Postoperative Complications Linked to Pancreaticoduodenectomy. An by warrent


									Postoperative Complications Linked to Pancreaticoduodenectomy.
An Analysis of Pancreatic Stump Management
Enrico Benzoni, Aron Zompicchiatti, Enrico Saccomano, Dario Lorenzin, Umberto Baccarani, Gianluigi Adani, Luigi
Noce, Alessandro Uzzau, Carla Cedolini, Fabrizio Bresadola, Sergio Intini

Department of Surgery, University of Udine, School of Medicine, Udine, Italy.

    Abstract                                                         Introduction
     Aims. To analyze the role of different procedures in the
                                                                      The treatment of pancreatic cancer is undertaken with two
management of pancreatic stump according to the incidence
                                                                  different objectives. The first is radical surgery for patients
of postoperative morbidity derived from the data of a single
                                                                  with early stage of disease, mainly stage I and partially II.
center surgical population. Methods. From 1989 to 2005
                                                                  In all other cases, the aim of treatment is the palliation of
we performed 76 pancreaticoduodenectomies (PD) and 26
                                                                  the distressing symptoms related to this cancer.
distal pancreatectomies (DP). The surgical reconstruction
                                                                      Despite the advances made in surgical technique and
after PD was as follows: 11 manual non-absorbable stitches
                                                                  perioperative care, limited progress has been made in
closure of the main duct, 24 closures of the main duct with
                                                                  improving the survival of patients with this disease. Five-year
linear stapler, 17 occlusions of the main duct with neoprene
                                                                  survival rates are 5% to 20% for patients undergoing potentially
glue and 24 duct-to-mucosa anastomosis. Results. In the PD
                                                                  curative resection; postoperative disease recurrence occurs
group, the morbidity rate was 60%, caused by: pancreatic
                                                                  commonly [1-3]. Despite this, surgical resection remains the
leakage in 48% of patients, hemorrhagic complications
                                                                  only potentially curative therapeutic option in 10% of patients
in 10% following surgical procedure and infectious
                                                                  for whom resection is possible [2, 3]. The most recent series
complications in 15%. After DP we recorded: leakage in
                                                                  from institutions specializing in the treatment of pancreatic
3.9%, haemoperitoneum in 15.4% and no complications in
                                                                  cancer report mortality rates after surgical procedure less
80.7%. The multivariate analysis showed that the in-hospital
                                                                  than 5% [1, 2]. But morbidity rates remain high: 30% to
mortality was linked to the surgical procedure (PD, p=0.003)
                                                                  60% [1, 2]. The majority of perioperative complications are
and to the following complications: pancreatic leakage
                                                                  not life threatening, though they result in increased length
(p=0.004), haemoperitoneum (p=0.00045) and infectious
                                                                  of hospital stay and costs, readmissions for care, and delay
complications (p=0.0077). Bleeding complications, biliary
                                                                  in adjuvant therapy. Hemorrhagic complication occurs in
anastomosis leakage and infectious complications were
                                                                  5–16% of patients following pancreaticoduodenectomy (PD);
consequences of pancreatic leakage (p=0.025, p=0.025 and
                                                                  pancreatic leakage is a major cause of morbidity and mortality
p=0.025 respectively). Conclusion. Manual non-absorbable
                                                                  after PD, with incidence varying between 6 and 24% and a
stitch closure of the main duct and occlusion of the main duct
                                                                  mortality rate up to 40% [1, 4].
with neoprene glue should be avoided in the reconstructive
                                                                      The variations in methods of pancreatic stump
                                                                  management and the volume of literature available on both
                                                                  main pancreatic duct and pancreaticoenteric anastomosis
                                                                  leak indicate the concern associated with the leakage and
    Key words                                                     the continuing efforts to prevent it.
    Pancreaticoduodenectomy - postoperative complication              In this study we have analyzed the role of different
- anastomotic leak - Whipple’s procedure                          procedures in the management of pancreatic stump after
                                                                  PD, according to the incidence of postoperative morbidity
                                                                  derived from data in a single center surgical population.
J Gastrointestin Liver Dis
March 2008 Vol.17 No 1, 43-47
Address for correspondence:   Dr. Benzoni Enrico
                              University of Udine
                                                                     Patients and methods
                              Schoool of Medicine
                              P.le S. Maria della Misericordia,
                                                                     From 1989 to 2005, 137 consecutive patients, who
                              33100 Udine, Italy                  had undergone surgical interventions for pancreatic
                              e mail :     cancer, were followed up at our department. Preoperative
44                                                                                                                 Benzoni et al

