Early postoperative pancreatitis following pancreaticoduodenectomy: what is clinically relevant postoperative pancreatitis?

HPB

https://doi.org/10.1016/j.hpb.2018.11.006

ORIGINAL ARTICLE

Early postoperative pancreatitis following pancreaticoduodenectomy: what is clinically relevant postoperative pancreatitis? Emrullah Birgin, Alina Reeg, Patrick Téoule, Nuh N. Rahbari, Stefan Post, Christoph Reissfelder & Felix Rückert Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

Abstract Background/objectives: Postoperative pancreatitis (POP) has recently been shown to be the cause of pancreatic fistula (POPF) following pancreaticoduodenectomy (PD). The aim of the present study was to document the perioperative outcome associated with POP and determine potential risk factors for POP. Methods: Patients undergoing PD between 2009 and 2015 were identified from the prospective data base at a single center. The previous suggested definition of POP by Connor was used. Complications were graded according to the Clavien–Dindo classification and by the grading proposed for POP. Risk factors for POP were analyzed by univariate and multivariate analysis. Results: Of 190 patients, a total of 100 patients (53%) developed POP of whom 22 (12%) and 13 (7%) had grade B and grade C complications, respectively. Elevated serum CRP-levels on postoperative day (POD) 2 and elevated serum lipase on POD 1 were associated with onset of cr-POP. Conclusion: The proposed definition of POP constitutes a valuable tool to assess a serious pancreaticsurgery associated complication. Routine serum CRP and serum lipase levels on the first two postoperative days enable sufficient discrimination of clinically relevant POP. Received 15 June 2018; accepted 19 November 2018

Correspondence Emrullah Birgin, Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. E-mail: emrullah.birgin@ umm.de

Introduction The definition of postoperative pancreatic fistula (POPF) following pancreaticoduodenectomy (PD) was initially introduced by the international study group of pancreatic surgeons (ISGPS) in 2005.1 This was widely adopted by the international surgical community and underwent revision in 2016.2 The key component of this definition remained unchanged and hinged around the statement “an abnormal communication between the pancreatic ductal system and another epithelial surface”.1,3 However, there is now considerable evidence that the underlying pathophysiology of POPF is, in fact, postoperative pancreatitis (POP).4 Connor proposed an alternative definition based on a systematic review of the available literature.5 The critical difference proposed by Connor was that if there was an elevation in the serum amylase or lipase level above the upper limit of normal

HPB 2019, 21, 972–980

on postoperative day (POD) 0 or 1, the diagnosis was POP irrespective of the amylase level in the drains. Alternatively, POPF could only be diagnosed if the serum amylase or lipase level was normal and the drain amylase level was >3× serum level on POD 3. Subsequent to this, a large retrospective study using the definition proposed by Connor confirmed that 58 out of 65 patients (91%) of all ISGPS defined POPF following PD occurs in the setting of POP and that true POPF is actually very rare.6 However, a further analysis of risk factors for clinically relevant POP (grade B and C) was not performed by the authors. Given that the proposed definition of POP and POPF by Connor has not been internationally adopted, the aim of the current study was to evaluate its validity and reproducibility. Additionally, the aim was to assess perioperative factors that may predict clinically relevant POP (cr-POP).

© 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

HPB

973

Patients and methods Patients and data collection This study was approved by the local ethics committee. Data was recorded prospectively in an electronic database of all patients who underwent pancreatic surgery.7 Only patients with PD for malignant or benign disease at the University Medical Center Mannheim between January 2009 and December 2015 were included for further analysis. Demographic clinical data included: age, gender, body mass index (BMI), American Society of Anesthesiologists (ASA) score, cardiac and pulmonary comorbidities, pre-existing diabetes mellitus type II, arterial hypertension, tobacco and alcohol use, history of chronic pancreatitis and perioperative serum biochemical markers including albumin [normal: 35 mg/dl], bilirubin [normal: 1.2 mg/d], amylase [normal: <115 units/l], lipase [normal: <393 units/l] and CRP level [normal: <3 mg/l]. Intraoperative measure included anastomosis type, use of epidural and somatostatin analogs. The fistula score and its components were also recorded.8 Postoperative drain outflow was recorded daily with respect to volume and appearance. Drain removal was routinely on POD 5 according to the local clinical pathway unless there was a drain amylase or lipase content greater than three times the serum amylase or lipase level. Daily serum laboratory measurements of CRP, WBC, bilirubin, amylase and lipase were available until POD 5. Neoadjuvant therapy was not used during the study period. Surgery was performed using a classical Whipple–Kausch or pylorus-preserving PD technique as reported previously.9 Diathermy was used for transection of the pancreas. Anastomosis of the pancreatic remnant was done either as pancreaticogastrostomy or pancreaticojejunostomy (two-layer interrupted duct-to-mucosa technique) on surgeon’s preference. For both techniques absorbable monofilament suture was used. Intraabdominal non-suction silicon drains were placed at the pancreatic and biliary anastomosis. Epidural analgesia was administered to all patients if there was no relevant contraindication (e.g. abnormal spinal anatomy, coagulopathy, allergies) and if informed consent was present. The use of non-steroidal anti-inflammatory drugs (NSAID) or hydrocortisone was recorded if this was part of the previous patients’ medication. There was no usage of pancreatic duct stents. Histological findings were grouped by pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis and other pathology (duodenal carcinoma, cholangiocarcinoma, lymphoma, neuroendocrine tumors). Definitions Severity of delayed gastric emptying (DGE) and postpancreatectomy hemorrhage (PPH) were assessed in accordance with ISGPS classification.10,11 POP and POPF and the severity were defined as proposed by Connor (Fig. 1).5

