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A prospective multicentre survey on the treatment of acute pancreatitis in Italy
Digestive and Liver Disease 39 (2007) 838–846
Liver, Pancreas and Biliary Tract
A prospective multicentre survey on the treatment of acute pancreatitis in Italy R. Pezzilli a,∗ , G. Uomo b , A. Gabbrielli c , A. Zerbi d , L. Frulloni e , P. De Rai f , L. Castoldi f , G. Cavallini e , V. Di Carlo d , the members of the ProInf-AISP Study Group1 a
f
Department of Internal Medicine and Gastroenterology, S. Orsola-Malpighi Hospital, Bologna, Italy b Department of Internal Medicine, Ospedale A. Cardarelli, Naples, Italy c Digestive Endoscopy, Campus Biomedico, Rome, Italy d Department of Surgery, University Vita e Salute, IRCCS S. Raffaele, Milan, Italy e Department of Surgical and Gastroenterological Sciences, University of Verona, Verona, Italy Department of Emergency Surgery, Fondazione IRCCS Maggiore, Mangiagalli and Regina Elena Hospital, Milan, Italy Received 5 March 2007; accepted 14 May 2007 Available online 29 June 2007
Abstract Background. The Italian Association for the Study of the Pancreas released a diagnostic and therapeutic algorithm for acute pancreatitis in 1999. Aim. This study focused on the analysis of the therapeutic approach for the treatment of acute pancreatitis in Italy. Patients. One thousand, one hundred and seventy-three patients were recruited: 1006 patients (85.8%) had mild acute pancreatitis (MAP) and 167 (14.2%) had the severe acute pancreatitis (SAP); 161 patients showed pancreatic necrosis at computed tomography; 121 patients (10.3%) had sequelae and 36 (3.1%) died. Results. Non-steroidal anti-inflammatory drugs and tramadol were used more frequently in patients with the MAP whereas opioids and the association schedules were used more frequently in patients with the SAP (P < 0.001). Gabexate mesilate was utilised in 831 out of 1173 patients (70.8%); in particular, gabexate mesilate was used in 70.6% patients with MAP and in 73.1% of those with SAP (P = 0.521). The duration of the drug administration was significantly shorter in those having MAP than in those having the SAP (P < 0.001). The antibiotics most frequently used for the prophylaxis against infection from pancreatic necrosis (43.1%) were carbapenems. Only a small number of patients received enteral nutrition (4.7%). Endoscopic retrograde cholangiopancreatography was carried out in 344 of the 1173 patients (29.3%). Surgery was performed in 48 with SAP (19 had elective biliary surgery and 29 had pancreatic surgery). Conclusions. The results of this survey indicate a lack of compliance with the guidelines which regard the indications mainly for interventional endoscopy and surgery. © 2007 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: ERCP; Pancreatitis; Pancreatitis acute necrotising
1. Introduction ∗
Corresponding author at: Department of Digestive Diseases and Internal Medicine, Sant’Orsola-Malpighi Hospital, Via Massarenti, 9, 40138 Bologna, Italy. Tel.: +39 051 6364148; fax: +39 051 6364148. E-mail address: [email protected] (R. Pezzilli). 1 See Appendix A for the list of members.
Acute pancreatitis may range from mild self-limiting forms to the more severe forms which are affected by high morbidity and mortality [1]. Therefore, the range of applicability of therapeutic protocols differs according to the severity of the pancreatitis. In order to implement cost-effective,
1590-8658/$30 © 2007 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2007.05.014
R. Pezzilli et al. / Digestive and Liver Disease 39 (2007) 838–846
widely applicable therapeutic guidelines, it is necessary to acquire adequate knowledge of the national epidemiological and clinical data. The first Italian prospective multicentre evaluation of the epidemiological and clinical status of acute pancreatitis in Italy [2] enrolled 1005 patients between September 1996 and June 2000, mainly with the mild form (753 patients (74.9%) had the mild form and 252 (25.1%) had the severe form). The aetiology was biliary in the majority of cases (60%); more than 80% of the patients were admitted to hospital within 24 h from the onset of clinical symptoms while only 6% were admitted after 48 h. The mean duration of hospitalisation for patients with mild pancreatitis was 13 ± 8 days while, for the severe form, it was 30 ± 14 days and the overall mortality rate was 5% (17.0% in severe and 1.5% in mild pancreatitis). During the enrolment of patients in this study, the Italian Association for the Study of the Pancreas released a diagnostic and therapeutic algorithm [3]. Furthermore, in the Italian survey of 1005 patients, no extensive data concerning conservative treatment were available. Thus, in January 2000, a new multicentre study was planned which was aimed at a thorough analysis of the diagnostic assessment and therapeutic methods, and involving a more extensive network of Italian centres. In this paper, we report the final results of the survey as regard the therapeutic features of acute pancreatitis in Italy.
2. Methods The present study involved 56 Italian centres, equally distributed throughout Italy. Ad hoc software including 530 items designed by the scientific committee of the study was furnished to each participating centre. All cases of acute pancreatitis consecutively observed during the period from December 2001 to November 2003 were included in the study. The diagnosis of acute pancreatitis was based on clinical (onset of pancreatic type pain), biochemical (a threefold increase of amylase and/or lipase) and radiological (ultrasonography, computer tomography scan, magnetic resonance) findings. The disease was classified according to Atlanta criteria [1] into mild and severe forms. Sequelae of acute pancreatitis were defined as the presence of pseudocysts, fluid collections and fistulae. Data were collected and tabulated centrally; during the period of the study, a careful monitoring process was carried out. At the end of the study, additional quality control regarding the completeness and congruence of each single chart was carried out in order to exclude cases with incomplete and/or inconsistent charts. The endpoint of the study was to evaluate the treatment (conservative, nutritional, endoscopic and surgical) of acute pancreatitis in Italy. Data were presented as mean ± standard deviation (S.D.) and frequencies. Statistical analysis was carried out using the Student’s t-test, the chi-squared test and the Fisher’s exact
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test. Data ran on SPSS version 10. Significant difference was considered to be a P value of less than 0.05.
