 2006;244: 931–7. 47. Gouma DJ, Coelho JC, Fisher JD, Schlegel JF, Li YF, Moody FG. Endotoxemia after relief of biliary obstruction by internal and external drainage in rats. Am J Surg 1986;151:476–9. 48. Gouma DJ, Roughneen PT, Kumar S, Moody FG, Rowlands BJ. Changes in nutritional status associated with obstructive jaundice and biliary drainage in rats. Am J Clin Nutr 1986;44:362–9. 49. Assimakopoulos SF, Scopa CD, Zervoudakis G, Mylonas PG, Georgiou C, Nikolopoulou V. Bombesin and neurotensin reduce endotoxemia, intestinal oxidative stress, and apoptosis in experimental obstructive jaundice. Ann Surg 2005;241:159–67. 50. Braga M, Gianotti L, Gentilini O, Parisi V, Salis C, Di Carlo V. Early postoperative enteral nutrition improves gut oxygenation and reduces costs compared with total parenteral nutrition. Crit Care Med 2001;29: 242–8. 51. Johnson CD, Kudsk KA. Nutrition and intestinal mucosal immunity. Clin Nutr 1999;18:337–44.
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Clinical risk factors of delayed gastric emptying in patients after pancreaticoduodenectomy: A systematic review and meta-analysis* H. Qu a, G.R. Sun a, S.Q. Zhou b, Q.S. He a,* a
Department of General Surgery, Shandong University Qilu Hospital, No. 107 of the West Cultural Road, Jinan 250012, Shandong, China b Department of Internal Medicine, Jinan Central Hospital, Shandong, China Accepted 7 December 2012 Available online 5 January 2013
Abstract Background: The clinical risk factors of delayed gastric emptying (DGE) in patients after pancreaticoduodenectomy (PD) remains controversial. Herein, we conducted a systematic review to quantify the associations between clinical risk factors and DGE in patients after conventional PD or pylorus preserving pancreaticoduodenectomy (PPPD). Methods: A systematic search of electronic databases (PubMed, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2012 was performed. Cohort, caseecontrol studies, and randomized controlled trials that examined clinical risk factors of DGE were included. Results: Eighteen studies met final inclusion criteria (total n ¼ 3579). From the pooled analyses, preoperative diabetes (OR 1.49, 95% CI, 1.03e2.17), pancreatic fistulas (OR 2.66, 95% CI, 1.65e4.28), and postoperative complications (OR 4.71, 95% CI, 2.61e8.50) were significantly associated with increased risk of DGE; while patients with preoperative biliary drainage (OR 0.68, 95% CI, 0.48e0.97) and antecolic reconstruction (OR 0.17, 95% CI, 0.07e0.41) had decreased risk of DGE development. Gender, malignant pathology, preoperative jaundice, intra-operative transfusion, PD vs. PPPD and early enteral feeding were not significantly associated with DGE development (all P > 0.05). Conclusions: Our findings demonstrate that preoperative diabetes, pancreatic fistulas, and postoperative complications were clinical risk factors predictive for DGE. Antecolic reconstruction and preoperative biliary drainage result in a reduction in DGE. Knowledge of these risk factors may assist in identification and appropriate referral of patients at risk of DGE. Ó 2012 Elsevier Ltd. All rights reserved. Keywords: Pancreaticoduodenectomy; Complication; Delayed gastric emptying; Risk factors
Introduction Pancreatic cancer is a deadly disease worldwide.1 Although surgical resection provides the only chance of cure, most patients present with advanced disease that precludes complete resection and contributes to the poor outcome.2 Patients with pancreatic cancer can anticipate a median survival of <12 months and a 5-year survival of <5%.3e6 However, the decrease in peri-operative mortality rates in patients undergoing pancreatic operations in experienced centers, as well as the increasing interest of the * Meeting Presentation: Neither this paper nor any part of its content has been submitted for presentation in meeting(s). * Corresponding author. Tel.: þ86 0531 82166331. E-mail address: [email protected] (Q.S. He).