HPB 2019, 21, 972–980

Postoperative mortality was assessed as 30-day mortality and inhospital mortality. Postoperative complications were recorded according to Clavien–Dindo classification noting that a complication IIIa aligns with grade B severity by the ISGPS definitions and a complication IIIb or greater is equivalent to grade C.12 Day of surgery was defined as POD 0 and the day after surgery as POD 1. Preoperative cachexia or hypoalbuminemia was existent if serum level of albumin was below 35 mg/dl as indicator for a catabolic metabolism. Obstructive jaundice was present in patients with preoperative hyperbilirubinemia indicated by serum levels higher than 1.2 mg/dl. Statistics SPSS software version 24 was used for statistical analysis. Quantitative variables are reported as median (interquartile range) unless indicated otherwise. Mann–Whitney U-test was performed for continuous parameters. Categorical parameters are expressed as frequencies (%) and compared using the c2 test, if appropriate, Fisher-exact test. Univariate analysis was used to determine the association between perioperative parameters and POP. Multivariable logistic regression analysis was conducted including variables with a p-value below 5% or significant trend on univariate analysis for onset of POP. The relationship between serum CRP and lipase levels in predicting cr-POP in the cohort of patients with POP was presented by receiver operating characteristic (ROC) curve analysis. Threshold values of serum CRP and serum lipase values were determined by Youden’s index. pvalues <0.05 were defined as statistically significant.

Results Patients characteristics Of 448 patients that underwent pancreatic resection, a total of 210 (47%) patients underwent PD, however, 20 (4%) patients were excluded because of missing data (postoperative serum amylase or lipase levels on day 0/1). One hundred patients (53%) met criteria for POP and four (2%) patients for POPF. Of the four patients with POPF, two were grade A (biochemical leaks). Of the patients with POP, 43 (43%) had CRP  180 mg/l on POD 2. Baseline and intraoperative characteristics of the patient cohort as well as univariate and multivariate analysis of patients with POP and without POP are shown in Tables 1 and 2. Data on postoperative outcome is depicted in Table 3. Clinically relevant POP (cr-POP) Out of 100 patients with POP, 35 had cr-POP. There were no perioperative parameters to be associated with the onset of cr-POP (Table 4). Outcomes of patients with cr-POP are shown in Table 5. As proposed by Connor a CRP value of 180 mg/l on POD 2 was first used to differentiate cr-POP in the study cohort. However, only 20 patients (57%) with cr-POP had a CRP value of 180 mg/l on POD 2 (sensitivity 57%, specificity 65%, PPV 47%, NPV74%; p = 0.056). CRP over time split by cr-POP vs. no cr-POP (POP

© 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

HPB

974

5

Figure 1 Definition of POP and POPF by Connor (reuse of table was kindly provided by Elsevier)

grade A) is demonstrated in Fig. 2a showing higher median CRP values on POD 2 in patients with cr-POP. Therefore, ROC curve analysis was performed to determine a relevant threshold value for

a CRP level on POD 2 (Fig. 2b). A CRP-level of 150 mg/l on POD 2 (sensitivity of 71%, specificity 52%, PPV 45%, NPV 77%; p = 0.034) revealed an area under the curve (AUC) of 0.629

Table 1 Baseline characteristics of patient cohort

Total (n [ 190)

Univariate analysis

Multivariate analysis

POP (n [ 100)

no POP (n [ 90)

p-value

Age (years)

68 (59–74)

69 (59–75)

67 (59–74)

0.273

Sex ratio (M:F)

108:82

59:51

49:41

0.527

BMI

25 (23–28)

25 (23–28)

25 (22–28)

0.405

ASA

CI 95%

p-value

2.6

1.2–5.8

0.017*

0.285

I

12 (6%)

9 (9%)

3 (3%)

II

99 (52%)

47 (47%)

52 (58%)

III

77 (41%)

43 (43%)

34 (37%)

IV

OR

2 (1%)

1 (1%)

1 (1%)

Cardiac comorbidity

55 (29%)

37 (37%)

18 (20%)

0.016*

Pulmonary comorbidity

31 (16%)

16 (16%)

15 (17%)

0.901

HTN

123 (65%)

65 (65%)

58 (64%)

0.564

Diabetes mellitus

54 (28%)

24 (24%)

30 (33%)

0.198

Use of hydrocortisone

2 (1%)

2 (2%)