3. Results One thousand, five hundred and forty case report forms of patients affected by acute pancreatitis were collected; 367 of them (23.8%) were subsequently withdrawn from the final analysis because of the incompleteness and/or inconsistency of the charts. Therefore, 1173 patients (581 females and 592 males) were analysed. A mean of 21 patients for each centre (range 2–28) was enrolled. The mean age of the patients was 62.0 ± 18.2 years. Biliary forms represented the most frequent aetiological category (813 cases, 69.3%) while alcoholic forms occurred in only 77 cases (6.6%); all together the remaining aetiologies (post-surgery, post-endoscopic cholangiopancreatography, traumatic, hyperlipemic, drug-induced and pancreas divisum) accounted for 7.1% (83 cases). Two hundred cases (17.1%) remained without a definite aetiological factor (idiopathic forms). One thousand and sixteen patients (86.6%) had complete clinical, laboratory and morphological resolution of the disease, 121 patients (10.3%) had sequelae, and 36 patients (3.1%) died. Thirteen patients died from infected necrosis associated with multi-organ failure, 12 from infected necrosis associated with sepsis-like syndrome, 3 from heart failure or arrhythmias, 2 patients died from acute respiratory distress syndrome, 2 from gastrointestinal haemorrhage, 1 from aortic aneurism rupture, 2 from multi-organ failure and 1 from pulmonary embolism. At computed tomography, pancreatic necrosis was found in 161 patients. On the basis of the Atlanta classification system for acute pancreatitis [1], 1006 patients (85.8%) were defined as having mild pancreatitis and 167 (14.2%) as having the severe form. The mean interval between the onset of pain and hospital admission was not statistically significant (P = 0.374) between patients with mild (14.9 ± 37.2 h) and those with severe pancreatitis (17.8 ± 39.1 h). 3.1. Conservative treatment Data on fluids administered during the first three days were available for 1008 of the 1173 patients (85.9%): 141 patients with severe (14.0%) and 867 patients with mild pancreatitis (86.0%). As shown in Fig. 1, the amount of fluids administered was significantly higher (P < 0.001) in patients with severe acute pancreatitis than in those with the mild form. Data on analgesic administration were available in 840 of the 1173 patients (71.6%) (Table 1). Non-steroidal antiinflammatory drugs (NSAIDs) were administered in 459 patients (54.6%), tramadol in 216 (25.7%), opioids in 32 (3.8%) and a combination of the various drugs in the remaining 133 (13.8%) patients. There was a significant difference in the type of analgesics administered between patients with
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Fig. 1. Fluids administered during the first three days of acute pancreatitis in patients with mild acute pancreatitis and in those with severe acute pancreatitis. AP: acute pancreatitis.
mild and those with severe disease (P < 0.001); NSAIDs and tramadol were used more frequently in patients with mild disease whereas opioids and the association schedules were used more frequently in patients with severe disease. The duration of analgesic treatment was significantly longer in patients with severe acute pancreatitis in comparison to those suffering from the mild form; NSAIDs: 3.0 ± 2.3 days in patients with mild acute pancreatitis and 6.7 ± 10.1 days in patients with severe acute pancreatitis (P < 0.001); tramadol: 3.2 ± 2.3 days in patients with mild acute pancreatitis and 8.0 ± 11.7 days in patients with severe acute pancreatitis (P < 0.001). Histamine H2 antagonists were used in 489 patients (427 patients with mild acute pancreatitis, 87.3%; 62 patients with severe acute pancreatitis, 12.7%), proton pump inhibitors in 606 patients (505 patients with mild acute pancreatitis, 83.3%; 101 patients with severe acute pancreatitis, 16.7%) and a simultaneous association of these two drugs in 62 patients (50 patients with mild acute pancreatitis, 80.6%; 12 patients with severe acute pancreatitis, 19.4%). The duration of treatment with drugs inhibiting gastric acid secretion was significantly longer in severe acute pancreatitis patients than in those with the mild form of the disease (9.6 ± 6.5 days in patients with mild acute pancreatitis and 25.3 ± 23.8 days in patients with severe acute pancreatitis; P < 0.001). Gabexate mesilate was utilised in 831 out of the 1173 patients (70.8%). In 709 of 1004 (70.6%) patients with
mild acute pancreatitis and in 122 of the 167 patients with severe acute pancreatitis (73.1%) (P = 0.521). Gabexate was utilised at a similar dosage in the two forms of acute pancreatitis (1112 ± 434 mg in mild acute pancreatitis and 1148 ± 387 mg in severe acute pancreatitis) (P = 0.391). However, the duration of drug administration was significantly shorter in mild acute pancreatitis than in patients with the severe form (4.7 ± 3.3 days versus 9.2 ± 7.8 days; P < 0.001). Octreotide was utilised subcutaneously three times a day in 175 of the 1173 patients (14.9%). It was utilised in 134 of the 1004 (13.3%) patients with mild acute pancreatitis and in 41 of the 167 patients with severe acute pancreatitis (24.6%) (P < 0.001) at a similar dosage in both forms of pancreatitis (0.5 ± 0.7 g per day in the mild acute form and 0.5 ± 0.3 g per day in the severe form; P = 0.823). Octreotide was administered for a longer period of time in severe acute pancreatitis patients than in those with the mild acute form (13.6 ± 15.6 days in patients with severe acute pancreatitis versus 5.2 ± 3.6 days