studies employed abdominal ultrasonography, abdominal             7th days after resection. All patients underwent an X-ray
computed tomography (CT) and endoscopic retrograde                chest examination on the 3rd postoperative day, and a
cholangiopancreatography (ERCP), with brushing for                US examination or a CT scan during the first week after
cytology. Only a few cases had undergone fine needle               resection.
transduodenal biopsy during ERCP. Serum tumor markers                 When the CT scan during the 1st week after resection
such as carcinoembryonic antigen (CEA) and carbohydrate           recorded a fluid collection around the surgical field with
antigen 19-9 (CA19-9) were measured preoperatively. The           no accompanying symptoms, a percutaneous drainage
following biological investigation were also performed            was performed to assess the amylase content and for
preoperatively: hemoglobin, red blood cell count, white blood     microbiological analysis.
cell count, hematocrit, platelet count, partial thromboplastin        Pancreaticoenteric anastomotic leak was defined as:
time, prothrombin time, international normalized ratio,           drainage of >10 mL of fluid with high amylase content (>3
serum albumin, serum proteins, and liver function tests           times serum amylase level) for > 4 days postoperatively;
(serum bilirubin, transaminases, γ-glutamil transpeptidase,       or percutaneous drainage of amylase-rich intra-abdominal
lactic dehydrogenases).                                           collection/abscess; or as intraoperative demonstration
    An endoscopic stenting was positioned during ERCP             of pancreaticoenteric anastomosis disruption at re-
whenever required (obstructive jaundice) in order to reduce       exploration. Blood transfusion was considered necessary
bilirubin serum level before surgery.                             when hemoglobin level was less than 8 g/dL and important
    The final assessment of resectability was made during          bleeding was considered when a fall in haemoglobin >2 g/dL,
surgical intervention considering: retroperitoneal extension      haemodynamic instability and/or patient requiring >2 units
of the tumors, liver metastases not identified by CT,              of blood transfusion were recorded. Hepaticojejunostomy
involvement or encasement of superior mesenteric artery,          leak was diagnosed when a drainage of >50 mL of bilious
superior mesenteric vein or portal vein. An intraoperative        fluid after postoperative day 4 was recorded or a leak was
pathological examination was performed on the lymph               shown by contrast radiology. Infectious complications,
nodes of the inferior vena cava and aorta groups and of any       diagnosed when the leucocyte count was >12 000/mmc,
group around the pancreatic area if they were tangible. A         body temperature >38.5°C and blood culture positive, were
pathological examination of the pancreatic, duodenal and          treated with antibiotics selected according to blood culture
bile duct margin was made to assess the radicality of the         results and antibiograms.
resection. Lymph nodes were considered positive if they               Statistical analysis
showed evidence of carcinoma, whether by direct extension             Data are expressed as mean ± standard deviation and
of tumor or by metastases. Margins were considered positive       incidence is reported as percentage; χ2 test was used to
if there was histological evidence of adenocarcinoma in           compare the mean values of the incidence of complications
any of the surgical margins of the resected specimen (i.e.,       resulting between different types of “management of the
pancreatic neck, duodenal, or bile duct margins).                 duct” during PD. DP patients were assumed as a control group
    We performed 76 PDs, 26 distal pancreatectomies (DP)          for comparing the postoperative complications incidence.
and 35 total pancreatectomies. We excluded from the study         Multivariate analysis was used to assess independent
35 patients who had undergone total pancreatectomy, and           variables, which may influence survival, in-hospital death
we recorded the results of 102 patients who had underwent         and occurrence of complications. Significant difference was
PD or DP.                                                         defined as p< 0.05. Data processing was performed using
    We did not perform pylorus-preserving procedures in this      SPSS® 13.0 for Windows® Evaluation Version.
series of patients. During DP, the parenchymal transection
was performed with a linear stapler (either Tyco® GIA™ 60-
80, or Tyco® TA™ 60-90). The surgical reconstruction after           Results
PD was as follows: 11 manual non-absorbable stitches closure
of the main duct, 24 closures of the main duct with linear            Mean age was 62.06 ± 9.81 years. Ninety four patients
stapler (Tyco® TA™ 60-90), 17 occlusions of the main duct         had ductal adenocarcinoma; 6 of these had adenosquamous
with neoprene glue and 24 duct-to-mucosa anastomosis.             carcinoma, 24 mucinous cystadenocarcinoma, 2 serous
    We always placed drains at the time of surgery: one was       cystadenocarcinoma. Eight patients had neuroendocrine
placed near the suture of the transected parenchyma, if a         tumors. Pathologic staging was as follows: Ia - 3.6%, Ib -
transection with a linear stapler or a main duct closure was      16%, IIa - 13.9%, IIb - 48.9%, III - 6.6%, IV 11%. In-hospital
performed, or near the anastomosis, if a duct-to-mucosa           mortality rate was 4.37%. In the PD group, the morbidity
anastomosis was performed. Another one was placed near            rate was 60%, caused by: pancreatic leakage in 48% patients,
the hepaticojejunostomy.                                          haemorrhagic complication in 10% of patients following
    Postoperative care                                            surgical procedure, and infectious complications in 15%.
    Starting with the first postoperative day, we administered         Blood transfusion was requested during 50 PD procedures
somatostatin or its analogs in all patients in order to inhibit   and the mean blood amount transfused was 1103.43 ± 978.7
pancreatic secretion.                                             cc. No differences among the PD subtype groups in the
    Blood tests were performed on the 1st, 3rd, 5th and           estimated blood loss were recorded.
Postoperative complications linked to pancreaticoduodenectomy.                                                                        45