0

0.499

Use of NSAIDS

0

0

0

Use of statins

32 (17%)

22 (22%)

10 (11%)

0.054

Use of platelet inhibitors

47 (25%)

31 (31%)

16 (18%)

0.090

Use of anticoagulants

Medications before admission

12 (6%)

10 (10%)

3 (3%)

0.142

Tobacco use

55 (29%)

33 (33%)

22 (24%)

0.196

Alcohol use

41 (21%)

21 (21%)

20 (22%)

0.126

History of CP

59 (31%)

25 (25%)

34 (38%)

0.986

Preoperative bilirubin level (mg/l)

0.7 (0.4–8.4)

0.6 (0.4–5.4)

1.0 (0.4–9.9)

0.082

Preoperative albumin level (mg/dl)

34 (31–38)

36 (31–39)

34 (31–37)

0.081

BMI, body mass index; ASA, American society of anesthesiologists; HTN, arterial hypertension; NSAIDS, non-steroidal anti-inflammatory drugs; CP, chronic pancreatitis, *p < 0.05.

HPB 2019, 21, 972–980

© 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

HPB

975

Table 2 Intraoperative characteristics of patient cohort

Total (n [ 190)

Univariate analysis

Multivariate analysis

POP (n [ 100)

no POP (n [ 90)

p-value 0.074

OR

CI 95%

p-value

1.9

0.7–5.1

0.209

0.001*

1.3

0.5–3.6

0.548

0.001*

2.5

1.1–5.7

0.025*

0.008*

2.4

1.0–5.6

0.044*

0.001*

3.4

1.7–7.0

0.001*

Duration of surgery (min)

359 (311–409)

346 (305–398)

373 (326–416)

EBL (ml)

700 (500–1100)

650 (450–1100)

775 (500–1175)

0.250

Epidural analgesia

156 (82%)

77 (77%)

79 (88%)

0.038*

Somatostatin analog

137 (72%)

79 (79%)

58 (65%)

0.067

Vascular resection

43 (23%)

19 (19%)

24 (27%)

0.448

Pancreaticogastrostomy

53 (28%)

40 (40%)

13 (14%)

Pancreaticojejunostomy

137 (72%)

60 (60%)

77 (86%)

Firm

72 (38%)

27 (27%)

45 (50%)

Soft

104 (55%)

69 (69%)

35 (39%)

5 mm

42 (22%)

14 (14%)

28 (31%)

<5 mm

106 (56%)

65 (65%)

41 (46%)

PDAC

81 (43%)

29 (29%)

52 (58%)

CP

27 (14%)

12 (12%)

15 (17%)

Other

82 (43%)

59 (59%)

23 (26%)

Negligible

4 (2%)

2 (2%)

2 (2%)

Low

17 (9%)

4 (4%)

13 (14%)

Moderate

85 (%)

45 (45%)

40 (44%)

High

29 (15%)

22 (22%)

7 (8%)

Pancreatic anastomosis

Pancreatic texturea

Pancreatic duct sizea

Pathology

Fistula risk scorea

0.001*

EBL, estimated blood loss; CP, chronic pancreatitis; PDAC, pancreatic ductal adenocarcinoma. Missing values (pancreatic texture: n = 14; pancreatic duct size: n = 42; Fistula Risk Score: n = 55), *p < 0.05.

a

[0.512–0.746] predicting the onset of cr-POP in the cohort of patients with POP. Thus, 25 patients (71%) with cr-POP were identified using a CRP cutoff-level of 150 mg/l on POD 2. Lipase levels over time in patients with cr-POP vs. no cr-POP are demonstrated in Fig. 3. Patients with cr-POP developed significantly higher median lipase levels on POD 1 (934 U/l (370–2656) vs. 570 U/l (390–2044); p = 0.004) and on POD 2 (514 U/l (300–1290) vs. 294 U/l (126–700); p = 0.016) compared to POP grade A. A lipase level of 924 U/l on POD 1 (sensitivity of 63%, specificity 78%, PPV 54%, NPV 78%; p = 0.004) was identified as a significant threshold value to stratify patients with onset of crPOP (AUC 0.680 [0.568–0.793]).

Discussion Recent evidence suggests POP as a main risk factor for POPF following PD.13 Although POP is frequent after pancreatic surgery and incidence ranges up to 56%, there is great uncertainty in literature.5,6 First, definitions for POP are inconsistent resulting in varying numbers of incidence in literature.14,15 Second, POP

HPB 2019, 21, 972–980

as a specific complication after pancreatic surgery is missing approval by the ISGPS as a separate entity to the common pancreatic complications POPF, DGE and PPH.5 Third, further discrimination of cr-POP is missing in literature. The aim of the current study was therefore to evaluate the new definitions of POP and POPF by Connor, assess potential risk factors for the onset of POP and characterize cr-POP. Characteristics of the study cohort were similar to numbers of previous studies.16,17 The overall morbidity and mortality as well as pancreatic-surgery associated complications (DGE, PPH) were also comparable to current trends in literature.18,19 The data showed, that 100 out of 190 patients (53%) developed POP. Of these, a total of 35 (35%) patients had POP Grade B/C. This study has characterized for the first time in literature the cohort of patients with cr-POP to have a significantly worse postoperative outcome. As recent studies reported raised CRPlevels to correlate well with severity of pancreatitis-associatedcomplications in acute pancreatitis and predict complications following pancreatic surgery, serum CRP and serum lipase levels were correlated with onset of cr-POP.5,20–23 A CRP-value of