in patients with the mild acute form; P < 0.001). Somatostatin was used i.v. in 136 patients with acute pancreatitis (116 with mild acute pancreatitis (85.3%) and 20 with severe acute pancreatitis, 14.7%; P = 0.346) at a similar dosage in both forms of pancreatitis (5.6 ± 1.2 mg per day in patients with mild acute pancreatitis and 5.6 ± 1.1 mg per day in patients with the severe form; P = 0.898). Somatostatin treatment duration was significantly longer in severe acute pancreatitis patients than in those with mild acute pancreatitis (13.0 ± 15.7 days in patients with severe acute pancreatitis versus 4.8 ± 3.5 days in patients with the mild acute pancreatitis; P = 0.003). Antibiotics were used for the treatment of extrapancreatic infections and for the treatment of proven infection of pancreatic necrosis as well as for the prophylaxis against infection from pancreatic necrosis. Regarding the extrapancreatic infections, the antibiotics used are reported in Table 2; cephalosporin was the antibiotic principally used for these infections, followed by carbapenemens. Carbapenemens, glycopeptides and antifungal antibiotics were the antibiotics most frequently used in the treatment of proven infected pancreatic necrosis (Table 3). As is
Table 1 Type and frequency of analgesics administered to patients with mild acute pancreatitis and to those with severe acute pancreatitis Mild acute pancreatitis
Severe acute pancreatitis
No. patients
Frequency (%)
No. patients
Frequency (%)
NSAIDs Tramadol Opioids NSAIDs + tramadol NSAIDs + opioids Tramadolo + opioids NSAIDs + tramadol + opioids
412 183 16 63 14 5 7
89.8 84.7 50.0 75.9 63.6 38.5 46.7
47 33 16 20 8 8 8
10.2 15.3 50.0 24.1 36.4 61.5 53.3
Overall
700
83.3
140
16.7
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Table 2 Type and frequency of antibiotics administered for extrapancreatic infection in mild and severe acute pancreatitis Mild acute pancreatitis
Cephalosporins Beta-lactam antibiotics, penicillins Carbapenems Aminoglycosides Quinolones Glycopeptide antibiotics Fluconazole Antifungal antibiotics Sulfonamides Others
Severe acute pancreatitis
No. cases
Frequency (%)
No. cases
Frequency (%)
32 20 18 5 5 4 2 1 0 1
36.4 22.7 20.5 5.7 5.7 4.5 2.3 1.1 0.0 1.1
11 9 12 3 10 8 4 7 1 1
16.7 13.6 18.2 4.5 15.2 12.1 6.1 10.6 1.5 1.5
also shown in Table 3, carbapenems were the antibiotics most frequently used for the prophylaxis against infection from pancreatic necrosis (128 patients, 43.1%) followed by cephalosporin (78 patients, 25.3%) and by beta-lactam antibiotics (43 patients, 14.5%). 3.2. Nutritional support Nutritional support was used in 403 patients: 269/1006 (26.7%) with mild acute pancreatitis and 134/167 (80.2%) with severe acute pancreatitis. Three hundred and fifty-eight patients received parenteral nutritional support (88.8%): 250 (69.8%) with the mild acute form and 108 (30.2%) with the severe acute form) whereas only 19 of the 403 patients (4.7%) received enteral nutrition: 10 with the mild form and 9 with the severe form. Twenty-six patients (9 with the mild and 17 with the severe form of the disease) received both enteral and parenteral nutrition. The length of parenteral nutrition was significantly longer (P < 0.001) in severe acute pancreatitis patients than in those with the mild acute form (15.9 ± 14.3 days for patients with severe acute pancreatitis versus 6.0 ± 4.1 days for patients with mild acute form). In the same way, the length of enteral nutrition was significantly longer (P < 0.001) in patients with severe acute pancreatitis (22.0 ± 21.2 days) with respect to those having the mild form of the disease (6.9 ± 5.4 days).
3.3. Endoscopic treatment Endoscopic retrograde cholangiopancreatography (ERCP) was carried out in 344 of the 1173 patients (29.3%). The mean interval between the onset of symptoms and ERCP was 6.7 ± 5.0 days and the mean interval between hospital admission and ERCP execution was 5.7 ± 5.0 days. Eighty-nine examinations (25.9%) were performed within 72 h from the onset of symptoms while, for the remaining patients, the procedure was performed within 72 h after hospital admission. Three hundred and twenty (93.0%) patients had biliary pancreatitis: 288 (90.0%) of them had mild acute pancreatitis and 32 (10.0%), had the severe form (P = 0.303) The reasons for carrying out ERCP in patients with biliary pancreatitis (more than one indication may be present in the same patient) were as follows: common bile duct stones in 289 patients (89.4%), jaundice in 153 (47.8%), clinical worsening of acute pancreatitis in 45 (14.1%) and cholangitis in 21 (6.6%). In the remaining 24 patients (4 with severe disease) the indications for the procedure were suspicion of common bile duct stones in 17 patients, deterioration of the disease in 4, disruption of the main pancreatic duct in 2 and suspicion of malignancy in 1. Common bile duct visualization was obtained in 305 patients (88.7%), and 295 patients underwent biliary sphinc-
Table 3 Type and frequency of antibiotics used for the treatment of proven pancreatic necrosis infection and for prophylaxis in preventing infection of pancreatic necrosis
Carbapenems Glycopeptide antibiotics Antifungal antibiotics Aminoglycosides Beta-lactam antibiotics, penicillins Cephalosporins Fluconazole Quinolones Others
Proven pancreatic necrosis infection (No. 56)
Prophylaxis against infection of pancreatic necrosis (No. 297)
No. cases
No. cases
16 11 7 4 3 3 3 2 2
Frequency (%) 31.4 21.6 13.7 7.8 5.9 5.9 5.9 3.9 3.9
More than one antibiotic was utilised on the same patient.