0748-7983/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejso.2012.12.010
surgical community regarding not only patients quality of life but also matters of cost/benefit, led scientists to focus on specific morbidity parameters associated with PD, including DGE.7e9 DGE is one of the most troublesome postoperative complications following PD. It prolongs the hospital stay, increasing costs and compromising quality of life.10 In the last two decades, DGE has come on the front scene as the leading cause of postoperative complications following pancreatic surgery. Numerous prior studies have analyzed the clinical risk factors associated with DGE in patients undergoing PD.7,9e25 However, the results of these studies were not consistent and the sample sizes were relatively modest. We perform a systematic review to evaluate the risk factors predictive for DGE in patients undergoing conventional PD or pylorus preserving pancreatoduodenectomy (PPPD).
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Methods The methods for this meta-analysis are in accordance with “Meta-Analysis of Observational Studies in Epidemiology: A Proposal for Reporting”.26 Selection of risk factors We performed a systematic review and meta-analysis of a selection of risk factors for development of DGE after PD or PPPD. Initially, we scrutinized in detail the literature on DGE to identify all possible risk factors. The initial search yielded 11 possible risk factors. Search strategy We conducted a systematic search of publications listed in the electronic databases (Medline via PubMed, EMBASE, OVID, Web of Science, the Cochrane Library) from 1970 to 2012. For the first search, text key words were “pancreaticoduodenectomy” or “pylorus-preserving pancreaticoduodenectomy” or “whipple” or ‘‘pancreatic surgery’’ or ‘‘pancreatic resection’’ and excluded “infant,” “newborn,” and “fetus”. The results of this search were combined with a subsequent search using terms “delayed gastric emptying” or “complications”. Language restrictions were not applied, but our search was limited to human studies. The ‘‘related articles’’ function was used to broaden the search, and all abstracts, studies, and citations scanned were reviewed. The list of articles was reviewed independently by two authors. The references from articles were also searched by hand. Study selection Cohort, caseecontrol studies, and randomized controlled trials were included if they investigated which clinical and peri-operative factors directly influencing the occurrence of DGE after conventional PD or PPPD. The potential variables assessed including patient baseline characteristics (e.g., age, gender and disease history), perioperative clinical and laboratory data, operative methods and postoperative complications. After obtaining full reports of candidate studies, the same reviewers independently assessed eligibility. Differences in data between the two reviewers were resolved by reviewing corresponding articles, and the final set was agreed on by consensus. If the publications did not contain the full information necessary for meta-analysis, we obtained the missing information directly from the authors. Data extraction For each study, the following data were extracted: first author’s last name, publication year, study design, sample size, patient characteristics and definition of DGE. Initially,
we scrutinized in detail the literature on PD to identify all possible risk factors for DGE. The initial search yielded 22 possible risk factors. Following review by an expert panel (GRS, SQZ and QSH), 11 factors that were considered to be easily measured in routine clinical practice and had been analyzed in at least 3 studies were selected for the full systematic review. These factors assessed including gender, malignancy, preoperative diabetes, preoperative jaundice, preoperative biliary drainage, PPPD vs. PD, intra-operative blood transfusion, antecolic vs. retrocolic route for duodenojejunostomy, pancreatic fistulas, postoperative (non-DGE) complications, and early enteral feeding. In this meta-analysis, we compared the risk of developing DGE in patients with and without the above factors. Study quality assessment The assessment of quality characteristics used the following criteria: 1. The Jadad score was introduced to evaluate the quality of randomized controlled trials (RCTs).27 Trials scored one point for each area addressed in the study design (randomization, blinding, concealment of allocation, reporting of withdrawals, and generation of random numbers) with a possible score of between 0 and 5 (highest level of quality). “Good” was defined as a Jadad score 4; “fair,” a Jadad score of 3; and “poor,” defined as a Jadad score <3. 2. The NewcastleeOttawa Scale was used to assess the quality of observational studies based on the following nine questions: (1) representativeness of the exposed cohort; (2) selection of the non-exposed cohort; (3) ascertainment of exposure; (4) demonstration that the outcome was not present at outset of study; (5) comparability; (6) assessment of outcome; (7) length of follow-up sufficient; (8) Adequacy of participant follow-up; (9) total stars. Maximum score on this scale is a total of 9.28 “Good” was defined as a total score of 7e9; “fair,” a total score of 4e6; and “poor,” defined as a total score of 4.