© 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

HPB

976

Table 3 Postoperative outcome of patient cohort

Total (n [ 190)

POP (n [ 100)

no POP (n [ 90)

Clavien– Dindoa

Table 4 Characteristics of patient cohort with cr-POP

p-value 0.014*

I

31 (16%)

14 (14%)

17 (19%)

II

50 (26%)

30 (30%)

20 (22%)

III

18 (9%)

15 (15%)

3 (3%)

IV

27 (14%)

17 (17%)

10 (11%)

V

5 (3%)

3 (3%)

2 (2%)

12 (12%)

0

0.001*

Intraabdominal 2 (1%) abscess

2 (2%)

0

0.499

Interventional/ 29 (15%) surgical drains

27 (27%)

0.001*

POP A

65 (35%)

65 (65%)

0

B

22 (12%)

22 (22%)

0

C

13 (7%)

13 (13%)

0

POPF

0.111

A

2 (2%)

0

2 (2%)

B

2 (2%)

0

2 (2%)

C

0

0

0

A

4 (2%)

3 (3%)

1 (1%)

B

7 (4%)

3 (3%)

4 (4%)

C

5 (3%)

3 (3%)

2 (2%)

PPH

36 (19%)

B

13 (7%)

11 (11%)

2 (2%)

C

9 (5%)

6 (6%)

3 (3%)

CRP level (mg/l) on POD 2 180 mg/l

23 (23%)

13 (14%)

43 (43%)

24 (27%)

69 (58–75)

68 (60–77)

0.642

Sex ratio (M:F)

36:28

23:12

0.398

BMI

26 (24–30)

25 (23–28)

0.284

0.023*

CRP level (mg/l) on POD 3

147 (107–210) 180 (128–235) 128 (88–169) 0.001*

I

7 (11%)

2 (6%)

II

29 (45%)

18 (51%)

III

28 (43%)

15 (43%)

IV

1 (2%)

0

Cardiac comorbidity

23 (36%)

14 (40%)

HTN

41 (64.1%)

23 (66%)

0.869

History of CP

18 (28%)

7 (20%)

0.624

Preoperative bilirubin level (mg/l)

0.6 (0.4–3.9)

0.7 (0.4–6.2)

0.246

Preoperative albumin level (mg/dl)

35 (19–44)

37 (32–40)

0.305

Duration of surgery (min)

346 (309–397) 338 (303–409)

EBL (ml)

600 (400–900) 800 (488–1400) 0.089

Epidural analgesia

51 (80%)

CRP level (mg/l) on POD 5

80 (40–148)

Hospital stay

16 (14–24)

17 (14–28)

16 (14–21)

0.066

30-day mortality

3 (2%)

1 (1%)

2 (2%)

0.358

0.001*

POP, postoperative pancreatitis; POPF, postoperative pancreatic fistula; PPH, postoperative pancreatectomy hemorrhage; DGE, delayed gastric emptying; POD, postoperative day. a Missing values (n = 45), *p < 0.05.

HPB 2019, 21, 972–980

0.828

0.869

26 (74%)

0.435

Somatostatin analog

12 (19%)

9 (26%)

0.448

Vascular resection

16 (25%)

3 (9%)

0.125 0.282

Pancreaticogastrostomy 29 (44%)

11 (31%)

Pancreaticojejunostomy 36 (55%)

24 (69%) 0.479

Firm

16 (25%)

11 (31%)

Soft

46 (72%)

22 (63%)

5 mm

12 (19%)

2 (6%)

<5 mm

36 (55%)

28 (80%)

PDAC

16 (25%)

13 (37%)

CP

9 (14%)

3 (9%)

other

39 (60%)

19 (54%)

2 (3%)

0

Pancreatic duct sizea

0.206

0.510

Fistula risk scorea Negligible

112 (61–184) 55 (29–90)

0.703

Pathology

147 (99–193) 164 (109–215) 138 (87–179) 0.008*

67 (35%)

Age (years)

Pancreatic texturea

0.014*

A

p-value

Pancreatic anastomosis 0.756

DGE

POP B/C (n [ 35)

ASA

Intraabdominal 12 (6%) fluid collection

2 (2%)

POP A (n [ 65)

0.437

Low

4 (6%)

0

Moderate

24 (37%)

21 (60%)

High

14 (22%)

8 (23%)

23 (36%)

20 (57%)

CRP level on POD 2 180 mg/l

0.056

BMI, body mass index; ASA, American society of anesthesiologists; HTN, arterial hypertension; EBL, estimated blood loss; CP, chronic pancreatitis; PDAC, pancreatic ductal adenocarcinoma. a Missing values (pancreatic texture: n = 4; pancreatic duct size: n = 21; fistula risk score: n = 27), POD postoperative day, *p < 0.05.