128 7 4 8 43 78 13 14 2
Frequency (%) 43.1 2.4 1.3 2.7 14.5 26.3 4.4 4.7 0.7
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terotomy (295/305, 96.7%). A standard sphincterotomy was performed in 242 of the 295 patients (82.0%) whereas precut sphincterotomy was performed in 53 patients (18.0%). Stones were found in 159 patients (53.9%) and in stones together with sludge in 154 patients (52.2%) of the 295 patients, respectively. The morbidity of the endoscopic procedure was 6.1% (11/344): nine bleeds, one retroperitoneal perforation and one acute cholecystitis. All these complications were treated conservatively. Mortality in the patients who underwent operative endoscopy was 1.7% (6 out of 344), and all the patients who died had severe pancreatitis. 3.4. Surgical treatment Of the 1173 patients observed in the study, 277 (23.7%) underwent surgery: 229 had mild pancreatitis and 48 had severe pancreatitis (19 had elective biliary surgery and 29 had pancreatic surgery). 3.4.1. Elective biliary surgery Of all the patients with mild acute biliary pancreatitis, 88 had previously been cholecystectomised. The gallbladder was reported as abnormal (due to lithiasis or inflammation) in 593 patients and it was removed in 212 of them (29.6%) (in 76% cases using a laparoscopic approach); in 80 out of 212 cases (71.5%), a pre-operative ERCP was associated. Seventeen patients underwent other surgical procedures for the treatment of biliary lithiasis (mainly, common bile duct exploration with stone removal and bilio-enteric anastomosis). The mean length of the hospital stay for patients undergoing cholecystectomy was 15 days (13.0 ± 6.3 days, range 3–44, for patients having the laparoscopic approach and 17.9 ± 8.8 days, range 6–50 days, for the remaining patients). In patients undergoing ERCP and surgery during the first admission (N = 66), the first was performed within 5.7 ± 5.3 days (range 0–36 days) and the latter within 10.4 ± 5.8 (range 2–36 days) respectively. In all but two patients (discharged with fluid collections) the course was uneventful. Cholecystectomy was performed in 165 (78%) cases during the same hospital observation for pancreatitis (15.4 ± 7.46 days on average after the onset of pancreatitis) and in the remaining 47 patients during a second admission (38.5 ± 42.7 days, range 10–260 days) after pancreatitis onset. Among the patients with severe biliary pancreatitis, 19 underwent elective cholecystectomy an average of 40 days after the onset of pancreatitis; in 47% of the cases this procedure was performed during second hospitalisation; no patient was hospitalised more than two times. there were two mortalities and 11 cases of long-term sequelae were observed (6 fluid collections, 4 pseudocysts, 1 fistula). 3.4.2. Pancreatic surgery In 29 cases of severe pancreatitis, pancreatic surgery was performed. Indications for surgery were: acute abdomen in
16 cases (55.1%: acute abdomen alone in 9 cases, combined with other indications in 7 cases), MOF in 10 cases (34.5%: MOF alone in 2 cases, combined with other indications in 8 cases), infected necrosis in 8 cases (27.6%: infected necrosis alone in 6 cases, combined with other indications in 2 cases) and sterile necrosis in 3 cases (10.3%: sterile necrosis alone in 2 cases, combined with other indications in 1 case). Surgery was performed 12.3 days on average after the onset of pancreatitis (range 0–64 days): in 19 cases (65.5%) before the 5th day, in 3 cases (10.3%) between the 6th and the 14th day and in 7 cases (24.1%) after the 14th day. In 26 cases (89%), a necrosectomy was carried out and, in the remaining 3 cases, simple drainage was carried out; in only 1 case was a laparostomy performed. Necrosectomy was associated with postoperative continuous lavage in 21 cases (72.4%). A feeding jejunostomy was added in only 11 cases (37.9%). In 14 cases (48%), postoperative complications occurred: 6 infections, 6 MOF, 4 pancreatic fistulas, 1 haemorrhage, 1 occlusion, 1 pseudocyst and 1 colic fistula. Mortality was 20.7% (6 cases) and 11 patients (37.9%) were discharged with sequelae (6 fluid collections, 4 pseudocysts, 4 fistulas).
4. Discussion In recent years, several therapeutic guidelines on acute pancreatitis have been released [4]. However, very few studies have been published which evaluate whether the suggestions of these guidelines have been extensively followed in clinical practise [5–9], and all of these papers showed a lack of compliance in following the guidelines. In 1999, the Italian Association for the Study of the Pancreas released a diagnostic and therapeutic algorithm on the diagnosis and treatment of acute pancreatitis [3]. Thus, in January 2000, a new multicentre study was planned which was aimed at a thorough analysis of the therapeutic methods, involving many Italian centres. The final results of the study concerning the therapeutic features of acute pancreatitis in Italy are reported in this paper. Many of the findings observed in the first ProInfAISP Study I [2] were confirmed, namely, the preponderance of mild pancreatitis (85.8%), the high percentage of biliary forms (69.3%) and the low rate of mortality (3.1%). The overall hospital stay was similar to that of our previous experience [2] and was similar to those reported in other countries [10,11]. Taking into consideration the basic treatment of acute pancreatitis, the present study demonstrates that patients with severe acute pancreatitis received a significantly higher amount of fluids than those with mild acute pancreatitis and that analgesics were also graded according to the severity of the pain. In fact, patients with mild acute pancreatitis received mainly NSAIDs and tramadol whereas patients with severe pancreatitis received a high percentage of opioids or an association of analgesics comprising NSAIDs, tramadol and opioids. There are no extensive studies on the pharma-
R. Pezzilli et al. / Digestive and Liver Disease 39 (2007) 838–846
cological control of pain in acute pancreatitis [12–15]; this is quite surprising due to the importance of this symptom. There is a lack of evidence about the different efficacy of various pharmacological substances in the different forms of acute pancreatitis, so studies comparing different schedules of pain-relieving drugs in patients with acute pancreatitis and utilising objective methods to evaluate pain decrease are welcome. Another open question in the treatment of acute pancreatitis is the efficacy of inhibiting gastric acid secretion; there are very few studies on this issue and the results are not conclusive [16,17]. However, in our observational study, gastric acid secretion inhibition is largely used in patients with acute pancreatitis and the finding that the duration of treatment with drugs inhibiting gastric acid secretion was significantly higher in patients with severe acute pancreatitis than in patients with the mild form is due to the fact that the hospital stay of patients which severe pancreatitis is significantly longer than that of those having the mild disease. One of the intriguing issues in acute pancreatitis is that of specific treatment for acute pancreatitis by using drugs such as those capable of reducing pancreatic secretion and those having antiprotease activity. Octreotide and somatostatin were prescribed by our clinician in only about 15% of patients. Why these drugs were administered is quite surprising because none of the available guidelines suggest their use in the early phases of acute pancreatitis. Regarding antiprotease therapy, it should be mentioned that among the various published guidelines only the Italian and Japanese ones recommend its use in acute pancreatitis [3,18]. In our present survey, gabexate mesilate was utilised in 70.8% of acute pancreatitis patients. Gabexate was utilised at a similar dosage in both forms of acute pancreatitis (mild and