Statistical analyses We used REVMAN software (version 5.0; Cochrane Collaboration, Oxford, United Kingdom) and Stata software (version 11.0; Stata Corporation, College Station, TX) to pool data for all outcomes. Random effects (DerSimonian and Laird method) model was conducted to estimate the association between the 11 clinical factors and development of DGE. The odds ratios (ORs) and 95% confidence interval (CI) were calculated for each study. As the definitions of DGE may be a potential source of heterogeneity. In order to analyze the heterogeneity associated with
H. Qu et al. / EJSO 39 (2013) 213e223
different definitions of DGE, we performed subgroup analyses by comparing summary results obtained from subsets of studies grouped by ISGPS or other definitions. Statistical heterogeneity was evaluated with the Cochran’s c2 and the I2 statistics, which assess the appropriateness of pooling the individual study results. The I2 value provides an estimate of the amount of variance across studies resulting from heterogeneity rather than chance. P value was considered statistically significant at <0.05. Results Study selection Our initial search yielded 274 potential literature citations. Of these, 242 were excluded after scanning titles and abstracts, leaving 32 citations for full text assessment. Of these, 18 studies met the inclusion criteria and were used for this meta-analysis.19,21,29e44 The remaining studies were excluded largely because they did not provide DGE data according to the risk factors we evaluated; or had no control data; or reported the risk factors in an unusable format that were not comparable to the other studies (Fig. 1).
215
Characteristics of the trials Baseline characteristics of the studies included are shown in Table 1. The 18 included studies consisted of 14 prospective19,29e37,41e44 and 4 retrospective studies.21,38e40 Two of the prospective studies (the studies by Kurahara et al.37 and Tani et al.43) were RCTs, and others were prospective observational study. The study population included 3579 patients underwent either PD or PPPD. Demographic features of study populations were similar across the studies, and the average age of the patients ranged from 49 to 67 years. The percent of malignant disease ranged from 51% to 99% across the 18 studies. The definitions of DGE were different among the studies. In the 11 studies published before 2007,19,21,29e32,38,39,41e43 the need for a nasogastric tube beyond the 10th postoperative day (DGE10GT) or failure to tolerate a regular diet after the 14th postoperative day (DGE14) was the most commonly used definitions. Other definitions for DGE included the inability to tolerate a regular diet after the 10th postoperative day (DGE10)30,31 and the need for nasogastric tube for more than 7 days postoperative (DGE7GT).19 The International Study Group of Pancreatic Surgery (ISGPS) consensus definition of DGE
Figure 1. QUOROM (Quality Of Reporting Of Meta-analyses) statement flow diagram.
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Table 1 Characteristics of selected studies. Author
Year
Study design
Sample size
Mean age, y
Male, %
Malignancy, %
Intervention
Definition of DGE*
Quality assessmenty
Henegouwen et al.41
1997
Prospective
200
61
50
88
PPPD/PD
Fair
Horstmann et al.19
1999
Prospective
51
59
73
76
PPPD
Fabre et al.29 Martignoni et al.42
1999 2000
Prospective Prospective
88 64
61 64
70 53
81 87
PD PPPD/PD
Park YC et al.21
2003
Retrospective
150
58
60
86
PPPD
Riediger et al.30
2003
Prospective
204
58
63
51
PPPD
Sugiyama et al.38 Hartel et al.31
2004 2005
Retrospective Retrospective
30 200
61 63
63 44
83 73
PPPD PPPD
Bu et al.39 Tani et al.43
2006 2006
Retrospective Prospective
186 40
55 65
59 52
99 80
PPPD PPPD
Lermite et al.32 Nikfarjam et al.33 Park JS et al.40 Hashimoto and Traverso 35 Malleo et al.36 Welsch et al.34 Sakamoto et al.44 Kurahara et al.37
2007 2009 2009 2010
Prospective Prospective Retrospective Prospective
131 151 129 507
60 67 62 61
66 54 60 53
66 60 91 51