© 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

HPB

977

Table 5 Outcome of patient cohort with POP stratified by cr-POP and CRP-level

Outcome stratified by onset of cr-POP

Outcome stratified by CRP-level on POD 2

POP A (n [ 65) POP B/C (n [ 35) p-value <150 mg/l CRP (n [ 44) ‡150 mg/l CRP (n [ 56) p-value Clavien–Dindoa

0.004*

0.206

I

12 (18%)

2 (6%)

8 (18%)

6 (11%)

II

21 (32%)

9 (26%)

10 (22%)

20 (36%)

III

5 (8%)

10 (29%)

6 (14%)

9 (16%)

IV

5 (8%)

12 (34%)

5 (10%)

12 (22%)

V

1 (2%)

2 (6%)

1 (2%)

2 (4%)

1 (2%)

11 (20%)

Intraabdominal fluid collection 1 (2%)

11 (31%)

0.001*

0.011*

Intraabdominal abscess

0

2 (6%)

0.125

0

2 (4%)

0.501

Interventional/surgical drains

0

27 (77%)

0.001*

7 (16%)

20 (36%)

0.040*

POP A

65 (65%)

0

34 (77%)

31 (55%)

0.034*

POP B/C

0

35 (35%)

10 (23%)

25 (45%)

0.035*

3 (7%)

0

PPH

0.401

0.190

A

2 (3%)

1 (3%)

B

3 (5%)

0

1 (2%)

2 (4%)

C

1 (2%)

2 (6%)

2 (5%)

1 (2%)

A

15 (23%)

8 (23%)

5 (11%)

18 (32%)

B

4 (6%)

7 (20%)

6 (14%)

5 (9%)

C

1 (2%)

5 (14%)

0

6 (11%)

CRP level (mg/l) on POD 2

145 (101–203)

192 (121–222)

0.042*

CRP level (mg/l) on POD 3

155 (115–218)

224 (155–299)

0.001*

CRP level (mg/l) on POD 5

90 (58–148)

166 (104–254)

0.001*

Hospital stay

15 (13–20)

27 (21–48)

0.001*

15 (13–22)

21 (14–39)

0.001*

30-day mortality

1 (2%)

1 (3%)

0.670

1 (2%)

1 (2%)

0.850

DGE

0.005*

0.005*

POP, postoperative pancreatitis; PPH, postoperative pancreatectomy hemorrhage; DGE, delayed gastric emptying; POD, postoperative day. Missing values (n = 18), *p < 0.05.

a

150 mg/l on POD 2 was determined as a cut-off value for cr-POP in contrary to Connor’s recommendation of a CRP-value of 180 mg/l on POD 2 with a higher sensitivity. This might be due to a variable time frame of postoperative blood sampling between institutions. Therefore, comparing CRP values by means of hours from surgery rather than days seems to be a more accurate approach for future trials. Recently, interval change of CRP within 48 h of admission was identified to be an additional predictor of severe acute pancreatitis.24 Thus, it is conceivable that interval change of CRP might also predict cr-POP but this needs to be evaluated in a prospective study design. Further, patients with cr-POP were associated with elevated serum lipase levels on POD 1. Unfortunately, potential risk factors for the onset of cr-POP could not be identified. However, independent risk factors for POP (Grade A–C) were cardiac comorbidity, soft pancreatic texture, small pancreatic duct and histological findings other than PDAC. This is in accordance with recent findings in literature except for the presence of cardiac comorbidity as a risk factor for POP.6

HPB 2019, 21, 972–980

Cardiac comorbidity has already previously been identified as a major risk factor for adverse outcomes after pancreatic resection.25,26 The current study identified patients with cardiac comorbidities to be 2.6 times at higher risk in developing POP on multivariate analysis. The relationship of cardiac comorbidity with POP is not clear. It is conceivable, that systemic hypoperfusion could lead to ischemic damage of the pancreatic remnant, resulting in acute pancreatitis. It is suggested that patients with cardiac comorbidities undergoing pancreatic surgery need particular attention paid to their pre-operative optimization. This should be considered when indicating pancreatic resection. Epidural analgesia was a protective factor for POP in univariate analysis, this did not reach statistical significance on multivariate analysis. In literature, an improved clinical outcome and decreased severity of pancreatitis was observed in patients with epidural analgesia and acute pancreatitis.27 The reason for this might be an increased pancreatic perfusion by sympathetic nerve blockade resulting in a decrease of metabolic acidosis and tissue injury.28 Furthermore, there is increasing evidence for the benefit