severe). However, the duration of drug administration was significantly shorter in patients having mild acute pancreatitis than in those with the severe form. This may be due to the fact that, in the Italian algorithm for treating acute pancreatitis it has been suggested that all patients with acute pancreatitis should be considered as having the severe form until prognostic assessment is made, thus gabexate mesilate is used in mild pancreatitis during the time necessary to obtain a precise diagnosis [3]. Furthermore, a new meta-analysis has recently been published on the use of antiproteases in acute pancreatitis showing that treatment with protease inhibitors does not significantly reduce mortality in patients with mild pancreatitis, but the drug may reduce mortality in patients with moderate to severe pancreatitis [19]. Two of the other open questions on the use of antiproteases in severe acute pancreatitis are treatment duration and the optimal dosage of the drug. In the present study, gabexate mesilate administration has a mean of 9.2 ± 7.8 days and this administration period is slightly higher than that usually suggested (7 days) [20,21]. Patients with severe pancreatitis received a mean of 1148 ± 387 mg per day of gabexate mesilate; this figure is higher than that suggested in a study in which a dosage
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of 900 mg/day of gabexate mesilate was demonstrated to be equally as effective as a dosage of 1500 mg/day [21]. Antibiotics have been used to cure both extrapancreatic infections which appeared during the course of acute pancreatitis and infected pancreatic necrosis and also as a prophylaxis in those patients who had pancreatic necrosis for the prevention of possible infection from the necrosis. In the treatment of extrapancreatic infections, the most used antibiotics were cephalosporins whereas carbapenemens, glycopeptides and antifungal antiobiotics were the most used antibiotics in the treatment of proven infected pancreatic necrosis. According to most of the guidelines published [1,3,18,22–27] and on the basis of the results of systematic reviews of randomised studies [28,29], carbapenems were also the antibiotics most frequently used in Italy for the prophylaxis against infection from pancreatic necrosis (43.1%), even if our clinicians use cephalosporins in 25.3% of the patients and beta-lactam antibiotics in 14.5% of the patients. Enteral feeding has been proven to decrease the inflammatory response and sepsis in severe acute pancreatitis patients [30,31]. However, in our country, enteral nutrition is used in a very low percentage of severe acute pancreatitis patients while parenteral nutrition is the preferred nutritional support. Three hundred and forty-four patients underwent ERCP; only 26% of the examinations were performed within 72 h from the onset of symptoms and this represents a clear deviation from the largely accepted guidelines [3,22]. Another lack of adherence to the international and national guidelines is that endoscopic sphincterotomy was performed in 90.0% of the patients with mild acute pancreatitis [3,22]. From a practical point of view, common bile duct visualization was obtained in about 90% of patients and biliary sphincterotomy was possible in 96.7% of the patients. The morbidity of the endoscopic procedure was 6.1% and all the complications were treated conservatively. Finally, the mortality rate in patients who underwent operative endoscopy was less than 2%. The role of cholecystectomy in mild biliary acute pancreatitis is aimed at preventing relapses [23,27,32,33]. In our series, only 29.6% of patients with biliary pancreatitis and in situ gallbladder underwent cholecystectomy. To partially explain this discrepancy from the international guidelines, it should be noted that some patients were initially observed in Medical Departments and then discharged. Some of them could have been operated on during subsequent hospitalisations and this data could have been missed. In any case, the rate of patients who did not undergo surgery remains too high. When cholecystectomy was performed, a laparoscopic approach was successfully accomplished in 76% of the patients with mild pancreatitis; this demonstrates that the recent pancreatitis did not modify the anatomy and allowed this mini invasive approach. In 39% of cases, an ERCP was performed before cholecystectomy; endoscopic treatment did not prolong the hospital stay, except for the small group of patients undergoing laparotomic cholecystectomy. A com-
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bined approach (ERCP plus laparoscopic cholecystectomy) seems to be the most logical and it was proven to be suitable in mild pancreatitis. The delay of 4 days between endoscopy and surgery appears to be slightly too long; it possibly reflects some challenges in planning surgical procedures and in transferring patients from medical to surgical departments. From our data, in 22% of cases, a cholecystectomy was performed during a second hospital admission, 38 days on average after the onset of pancreatitis. This finding, together with the high rate of non-operated patients, represents the main discrepancy between our series and the international guidelines on acute pancreatitis. However, in a recent report from the United Kingdom, non-compliance with the national guidelines was also reported, with only 30% of patients who had biliary acute pancreatitis undergoing surgery [5,33]. Among patients with severe biliary pancreatitis, cholecystectomy was delayed 40 days on the average and it was performed in about half of the cases during a second admission. In our opinion, this attitude is correct, because it is necessary to wait for the evolution of necrotic pancreatic areas. In this group of patients, the rate of change was the same as that obtained in patients with severe pancreatitis but without cholecystectomy. This procedure does not seem to affect the course of severe pancreatitis. In our series, 29 patients underwent pancreatic surgery for severe pancreatitis and it is difficult to draw firm conclusions from this small number of patients. We were surprised by the indications for surgery (acute abdomen in more than half of the cases) and by the timing of the surgery, since 34% of the patients underwent surgery on the same day they were admitted to hospital and 65% in the first 5 days after the onset of the pancreatitis. These data are difficult to understand. A very early surgical procedure is actually indicated only in the small group of patients with acute multiorgan failure not responding to intensive treatment. Necrosectomy is usually performed later, 2–3 weeks after the onset of the pancreatitis when infection from necrosis eventually occurs and when necrotic tissue is easily removed. Possibly, in our series, diagnostic uncertainties and mistakes are related, for the most part, to cases of early surgical intervention. In any case, the morbidity and mortality rates observed in patients with severe acute pancreatitis are similar to those usually reported in the literature [4] and in a previous Italian study [34]. We should, therefore, take into account some important points; only 29 patients of the 161 with necrotising pancreatitis were operated on and most of the necrotising pancreatitis patients were treated conservatively. It is possible that early and intensive medical treatment may have some beneficial influence on these results [35]. Furthermore, it is also possible that the so-called specific treatment with antiproteases may have been efficacious when carried out in the “therapeutic window” acting effectively on the early pathogenetic mechanisms of acute pancreatitis. Finally, appropriate antibiotic treatment may explain the low number of patients who required surgical treatment for the infection of pancreatic necrosis.