PD PPPD/PD PPPD/PD PPPD/PD
DGE14 or DGE10GT DGE14 or DGE7GT DGE10GT DGE14 or DGE10GT DGE14 or DGE10GT DGE10 or 14 or DGE10GT DGE10GT DGE10 or DGE10GT DGE10GT DGE14 or DGE10GT DGE10GT ISPGS ISPGS ISPGS
Good Good Good Good
2010 2010 2011 2011
Prospective Prospective Prospective Prospective
260 755 387 46
49 64 NA 65
57 56 60 70
78 NA 52 NA
PPPD PPPD/PD PPPD/PD PD
ISPGS ISPGS ISPGS ISPGS
Good Good Good Fair
Poor Poor Fair Fair Fair Poor Good Fair Fair
*Definitions of DGE. DGE10, the inability to tolerate a regular diet after the 10th postoperative day. DGE14, failure to tolerate a regular diet after the 14th postoperative day. DGE7GT, the need for nasogastric decompression for more than 7 postoperative days. DGE10GT, the need for a nasogastric tube beyond the10th postoperative day. ISGPS, the different grades of DGE were defined according to the requirement for a nasogastric tube in the postoperative period or inability to tolerate unlimited solid oral intake. Grade A was either 4e7 days with a nasogastric tube or reinsertion after postoperative day 3, or inability to tolerate solid oral intake by postoperative day 7. Grade B was 8e14 days with a nasogastric tube, or reinsertion after 7 day, or inability to tolerate solid oral intake by postoperative day 14. Grade C was more than 14 days with a nasogastric tube, or reinsertion after 14 days, or inability to tolerate solid oral intake by day 21. y Study quality was assessed using Jadad Score for the 2 randomized controlled trials (the studies by Kurahara et al.37 and Tani et al.43) with a possible score of between 0 and 5 (highest level of quality), and “Good” was defined as a Jadad score 4; “fair,” a Jadad score of 3; and “poor,” defined as a Jadad score <3. And the Newcastlee Ottawa Scale (NOS) was used to assess the quality of other 16 observational studies. Maximum score on this scale is a total of 9. “Good” was defined as a total score of 7e9; “fair,” a total score of 4e6; and “poor,” defined as a total score of 4.
was used in all the 7 studies published from 2009 to 2011.33e37,40,44 Fifteen of the 18 studies were of high methodological quality (good or fair) (Table 1).
Gender Ten studies investigated the influence of gender on the occurrence of DGE.21,29e37 These studies included 1522 male and 1174 female patients. The proportion of males was 60% in patients with DGE compared with 56% in patients without. Findings from this analysis suggested there was no significant association between gender and development of DGE (OR, 1.46; 95% CI, 0.85e2.50; P ¼ 0.17). Statistical heterogeneity among the studies was significant (I2 ¼ 84%; P < 0.001) (Figure was not shown).
Malignancy Ten studies evaluated the effect of pathology on DGE.21,30e32,35,36,40e42,44 1479 patients with malignant pathology and 746 patients with benign pathology. Malignancy was diagnosed in 72% of the DGE patients compared with 65% of those without. The pooled analysis of these studies showed a non-significant association between malignancy pathology and DGE (OR, 1.05; 95% CI, 0.74 to 1.49; P ¼ 0.79). No significant statistical heterogeneity was observed among the studies (I2 ¼ 42%; P < 0.08) (Figure was not shown). Preoperative diabetes From the 8 studies examining diabetes, preoperative diabetes tends to increase the risk for DGE.21,30,32,33,41,42,44
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217
Figure 2-1. Pooled odds ratio for DGE by preoperative diabetes (presence or absence).
The relative risk for DGE was 1.49 (95% CI 1.03e2.17, P ¼ 0.03) in patients with diabetes. The c2 test for heterogeneity was non-significant (I2 ¼ 30%; P ¼ 0.20) (Fig. 2-1). Preoperative biliary drainage Five studies reported the influence of preoperative biliary drainage (1061 patients).21,30,31,34 DGE was found in 12% of patients with preoperative biliary drainage compared to 17% of patients without. Analysis of these studies showed a significant benefit in preoperative biliary drainage (OR, 0.68; 95% CI, 0.48 to 0.97; P ¼ 0.03) (Fig. 2-2).