© 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

HPB

978

Figure 2 a, Median CRP level of patients and total number of patients (N) with clinically relevant postoperative pancreatitis (cr-POP) vs. patients

without cr-POP. b, receiver operating characteristic (ROC) curve for threshold analysis of CRP values on POD 2 predicting clinically relevant postoperative pancreatitis following pancreaticoduodenectomy

of adjustable fluid management following pancreaticoduodenectomy and also in acute pancreatitis. Therefore, further prospective studies seem to be promising.6,29,30 As POP is actually missing approval as autonomous entity, data on clinical management is very limited. The use of somatostatin analog was not a protective factor for POP or POPF in this study cohort. This is also in accordance with previous inconsistent data in terms of POPF occurrence and severity of POPF after somatostatin administration.31–33

Somatostatin analog primarily reduces exocrine secretion of the pancreas but also impacts splanchnic blood flow by acting as a vasoconstrictor of the foregut vessels.34,35 Although reduced enzyme secretion might be protective for the occurrence of POPF, one has to give serious consideration to potential hypoperfusion. Hypoperfusion can induce subsequent ischemia and reperfusion injury of the pancreatic remnant and result in pancreatic necrosis based on pancreatitis.36 In this study, there was a trend towards more use of somatostatin in patients with

Figure 3 a, Median lipase level of patients and total number of patients (N) with clinically relevant postoperative pancreatitis (cr-POP) vs. patients

without cr-POP. b, receiver operating characteristic (ROC) curve for threshold analysis of lipase values on POD 1 predicting clinically relevant postoperative pancreatitis following pancreaticoduodenectomy

HPB 2019, 21, 972–980

© 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

HPB

979

POP without a significance. However, this data could be confounded as somatostatin was only administered in high-risk patients defined by small pancreatic duct size and soft pancreatic texture. In this regard, patients with higher fistula risk score also were more likely to develop POP. The definition of POP and POPF by Connor is very strict and simple. Thus, patients with elevated serum amylase/lipase levels on POD 0/1 were defined as POP regardless of elevated drain amylase levels. Following this, a true POPF without POP is a rare condition (n = 4, 2%). Actually, early assessment of POPF by means of ISGPS definition will be challenging in future as there is rising evidence of avoiding a routine intraperitoneal drainage following PD.37 Therefore it is proposed to re-define POPF as initially proposed by the ISGPS and consider POP as a separate pancreatic-surgery associated complication. According to the ISGPS criteria, all patients with cr-POP would be potentially classified as cr-POPF. However, in contrary to the POPF definitions by the ISGPS, patients with POP can be identified by no later than POD 1 according to the definition by Connor. Official guidelines for optimal treatment strategies of POP are not available in current literature but it seems reasonable to follow the routine treatment of acute pancreatitis.5,38 Early detection of POP is pivotal for adequate therapeutic management and risk stratification of patients. As a consequence, this prompts an early appropriate adjustment of therapeutic strategies in the clinical postoperative setting.

Acknowledgments The authors would like to acknowledge the support of Ms Sylvia Büttner for her statistical advice in this study (Department for Statistical Analysis, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany). Conflict of interest None declared. References 1. Bassi C, Dervenis C, Butturini G, Fingerhut A, Yeo C, Izbicki J et al. (2005) Postoperative pancreatic fistula: an international study group (ISGPF)

definition.

Surgery

138:8–13.

https://doi.org/10.1016/

j.surg.2005.05.001. 2. Bassi C, Marchegiani G, Dervenis C, Sarr M, Abu Hilal M, Adham M et al. (2017) The 2016 update of the International Study Group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 years after. Surgery 161:584–591. https://doi.org/10.1016/j.surg.2016.11.014. 3. Lowy AM, Lee JE, Pisters PW, Davidson BS, Fenoglio CJ, Stanford P et al. (1997) Prospective, randomized trial of octreotide to prevent pancreatic fistula after pancreaticoduodenectomy for malignant disease. Ann Surg 226:632–641. 4. Kuhlbrey CM, Samiei N, Sick O, Makowiec F, Hopt UT, Wittel UA. (2017) Pancreatitis after pancreatoduodenectomy predicts clinically relevant postoperative pancreatic fistula. J Gastrointest Surg 21:330–338. https://doi.org/10.1007/s11605-016-3305-x. 5. Connor S. (2016) Defining post-operative pancreatitis as a new pancreatic specific complication following pancreatic resection. HPB 18:642–651. https://doi.org/10.1016/j.hpb.2016.05.006. 6. Bannone E, Andrianello S, Marchegiani G, Masini G, Malleo G, Bassi C et al. (2018) Postoperative acute pancreatitis following pancreatico-

Conclusion

duodenectomy: a determinant of fistula potentially driven by the intra-

The proposed definition of Connor is simple and might be valuable for the clinically routine use to assess POP. The current study determined CRP and serum lipase cut-off values that discriminate cr-POP with adequate sensitivity and specificity. Thus, simple laboratory analysis on the first two postoperative days are sufficient to assess the risk of cr-POP. It is proposed that a unifying definition of POP is necessary and prompts appropriate adjustment of therapeutic strategies in the clinical postoperative setting. This enables further studies on this topic in order to reduce postoperative morbidity based on POP.

operative

fluid

management.