    According to the type of surgical reconstruction after              temporary occlusion of the main duct with neoprene glue
PD we recorded the following complications: after manual                and 29.1% after duct-to-mucosa anastomosis.
non-absorbable stitches closure of the main duct: 27.3% no                  A significant statistical difference, regarding re-operation
complications, 27.3% leakage, 18.1% haemoperitoneum,                    rates, was found between closure of the main duct with
27.3% infections (intra-abdominal abscess concomitant                   linear stapler vs. temporary occlusion of the main duct with
to leakage); after closure of the main duct with linear                 neoprene glue (p= 0.049) and closure of the main duct with
stapler: 50% no complications, 33.3% leakage, 12.5%                     linear stapler vs. duct-to-mucosa anastomosis (p=0.003).
haemoperitoneum, 4.2% infections (wound infections);                        After DP we recorded: 80.7% no complications (a 40%
after occlusion of the main duct with neoprene glue: 32.9%              rate was recorded after PD, p=n.s.), 3.9% leakage (a 48% rate
no complications, 55.3% leakage, 5.9% haemoperitoneum,                  was recorded after PD, p=0.03), 15.4% haemoperitoneum
5.9% infections (one case of cholangitis resolved with                  (a 10% rate was recorded in PD, p=n.s.).
antibiotics); after duct-to-mucosa anastomosis: 58.2% no                    At the multivariate analysis, in-hospital mortality was
complications, 29.2% leakage, 4.2% haemoperitoneum, 8.4%                linked to the surgical procedure (PD, p=0.003) and the
infections (intra-abdominal abscess concomitant to leakage).            arising of complications: pancreatic leakage (p=0.004),
The statistical differences and incidence of complications              haemoperitoneum (p=0.00045) and infectious complication
resulting between different procedures of the management of             (p=0.0077). Overall complications were linked to: age >70 yr
pancreatic stump after PD are shown in Table 1 and Fig. 1.              (p=0.0139), T stage 3 (p=0.031) and N stage 2 (p=0.000001),
                                                                        surgical procedure (PD p=0.0018) and pancreatic residual
                                                                        treatment (neoprene glue closure p=0.003 and stapler closure
                                                                        p=0.002). Bleeding complications, biliary anastomosis
                                                                        leakage and infectious complications were consequences
                                                                        of pancreatic leakage (p=0.025, p=0.025 and p=0.025,