decreased risk of DGE (OR, 0.17; 95% CI, 0.09 to 0.33; P < 0.001) (Fig. 2-3). PPPD versus PD Seven studies compared the impact of PD and PPPD on development of DGE were included (1600 PD and 464 PPPD).33e35,40e42,44 There was a non-significant trend toward lower incidence of DGE in the PD group. The OR obtained through analysis of these studies was 1.25 (95% CI 0.97e1.62; P ¼ 0.08). No statistically significant heterogeneity was observed between studies (I2 ¼ 10%; P ¼ 0.35) (Fig. 2-4). 1000 mL",1,1,2,0>1000 mL", "pdflink",1,1,0>Intraoperative transfusions/blood loss >1000 mL
Preoperative jaundice In the 4 studies that reported the effect of preoperative jaundice.21,32,35,40 Analysis showed patients with and without preoperative jaundice had similar incidence of DGE (OR, 1.36; 95% CI, 0.59 to 3.17; P ¼ 0.47) (Figure was not shown). Antecolic vs. retrocolic reconstruction Seven studies evaluated if antecolic or retrocolic duodenojejunostomy was associated with the lower incidence of DGE (871 patients).21,31,33,36e38,43 DGE occurred in 10% of patients with the antecolic route for reconstruction versus 22% with the retrocolic route. From the pooled analysis, an antecolic reconstruction was significantly associated with
There were 8 studies that evaluated the influence of intra-operative transfusions or blood loss >1000 mL (2351 patients).21,30,31,33e36,44 No significant difference was observed in the risk for DGE in patients with and without intra-operative transfusion, while there was a trend toward a higher incidence of DGE in patients received intra-operative transfusion/with blood loss >1000 mL (OR, 1.46; 95% CI, 0.94 to 2.29; P ¼ 0.10) (Fig. 2-5). Pancreatic fistulas Six studies reported the effect of postoperative pancreatic fistulas on DGE development.33,35,36,39,40,44
Figure 2-2. Pooled odds ratio for DGE by preoperative biliary drainage (presence or absence).
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Figure 2-3. Pooled odds ratio for DGE by duodenojejunostomy route (antecolic vs. retrocolic).
Postoperative pancreatic fistula was defined according to the definition proposed by the International Study Group on Pancreatic Fistula45 (any measurable amount of fluid after postoperative day 3 with an amylase level three or greater times the serum amylase level) in 5 studies,33,35,36,40,44 and the definition was not reported in 1 study.39 The pooled analysis showed the incidence of DGE was 31% in the 324 patients with pancreatic fistulas, compared to 13% in the 1291 patients without. Findings from the meta-analysis show a significant association between postoperative pancreatic fistulas and DGE (OR 2.66; 95% CI 1.65e4.28; P < 0.001) (Fig. 2-6). Postoperative complications Postoperative complications was reported in 11 studies19,21,29e31,33,34,39e42 (1443 patients) (Table 2). DGE was significantly more frequent among patients with postoperative complications (39% vs. 16%). The OR obtained through analysis of these 11 studies was 4.71 (95% CI 2.61e8.50; P < 0.001) (Fig. 2-7). Early enteral feeding Estimates from three studies contributed to this analysis.30,32,42 Analysis of these studies showed no significant difference was observed in the incidence of DGE in patients
with and without early enteral feeding (OR, 1.05; 95% CI, 0.07e15.91; P ¼ 0.97) (Fig. 2-8). Subgroup analysis according to the definitions for DGE In the subgroup meta-analyses, we compared the associations between above risk factors and DGE in subsets of studies grouped by ISGPS or other definitions (Table 3). The results showed that no matter what definition was use in the original studies, no significant differences were observed in the effects of gender, malignancy, diabetes, biliary drainage, PPPD vs. PD, intra-operative transfusion, reconstruction route, and pancreatic fistulas in DGE development. Discussion Although DGE after PD is a well recognized complication, the pathogenesis appears to be multi-factorial. Our systematic review identified 14 prospective and 4 retrospective studies that addressed the clinical risk factors of DGE. In general, although the trials had some methodological limitations, including different conceptions of DGE, heterogeneity of the included studies and sample sizes were inadequate to completely assess the risk factors of DGE, we can say with confidence that of the 11 risk factors identified in
Figure 2-4. Pooled odds ratio for DGE by PPPD vs. PD.