Ann

Surg.

https://doi.org/10.1097/

SLA.0000000000002900. 7. Birgin E, Hablawetz P, Teoule P, Ruckert F, Wilhelm TJ. (2018) Chronic pancreatitis and resectable synchronous pancreatic carcinoma: a survival analysis. Pancreatology. https://doi.org/10.1016/j.pan.2018.04.009. 8. Callery MP, Pratt WB, Kent TS, Chaikof EL, Vollmer CM, Jr.. (2013) A prospectively validated clinical risk score accurately predicts pancreatic fistula after pancreatoduodenectomy. J Am Coll Surg 216: 1–14. https://doi.org/10.1016/j.jamcollsurg.2012.09.002. 9. Ruckert F, Kersting S, Fiedler D, Distler M, Dobrowolski F, Pilarsky C et al. (2011) Chronic pancreatitis: early results of pancreatoduodenectomy and analysis of risk factors. Pancreas 40:925–930. https://doi.org/ 10.1097/MPA.0b013e3182156d87. 10. Wente MN, Bassi C, Dervenis C, Fingerhut A, Gouma DJ, Izbicki JR

Author’s contribution

et al. (2007) Delayed gastric emptying (DGE) after pancreatic surgery:

EB, FR and CR were responsible for the design of the study. EB performed research, analyzed the data and drafted the manuscript. AR, PT, NNR, SP, CR and FR revised the manuscript. All authors have read and approved the final manuscript.

a suggested definition by the International Study Group of Pancreatic Surgery (ISGPS). Surgery 142:761 – 768. https://doi.org/10.1016/ j.surg.2007.05.005. 11. Wente MN, Veit JA, Bassi C, Dervenis C, Fingerhut A, Gouma DJ et al. (2007) Postpancreatectomy hemorrhage (PPH): an international study group of pancreatic surgery (ISGPS) definition. Surgery 142:20–25. https://doi.org/10.1016/j.surg.2007.02.001.

Disclosure

12. Clavien PA, Sanabria JR, Strasberg SM. (1992) Proposed classification

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

HPB 2019, 21, 972–980

of complications of surgery with examples of utility in cholecystectomy. Surgery 111:518–526.

© 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

HPB

980

13. Uemura K, Murakami Y, Hayashidani Y, Sudo T, Hashimoto Y, Ohge H

26. Ruckert F, Kuhn M, Scharm R, Endig H, Kersting S, Klein F et al.

et al. (2008) Randomized clinical trial to assess the efficacy of ulinastatin

(2014) Evaluation of POSSUM for patients undergoing pancreato-

for postoperative pancreatitis following pancreaticoduodenectomy.

duodenectomy. J Investig Surg 27:338 – 348. https://doi.org/10.3109/

J Surg Oncol 98:309–313. https://doi.org/10.1002/jso.21098.

08941939.2014.932475.

14. Winter JM, Cameron JL, Campbell KA, Arnold MA, Chang DC,

27. Sadowski SM, Andres A, Morel P, Schiffer E, Frossard JL, Platon A et al.

Coleman J et al. (2006) 1423 pancreaticoduodenectomies for pancre-

(2015) Epidural anesthesia improves pancreatic perfusion and de-

atic cancer: a single-institution experience. J Gastrointest Surg 10:

creases the severity of acute pancreatitis. World J Gastroenterol 21:

1199–1210. https://doi.org/10.1016/j.gassur.2006.08.018. discussion 1210-1.

12448–12456. https://doi.org/10.3748/wjg.v21.i43.12448. 28. Demirag A, Pastor CM, Morel P, Jean-Christophe C, Sielenkamper AW,

15. Duffas JP, Suc B, Msika S, Fourtanier G, Muscari F, Hay JM et al. (2005)

Guvener N et al. (2006) Epidural anaesthesia restores pancreatic

A controlled randomized multicenter trial of pancreatogastrostomy or

microcirculation and decreases the severity of acute pancreatitis. World

pancreatojejunostomy after pancreatoduodenectomy. Am J Surg 189: 720–729. https://doi.org/10.1016/j.amjsurg.2005.03.015. 16. Kulemann B, Hoeppner J, Wittel U, Glatz T, Keck T, Wellner UF et al.

J Gastroenterol 12:915–920. 29. Chen BP, Chen M, Bennett S, Lemon K, Bertens KA, Balaa FK et al. (2018) Systematic review and meta-analysis of restrictive perioperative

(2015) Perioperative and long-term outcome after standard pancreati-

fluid management in pancreaticoduodenectomy. World J Surg 42:

coduodenectomy, additional portal vein and multivisceral resection for

2938–2950. https://doi.org/10.1007/s00268-018-4545-6.

pancreatic head cancer. J Gastrointest Surg 19:438–444. https://

30. Thomson A. (2017) Intravenous fluid therapy in acute pancreatitis: a critical review of the randomized trials. ANZ J Surg. https://doi.org/

doi.org/10.1007/s11605-014-2725-8. 17. Distler M, Ruckert F, Hunger M, Kersting S, Pilarsky C, Saeger HD et al.