                                                                             Complications that are related to the pancreatic remnant
                                                                        still represent a substantial risk for death after pancreatic
                                                                        head resections [5-7].
                                                                             Failure of a surgical anastomosis has serious consequences
Fig.1 Incidence of complications. resulting after different             particularly in cases of anastomosis of the pancreas to the
managements of pancreatic stump after PD; absolute values               small bowel, because of the digestive properties of activated
(number of patients) upon the columns. See Table 1 for statistical      pancreatic secretions. An important factor in the prevention
                                                                        of pancreatic fistula in patients with a pancreaticojejunostomy
                                                                        is technical precision and gentleness in construction of the
   Re-operation rates were: 27.2% after manual non-                     pancreatic anastomosis. Cattell [8] in 1943 advocated the
absorbable stitches closure of the main duct, 23.8% after               necessity of a pancreaticoenteric anastomosis because of the
closure of the main duct with linear stapler, 6% after                  high mortality rate when leaving the pancreatic remnant in

Table 1. Incidence of complications due to different managements of pancreatic stump after PD (χ2 test) (n.s.: not significant)
 Type of management of pancreatic stump                  Overall complications   Leakage       Haemoperitoneum       Infectious disease
                                                         p-value                 p-value       p-value               p-value

 Manual stiches closure of the main duct (11 pts.) vs.   <0.05                   n.s.          n.s.                  n.s.
 Neoprene glue closure (17 pts.)

 Manual stiches closure of the main duct (11 pts.) vs.   <0.005                  <0.05         n.s.                  n.s.
 Main duct closure with stapler (24 pts.)

 Manual stiches closure of the main duct (11 pts.) vs.   <0.001                  <0.001        n.s.                  <0.05
 Duct to mucosa anastomosis (24 pts.)

 Neoprene glue closure (17 pts.) vs. Main duct closure   <0.05                   <0.05         <0.05                 <0.01
 with stapler (24 pts.)

 Neoprene glue closure (17 pts.) vs. Duct to mucosa      <0.005                  <0.001        <0.05                 n.s.
 anastomosis (24 pts.)

 Main duct closure with stapler (24 pts.) vs. Duct to    <0.05                   <0.05         <0.05                 <0.01
 mucosa anastomosis (24 pts.)
46                                                                                                                  Benzoni et al