5. Conclusion Although compliance with the guidelines on investigation for severity stratification of acute pancreatitis was adequate, the results of this survey indicate a lack of compliance with the guidelines regarding the indications for interventional endoscopy and surgery. We believe that further efforts should be made by the scientific societies in releasing updated guidelines and their correct application should thus be stressed.
Practice points • The type of drugs capable of reducing abdominal pain were used correctly, i.e. NSAIDs or tramadol in patients with mild acute pancreatitis and opioids in patients with severe pancreatitis. • According to the Italian guidelines regarding the severity of the disease as well as the dosage (about 900 mg/day), antiproteases were used correctly. • The use of antibiotics in preventing infection in patients with necrotising pancreatitis should be modified (carbapenems were used in only fewer than 50% of the patients). • The use of enteral nutritional support should be increased in severe acute pancreatitis patients. • Stricter criteria should be used when deciding to perform ERCP in patients with acute pancreatitis. • More attention should be paid to performing a cholecystectomy in mild biliary pancreatitis in the same hospitalization period.
Research agenda • Although there was adequate compliance with the guidelines regarding the severity stratification of acute pancreatitis, the results of this survey indicate a lack of compliance with the guidelines regarding the indications for interventional endoscopy and surgery. • Even if scientific societies have endeavoured to emphasise guidelines and continue to stress their correct application, it seems that they are not followed correctly.
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Acknowledgements The study was supported by an unrestricted grant from Sanofi-Aventis, Milan, Italy. The authors thank E. Sarli of Centro Consulenze, Firenze, Italy for his technical and statistical support.
Appendix A. Members of the ProInf-AISP Study Group
Investigator
Centre
City
S. Agugiaro, L. Turri A. Bartoli, F. Barberini, G. Cavazoni F. Bartolo, D. Della Papa C. Bassi N. Bassi, M. Massani A. Benedetti, G. Macarri, L. Piergallini G. Briani, L. Bartolasi L. Brugnano G.M. Buonanno, C. Esposito A. Cardovana E. Cavina, M. Seccia, P. Lipollis, B. Musco, M. Barletta E. Chilovi, A. De Guelmi P. Chirletti, R. Caronna, S. Scozzafava, M. Cardi E. Cirino, A. Buffone E. Colangelo, V. Caracino F. Cortese A. Cosentini G. Costamagna, A. Tringali M. Curzio, S. Clivio, S. Segato A. D’Alessandro, V. Ambrosini B. D’Amborsio, C. Chiodo M. Dicillo, L. Reale, A. Grandolfo P. Fabbrucci, A. Bruscino, P. Mugnaini S. Ferrarese, I. Ugenti G.B. Forte, P. Rocco A. Franz`e, A. Bertel`e, G. Sereni D. Friedman, L.M. Mariani, F. Murelli V. Gai, C. Antro D. Garcea, A. Gardini, E. Lucci P.C. Giulianotti, F. Sbrana, T. Balestracci S.M. Giulini, A. Pellizzari, M. Ronconi, S. Cimaschi M. Grassini S. Lacitignola, L. Caliandro R. Mazzitelli, S.M. Costarella, A. Egidio P. Mello Teggia, E. Stefano, P. Cassini G. Modica, F. Lupo, G. Giraci F. Mosca, M. Del Chiaro G. Mosella, G. Benassai M. Nanni, A. D’Aristotile P. Negro A. Pirazzoli P.G. Rabitti C. Romano, G. Gerardi, B. Troianello D. Russello, A. Di Stefano, S. Avelli M. Salvai, N. Bellini P. Scalon C. Staudacher, D. Parolini M. Strazzabosco, S. Signorelli U. Tedeschi P.A. Testoni, E. Masci, A. Mariani E. Torelli, M.R. Garcea, V. Lombardi, L. Cecconi A. Valeri, L. Presenti, F. Alessio M. Ventrucci, S. Virz`ı, A. Cipolla
Ospedale S. Chiara Policlinico Monte Luce Ospedale S. Luca Policlinico G. B. Rossi Ospedale Regionale C`a Foncello Ospedale Torrette Ospedale Schio Ospedale Civile Azienda Ospedaliera Moscati Ospedale Fatebenefratelli Ospedale S. Chiara Ospedale Generale Regionale Ospedale Policlinico Umberto I Ospedale Vittorio Emanuele Il Ospedale Civile Ospedale S. Filippo Neri Ospedale Civile Policlinico A. Gemelli Ospedale di Circolo Ospedale S. Bortolo Az. Ospedaliera Ospedale S. Paolo Ospedale S. Maria Annunziata Policlinico Consorziale Ospedale Civile Ospedale Riuniti di Parma Ospedale San Martino Azienda Ospedaliera San Giovanni Battista Ospedale G.B. Morgagni Ospedale della Misericordia Ospedale Policlinico Presidi Ospedalieri Ospedale Civile Ospedali Riuniti Ospedale San Luigi Gonzaga Policlinico P. Giaccone Ospedale Cisanello Policlinico Universitario Federico Il Ospedale di Pescara Ospedale Policlinico Umberto I Ospedale dagli Infermi Azienda Ospedaliera Cardarelli Ospedale Ascalesi Ospedale Cannizzaro Ospedale Generala Regionale Ospedale Bassano del Grappa Ospedale San Raffaele Ospedale Riuniti Ospedale San Martino Ospedale San Raffaele Ospedale Del Ceppo Azienda Ospedaliera Careggi Ospedale di Bentivoglio
Trento Perugia Vallo Della Lucania Verona Treviso Ancona Schio Locri Avellino Milano Pisa Bolzano Roma Catania Pescara Roma Catanzaro Roma Varese Vicenza Cosenza Bari Firenza Bari Caserta Parma Genova Torino Forl`ı Grosseto Brescia Asti Martina Franca Reggio Calabria Orbassano Palermo Pisa Napoli Pescara Roma Rimini Napoli Napoli Catania Aosta Bassano dal Grappa Milano Bergamo Belluno Milano Pistoia Firenze Bentivoglio