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219
Figure 2-5. Pooled odds ratio for DGE by intra-operative transfusion (presence or absence).
our systematic review and meta-analysis, postoperative complications, pancreatic fistulas and preoperative diabetes were strongly and consistently associated with DGE. Antecolic reconstruction and preoperative biliary drainage result in a reduction in DGE. PPPD and early enteral feeding were not risk factors of DGE.
may result in gastric motor dysfunction including autonomic neuropathy, enteric neuropathy involving excitatory and inhibitory nerves, acute fluctuations in blood glucose, incretin-based medications used to normalize postprandial blood glucose and psychosomatic factors.21,27
Postoperative complications and pancreatic fistulas
Reconstruction route and biliary drainage
In nearly all previous studies, the presence of postoperative complications was the most significant risk factor for DGE, and our meta-analysis confirmed this tendency.21,30,40,42 The reasons why postoperative complications may lead to DGE are not fully understood. It has been suggested that gastroparesis as a consequence of local inflammation or abscess may be the main cause of DGE.30,42 Pancreatic fistulas was one of the most frequent postoperative complications, and have been shown to be associated with some fatal consequences, such as intraabdominal bleeding and infection. Therefore, DGE could be considered a warning for postoperative complications, especially pancreatic fistulas, and would be justified by abdominal imaging during postoperative periods.
Antecolic reconstruction and preoperative biliary drainage were the only two factors associated with reduction of DGE in our meta-analysis. Theoretically, an antecolic reconstruction avoids the risk of mechanical outflow obstruction, allows an increased mobility of the stomach, and provides an anatomical barrier from the pancreas, thus minimizing the possible negative effects of an infected collection or a pancreatic fistula.32,37,43 Possible explanation of preoperative biliary drainage in reducing the incidence of DGE was that preoperative hyperbilirubinemia is considered an important risk factor for postoperative complications and death. Hyperbilirubinemia due to obstructive jaundice damages hepatic function, clearance of circulating endotoxins, coagulation system, immune function, and gastrointestinal barrier.21,30,31,35 Some reports have found an influence of jaundice and endotoxemia on intestinal motility in vitro and reported that intestinal motility was lower in the obstructive jaundiced rat, especially when combined with endotoxemia.47e49
Preoperative diabetes Preoperative diabetes was thought to be a risk factor for the development of DGE. Several abnormalities in diabetes
Figure 2-6. Pooled odds ratio for DGE by pancreatic fistulas (presence or absence).
220
H. Qu et al. / EJSO 39 (2013) 213e223
Table 2 Definition of postoperative complications.
PD vs. PPPD
Studies
Postoperative complications definitions in included articles
Hartel et al.31
Pancreatic fistulas, anastomotic leakage, abscess, and hematoma. Pancreatic leakage, intra-abdominal infection, intra-abdominal hemorrhage, liver function failure, bile leakage. Complications were graded according to the severity score suggested by DeOliveira et al.46 Pancreatic fistula, bleeding, intra-abdominal abscess, hepaticojejunostomy leak, wound infection. Pancreatic fistula, bleeding, intra-abdominal abscess, hepaticojejunostomy leak, wound infection. Wound infection, pancreatic leakage, intra-abdominal abscess, pneumonia, bleeding, pancreatitis, biliary leakage, cholangitis, vascular, cardiac Wound infections, intra-abdominal abscesses, bile fistulas, and a pancreatic fistula, sepsis, severe bleeding, peripheral nerve lesion Pancreatic leakage, biliary leakage, hemorrhage, intra-abdominal abscess, relaparotomy Bleeding, pancreatic fistula, wound infection, biliary leak, pulmonary and cardiac complications Bleeding, gastrojejunostomy leakage, burst abdomen, intra-abdominal collection, pancreatic fistula, biliary fistula, thrombosis, wound hematoma Pancreatic fistula, wound infections, postoperative bleeding, intra-abdominal abscess, pneumonia, urinary tract infection, thromboembolic, reoperation
Although PPPD was thought to be risk factor for the development of DGE in some previous studies compared with conventional PD, the majority of recently performed clinical trials and our meta-analysis demonstrated that DGE is not an exclusive characteristic of PPPD and that its incidence is equally distributed between PD and PPPD. The reasons appears to be multi-factorial. Improvement of surgical techniques and increased surgical experience as well as advances in peri-operative and critical care management, were potential contributors in decreased rates of DGE. Perioperative administration of drugs that have been shown to decrease postoperative DGE, like octreotide or erythromycin lactobionate, varies from study to study. The indication for performing PD varies significantly not only between different studies, but also within the same patient cohort. There is therefore a growing need for a multicentre, randomized clinical trial with specific guidelines for perioperative administration of pharmaceutical agents, standard definition of the term DGE, and specific etiology-based performance of pancreatic surgery, to compare the efficiency of the two methods regarding DGE.