situ, either with or without ligature of the pancreatic duct.          Based on our results, bleeding complication, biliary
    In the history of PD, some authors [9-11] reported that the   anastomosis leakage and infectious complications were the
absence of an anastomosis to the pancreatic remnant might         consequences of pancreatic leakage.
prevent a large proportion of postoperative complications.             Intra-abdominal abscesses are seen in about 3-10%
A pancreatic fistula from the oversewn pancreatic remnant          after PD, and a percutaneous drainage is recommended for
is less dangerous than one from the pancreaticojejunal            collections larger than 5 cm. Antibiotics should be given
anastomosis because there is no defect in the small bowel         intravenously [23, 24].
and no activation of pancreatic enzymes.                               Pancreatic fistula is still an unsolved problem, as there
    Another technique investigated has been obliteration          is still no consensus on a uniform definition of fistula. The
closure of the pancreatic duct with a chemical substance,         broad range drainage rates reported in the literature (2-28%)
thus avoiding a pancreaticojejunostomy. This method was           is largely a function of the definition used, and there is no
proposed by Gebhardt et al [12], who studied the effect of        evidence that a management of pancreatic stump after PD
occlusion of the pancreatic duct system with Ethibloc, an         is better than others [25, 26].
alcohol prolamine, in animal experiments. The pancreatic               We recorded a 60% rate of complications in the PD group,
duct may also be occluded with a fibrin glue solution,             while only 19.3% of patients in the DP group experienced
Tissucol®, which was found to have a more protective effect       postoperative complications, and in particular only 3.9% of
on beta cell function than the other solutions used [13].         DP vs. 48% of PD patients (p=0.03) recorded a pancreatic
    Di Carlo et al [14] described lower morbidity and             fistula. We believe that a higher duct pressure and volume
mortality in a non-randomized trial in 50 patients using duct     of pancreatic fluid into the main duct after pancreatic
occlusion with neoprene glue after Whipple’s procedure,           resection could explain the difference between PD and DP
even if a side effect of permanent occlusion, that induces        in developing complications, and the same factors could
pancreatic atrophy and complete loss of exocrine function,        explain the different rates of complications among different
was reported. Gail et al [15] found similar results with          approaches to the reconstructive phase. Furthermore, the
duct occlusion after Whipple’s operation in patients with         blockage of the main pancreatic duct, as recorded in the
chronic pancreatitis. Lorenz et al [16] noted fewer early         occlusion with fibrin glue, even transiently, might artificially
complications in oncologic pancreatic surgery, but not in         increase the secretion of pancreatic juice in the severed
patients with chronic pancreatitis. As recently reported by       secondary canals or on the suture line and, consequently,
Suc et al [17], who performed a prospective randomized            both yield and support a pancreatic fistula [27].
trial on fibrin glue occlusion on the pancreatic stump, this            As claimed by the literature, risk factors for pancreatic
technique did not significantly decrease the rate of intra-        leakage comprise general factors (age, gender, jaundice,
abdominal complications, notably pancreatic fistula, or their      malnutrition), disease-related factors (pancreatic pathology,
severity after pancreatic resection.                              pancreatic texture, pancreatic duct size, pancreatic juice
    Recently, Bilimoria et al [18] demonstrated that the          output) and procedure-related factors (operative time,
incidence of leakage is reduced significantly when the             resection type, anastomotic technique, intraoperative blood
pancreatic duct is identified and directly ligated: pancreatic     loss).
leak rates were 9.6 % in subgroups having duct ligation and            Clearly, the high morbidity and mortality rates associated
34.0 % in subgroup having no duct ligation (p<0.001). At          with this operation underscore the magnitude and difficulty
multivariate analysis, failure to ligate the pancreatic duct      of this type of procedure. This high leak rate in the different
was the only feature associated with an increased risk for        PD groups is consistent with reports of other authors and
pancreatic leak (p = 0.001).                                      highlights the difficulties in managing the pancreatic stump.
    In the past, a lower morbidity was recorded in the            It is interesting to note that the PD groups involving closure/
application of mechanical stapler during the parenchymal          occlusion of the pancreatic duct had similar or higher leaks
transection [19], but actually there is accordance in the         and overall complication rates when compared to the duct-
usage of the stapler and its benefits, and a careful drain         to-mucosa anastomosis group. This is an important finding,
management is recommended to achieve a good outcome               because patients in whom a duct occlusion is performed
in patients with fistula [20].                                     develop severe pancreatic exocrine insufficiency that causes
    The incidence of bleeding complications after PD              malabsorption.
ranges from 5 to 16%, and can occur in up to 60% in cases              Furthermore, as regards total pancreatectomy, which is
of pancreatic leakage [21-24]. The mortality of a bleeding        recommended instead of pancreaticojejunostomy in order
complication continues to be high, ranging from 30 to 58%         not to develop postoperative complications such as leakage,
[23, 24]. Jaundice, hepaticojejuno- and pancreaticojejuno         it has to be taken into consideration that this procedure is
anastomotic leaks are associated with an increased incidence      associated with severe endocrine and exocrine abnormalities.
of bleeding. The consistency of pancreas, type of pancreatic      Therefore a benefit could be achieved only in patients
reconstruction, tumor site and size and operative duration        affected by insulin dependent diabetes before surgery.
have no influence on the incidence or type of postoperative             In conclusion, based on our experience, we make the
bleed. Mortality in bleeders was 34% as compared with 3%          following recommendations: manual non-absorbable stitch
in non-bleeders [23, 24].                                         closure of the main duct and occlusion of the main duct with
Postoperative complications linked to pancreaticoduodenectomy.                                                                                      47

neoprene glue should be avoided in the reconstructive phase,                     240.
and a duct-to-mucosa pancreaticojejunoanastomosis should be                  12. Gebhardt C, Stolte M, Schwille PO, Zirngibl H, Engelhardt W.
preferred. We recommend pancreaticoenteric reconstruction                        Experimental studies on pancreatic duct occlusion with prolamine. Horm
as a standard procedure after pancreaticoduodenectomy,                           Metab Res Suppl 1983: 9–11.
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