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Conflict of interest statement None declared. [19]
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Liver, Pancreas and Biliary Tract
A prospective multicentre survey on the treatment of acute pancreatitis in Italy R. Pezzilli a,∗ , G. Uomo b , A. Gabbrielli c , A. Zerbi d , L. Frulloni e , P. De Rai f , L. Castoldi f , G. Cavallini e , V. Di Carlo d , the members of the ProInf-AISP Study Group1 a
f
Department of Internal Medicine and Gastroenterology, S. Orsola-Malpighi Hospital, Bologna, Italy b Department of Internal Medicine, Ospedale A. Cardarelli, Naples, Italy c Digestive Endoscopy, Campus Biomedico, Rome, Italy d Department of Surgery, University Vita e Salute, IRCCS S. Raffaele, Milan, Italy e Department of Surgical and Gastroenterological Sciences, University of Verona, Verona, Italy Department of Emergency Surgery, Fondazione IRCCS Maggiore, Mangiagalli and Regina Elena Hospital, Milan, Italy Received 5 March 2007; accepted 14 May 2007 Available online 29 June 2007
Abstract Background. The Italian Association for the Study of the Pancreas released a diagnostic and therapeutic algorithm for acute pancreatitis in 1999. Aim. This study focused on the analysis of the therapeutic approach for the treatment of acute pancreatitis in Italy. Patients. One thousand, one hundred and seventy-three patients were recruited: 1006 patients (85.8%) had mild acute pancreatitis (MAP) and 167 (14.2%) had the severe acute pancreatitis (SAP); 161 patients showed pancreatic necrosis at computed tomography; 121 patients (10.3%) had sequelae and 36 (3.1%) died. Results. Non-steroidal anti-inflammatory drugs and tramadol were used more frequently in patients with the MAP whereas opioids and the association schedules were used more frequently in patients with the SAP (P < 0.001). Gabexate mesilate was utilised in 831 out of 1173 patients (70.8%); in particular, gabexate mesilate was used in 70.6% patients with MAP and in 73.1% of those with SAP (P = 0.521). The duration of the drug administration was significantly shorter in those having MAP than in those having the SAP (P < 0.001). The antibiotics most frequently used for the prophylaxis against infection from pancreatic necrosis (43.1%) were carbapenems. Only a small number of patients received enteral nutrition (4.7%). Endoscopic retrograde cholangiopancreatography was carried out in 344 of the 1173 patients (29.3%). Surgery was performed in 48 with SAP (19 had elective biliary surgery and 29 had pancreatic surgery). Conclusions. The results of this survey indicate a lack of compliance with the guidelines which regard the indications mainly for interventional endoscopy and surgery. © 2007 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: ERCP; Pancreatitis; Pancreatitis acute necrotising
1. Introduction ∗
Corresponding author at: Department of Digestive Diseases and Internal Medicine, Sant’Orsola-Malpighi Hospital, Via Massarenti, 9, 40138 Bologna, Italy. Tel.: +39 051 6364148; fax: +39 051 6364148. E-mail address: [email protected] (R. Pezzilli). 1 See Appendix A for the list of members.
Acute pancreatitis may range from mild self-limiting forms to the more severe forms which are affected by high morbidity and mortality [1]. Therefore, the range of applicability of therapeutic protocols differs according to the severity of the pancreatitis. In order to implement cost-effective,
1590-8658/$30 © 2007 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2007.05.014
R. Pezzilli et al. / Digestive and Liver Disease 39 (2007) 838–846
widely applicable therapeutic guidelines, it is necessary to acquire adequate knowledge of the national epidemiological and clinical data. The first Italian prospective multicentre evaluation of the epidemiological and clinical status of acute pancreatitis in Italy [2] enrolled 1005 patients between September 1996 and June 2000, mainly with the mild form (753 patients (74.9%) had the mild form and 252 (25.1%) had the severe form). The aetiology was biliary in the majority of cases (60%); more than 80% of the patients were admitted to hospital within 24 h from the onset of clinical symptoms while only 6% were admitted after 48 h. The mean duration of hospitalisation for patients with mild pancreatitis was 13 ± 8 days while, for the severe form, it was 30 ± 14 days and the overall mortality rate was 5% (17.0% in severe and 1.5% in mild pancreatitis). During the enrolment of patients in this study, the Italian Association for the Study of the Pancreas released a diagnostic and therapeutic algorithm [3]. Furthermore, in the Italian survey of 1005 patients, no extensive data concerning conservative treatment were available. Thus, in January 2000, a new multicentre study was planned which was aimed at a thorough analysis of the diagnostic assessment and therapeutic methods, and involving a more extensive network of Italian centres. In this paper, we report the final results of the survey as regard the therapeutic features of acute pancreatitis in Italy.