10.1111/ans.14320.

(2013) Evaluation of survival in patients after pancreatic head resection

31. McMillan MT, Christein JD, Callery MP, Behrman SW, Drebin JA,

for ductal adenocarcinoma. BMC Surg 13:12. https://doi.org/10.1186/

Kent TS et al. (2014) Prophylactic octreotide for pancreatoduodenec-

1471-2482-13-12.

tomy: more harm than good? HPB 16:954–962. https://doi.org/

18. Grutzmann R, Ruckert F, Hippe-Davies N, Distler M, Saeger HD. (2012)

10.1111/hpb.12314.

Evaluation of the international study group of pancreatic surgery defi-

32. Allen PJ, Gonen M, Brennan MF, Bucknor AA, Robinson LM, Pappas MM

nition of post-pancreatectomy hemorrhage in a high-volume center.

et al. (2014) Pasireotide for postoperative pancreatic fistula. N Engl J Med

Surgery 151:612–620. https://doi.org/10.1016/j.surg.2011.09.039.

370:2014–2022. https://doi.org/10.1056/NEJMoa1313688.

19. Cameron JL, He J. (2015) Two thousand consecutive pancreaticoduo-

33. Volk A, Nitschke P, Johnscher F, Rahbari N, Welsch T, Reissfelder C

denectomies. J Am Coll Surg 220:530–536. https://doi.org/10.1016/

et al. (2016) Perioperative application of somatostatin analogs for

j.jamcollsurg.2014.12.031.

pancreatic surgery-current status in Germany. Langenbeck’s Arch Surg

20. Working Group IAPAPAAPG. (2013) IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatology 13: e1–e15. https://doi.org/10.1016/j.pan.2013.07.063. 21. Ansorge C, Nordin JZ, Lundell L, Strommer L, Rangelova E, Blomberg J et al. (2014) Diagnostic value of abdominal drainage in individual risk assessment of pancreatic fistula following pancreaticoduodenectomy. Br J Surg 101:100–108. https://doi.org/10.1002/bjs.9362.

401:1037–1044. https://doi.org/10.1007/s00423-016-1502-4. 34. Barthelmes D, Parviainen I, Vainio P, Vanninen R, Takala J, Ikonen A et al. (2009) Assessment of splanchnic blood flow using magnetic resonance imaging. Eur J Gastroenterol Hepatol 21:693–700. https:// doi.org/10.1097/MEG.0b013e32831a86e0. 35. Kostylev MV, Kopchak VM, Popovich OB, Egorova ON. (2006) The splanchnic blood flow indices in the patients, suffering external

22. Welsch T, Frommhold K, Hinz U, Weigand MA, Kleeff J, Friess H et al.

pancreatic fistula, and their dynamics under the influence of sandostatin

(2008) Persisting elevation of C-reactive protein after pancreatic re-

and somatulin according to the ultrasonographic duplex scanning data.

sections can indicate developing inflammatory complications. Surgery 143:20–28. https://doi.org/10.1016/j.surg.2007.06.010. 23. Palani Velu LK, McKay CJ, Carter CR, McMillan DC, Jamieson NB, Dickson EJ. (2016) Serum amylase and C-reactive protein in risk stratification of pancreas-specific complications after pancreaticoduo-

Klin Khir (Kiev), 30–35. 36. Cuthbertson CM, Christophi C. (2006) Disturbances of the microcirculation in acute pancreatitis. Br J Surg 93:518–530. https://doi.org/ 10.1002/bjs.5316. 37. Van

Buren

G,

2nd,

Bloomston

M,

Hughes

SJ,

Winter

J,

denectomy. Br J Surg 103:553–563. https://doi.org/10.1002/bjs.10098.

Behrman SW, Zyromski NJ et al. (2014) A randomized prospective

24. Stirling AD, Moran NR, Kelly ME, Ridgway PF, Conlon KC. (2017) The

multicenter trial of pancreaticoduodenectomy with and without

predictive value of C-reactive protein (CRP) in acute pancreatitis - is

routine intraperitoneal drainage. Ann Surg 259:605 – 612. https://

interval change in CRP an additional indicator of severity? HPB 19:

doi.org/10.1097/SLA.0000000000000460.

874–880. https://doi.org/10.1016/j.hpb.2017.06.001. 25. Ronnekleiv-Kelly SM, Greenblatt DY, Lin CP, Kelly KJ, Cho CS,

38. Ryska M, Rudis J. (2014) Pancreatic fistula and postoperative pancreatitis after pancreatoduodenectomy for pancreatic cancer.

Winslow ER et al. (2014) Impact of cardiac comorbidity on early out-

Hepatobiliary

comes after pancreatic resection. J Gastrointest Surg 18:512–522.

j.issn.2304-3881.2014.09.05.

Surg

Nutr

3:268 – 275.

https://doi.org/10.3978/

https://doi.org/10.1007/s11605-013-2399-7.

HPB 2019, 21, 972–980

© 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.