Bu et al.39
Welsch et al.34
Park YC et al.21
Park JS et al.40
Riediger et al.30
Martignoni et al.42
Henegouwen et al.41
Horstmann et al.19
Fabre et al.29
Nikfarjam et al.33
70.0 40.4
28.3
57.4
25.0
10.2
27.9
Early enteral feeding 1.16
25.4
27.7
2.8
Early enteral feeding have been demonstrated to be more physiological, better preventive in morphologic and functional alteration of the gut system, and less expensive than parental nutrition.50,51 Whereas several previous studies suggested early enteral feeding was associated with a higher frequency of postoperative complications including DGE.32,42 Our meta-analysis showed early enteral feeding was not a potential contributor to DGE. However, the relatively small sample size and fewer studies included results in wide confidence interval and mandates caution when interpreting this result. Therefore more high-quality and large studies are needed in the future.
Figure 2-7. Pooled odds ratio for DGE by postoperative complications (presence or absence).
H. Qu et al. / EJSO 39 (2013) 213e223
221
Figure 2-8. Pooled odds ratio for DGE by early enteral feeding (presence or absence).
Table 3 Subgroup analysis according to the definitions for DGE. No. of studies
Test for association OR (95% CI)
Male ISPGS Other definitions Malignancy ISPGS Other definitions Preoperative diabetes ISPGS Other definitions Biliary drainage ISPGS Othe definitions Antecolic vs. retrocolic route ISPGS Other definitions PPPD vs. PD ISPGS Othe definitions Transfusion ISPGS Other definitions Pancreatic fistulas ISPGS Other definitions Complications ISPGS Other definitions
Test for subgroup difference I2
P
5 5
1.49 (0.71e3.15) 1.50 (0.59e3.78)
0.18 0.15
4 6
0.92 (0.51e1.67) 0.93 (0.48e1.79)
0.79 0.82
3 5
1.37 (0.87e2.15) 1.54 (0.86e2.76)
0.18 0.15
1 3
0.78 (0.46e1.34) 0.61 (0.38e0.98)
0.37 0.04
3 4
0.26 (0.11e0.64) 0.12 (0.06e0.25)
0.003 <0.001
5 2
1.29 (0.96e1.73) 1.15 (0.69e1.91)
0.009 0.59
5 3
1.26 (0.66e2.41) 1.92 (1.17e3.14)
0.48 0.01
4 2
2.71 (1.82e4.03) 4.88 (0.34e70.2)
<0.001 0.24
3 8
1.75 (1.24e2.46) 7.85 (4.41e13.98)
0.001 <0.001
P
0%
0.99
0%
0.99
0%
0.75
0%
0.55
41%
0.19
0%
0.70
0.6%
Limitation Several limitations of this meta-analysis should be noted. First, the pooled studies differed in inclusion and exclusion criteria, definition of DGE. These may be the major source of heterogeneity. We used a random effects model in an effort to incorporate heterogeneity between trials in our analysis, but recognize that this does not eliminate the fact that heterogeneities were present. Second, the data included in some studies may have been too crude and also subject to measurement error. For example, definition of intraoperative transfusion may encompass a spectrum of conditions including large amount of blood loss; while the amount of blood loss are also determined by subjective judgment of the surgeon and cannot be quantified
0.32
0%
0.67
94%
<0.001
accurately. Several studies reported the intra-operative blood loss >750/1000 ml, we deemed this as intraoperative transfusion. Such potential measurement errors would likely dilute effects in the meta-analysis. Finally, given that a proportion of studies included are retrospective, a possibility of residual confounding by unmeasured factors cannot be eliminated. This provided associative, not causal, evidence and mandates caution when interpreting these results. Conclusion Our analysis provide evidence that postoperative complications, pancreatic fistulas and preoperative diabetes were strongly and consistently associated with DGE.
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Antecolic reconstruction and preoperative biliary drainage result in a reduction in DGE. The evidence does not permit any definite conclusions. Determining the impact these risk factors will require one or more large, well-designed, appropriately powered RCTs. Given the difficulty blinding the personnel involved and the extensive experience many surgeons have with the procedures, an expertise-based design would be the ideal method of exploring this question. Contributions of authors H. Qu and Q.S. He: Designed and performed the studies, and drafted the article. G.R. Sun, S.Q. Zhou: Designed and performed the studies, and revised the article. Conflicts of interest statement None declared.
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