2. Methods The present study involved 56 Italian centres, equally distributed throughout Italy. Ad hoc software including 530 items designed by the scientific committee of the study was furnished to each participating centre. All cases of acute pancreatitis consecutively observed during the period from December 2001 to November 2003 were included in the study. The diagnosis of acute pancreatitis was based on clinical (onset of pancreatic type pain), biochemical (a threefold increase of amylase and/or lipase) and radiological (ultrasonography, computer tomography scan, magnetic resonance) findings. The disease was classified according to Atlanta criteria [1] into mild and severe forms. Sequelae of acute pancreatitis were defined as the presence of pseudocysts, fluid collections and fistulae. Data were collected and tabulated centrally; during the period of the study, a careful monitoring process was carried out. At the end of the study, additional quality control regarding the completeness and congruence of each single chart was carried out in order to exclude cases with incomplete and/or inconsistent charts. The endpoint of the study was to evaluate the treatment (conservative, nutritional, endoscopic and surgical) of acute pancreatitis in Italy. Data were presented as mean ± standard deviation (S.D.) and frequencies. Statistical analysis was carried out using the Student’s t-test, the chi-squared test and the Fisher’s exact
839
test. Data ran on SPSS version 10. Significant difference was considered to be a P value of less than 0.05.
3. Results One thousand, five hundred and forty case report forms of patients affected by acute pancreatitis were collected; 367 of them (23.8%) were subsequently withdrawn from the final analysis because of the incompleteness and/or inconsistency of the charts. Therefore, 1173 patients (581 females and 592 males) were analysed. A mean of 21 patients for each centre (range 2–28) was enrolled. The mean age of the patients was 62.0 ± 18.2 years. Biliary forms represented the most frequent aetiological category (813 cases, 69.3%) while alcoholic forms occurred in only 77 cases (6.6%); all together the remaining aetiologies (post-surgery, post-endoscopic cholangiopancreatography, traumatic, hyperlipemic, drug-induced and pancreas divisum) accounted for 7.1% (83 cases). Two hundred cases (17.1%) remained without a definite aetiological factor (idiopathic forms). One thousand and sixteen patients (86.6%) had complete clinical, laboratory and morphological resolution of the disease, 121 patients (10.3%) had sequelae, and 36 patients (3.1%) died. Thirteen patients died from infected necrosis associated with multi-organ failure, 12 from infected necrosis associated with sepsis-like syndrome, 3 from heart failure or arrhythmias, 2 patients died from acute respiratory distress syndrome, 2 from gastrointestinal haemorrhage, 1 from aortic aneurism rupture, 2 from multi-organ failure and 1 from pulmonary embolism. At computed tomography, pancreatic necrosis was found in 161 patients. On the basis of the Atlanta classification system for acute pancreatitis [1], 1006 patients (85.8%) were defined as having mild pancreatitis and 167 (14.2%) as having the severe form. The mean interval between the onset of pain and hospital admission was not statistically significant (P = 0.374) between patients with mild (14.9 ± 37.2 h) and those with severe pancreatitis (17.8 ± 39.1 h). 3.1. Conservative treatment Data on fluids administered during the first three days were available for 1008 of the 1173 patients (85.9%): 141 patients with severe (14.0%) and 867 patients with mild pancreatitis (86.0%). As shown in Fig. 1, the amount of fluids administered was significantly higher (P < 0.001) in patients with severe acute pancreatitis than in those with the mild form. Data on analgesic administration were available in 840 of the 1173 patients (71.6%) (Table 1). Non-steroidal antiinflammatory drugs (NSAIDs) were administered in 459 patients (54.6%), tramadol in 216 (25.7%), opioids in 32 (3.8%) and a combination of the various drugs in the remaining 133 (13.8%) patients. There was a significant difference in the type of analgesics administered between patients with
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R. Pezzilli et al. / Digestive and Liver Disease 39 (2007) 838–846
Fig. 1. Fluids administered during the first three days of acute pancreatitis in patients with mild acute pancreatitis and in those with severe acute pancreatitis. AP: acute pancreatitis.
mild and those with severe disease (P < 0.001); NSAIDs and tramadol were used more frequently in patients with mild disease whereas opioids and the association schedules were used more frequently in patients with severe disease. The duration of analgesic treatment was significantly longer in patients with severe acute pancreatitis in comparison to those suffering from the mild form; NSAIDs: 3.0 ± 2.3 days in patients with mild acute pancreatitis and 6.7 ± 10.1 days in patients with severe acute pancreatitis (P < 0.001); tramadol: 3.2 ± 2.3 days in patients with mild acute pancreatitis and 8.0 ± 11.7 days in patients with severe acute pancreatitis (P < 0.001). Histamine H2 antagonists were used in 489 patients (427 patients with mild acute pancreatitis, 87.3%; 62 patients with severe acute pancreatitis, 12.7%), proton pump inhibitors in 606 patients (505 patients with mild acute pancreatitis, 83.3%; 101 patients with severe acute pancreatitis, 16.7%) and a simultaneous association of these two drugs in 62 patients (50 patients with mild acute pancreatitis, 80.6%; 12 patients with severe acute pancreatitis, 19.4%). The duration of treatment with drugs inhibiting gastric acid secretion was significantly longer in severe acute pancreatitis patients than in those with the mild form of the disease (9.6 ± 6.5 days in patients with mild acute pancreatitis and 25.3 ± 23.8 days in patients with severe acute pancreatitis; P < 0.001). Gabexate mesilate was utilised in 831 out of the 1173 patients (70.8%). In 709 of 1004 (70.6%) patients with
mild acute pancreatitis and in 122 of the 167 patients with severe acute pancreatitis (73.1%) (P = 0.521). Gabexate was utilised at a similar dosage in the two forms of acute pancreatitis (1112 ± 434 mg in mild acute pancreatitis and 1148 ± 387 mg in severe acute pancreatitis) (P = 0.391). However, the duration of drug administration was significantly shorter in mild acute pancreatitis than in patients with the severe form (4.7 ± 3.3 days versus 9.2 ± 7.8 days; P < 0.001). Octreotide was utilised subcutaneously three times a day in 175 of the 1173 patients (14.9%). It was utilised in 134 of the 1004 (13.3%) patients with mild acute pancreatitis and in 41 of the 167 patients with severe acute pancreatitis (24.6%) (P < 0.001) at a similar dosage in both forms of pancreatitis (0.5 ± 0.7 g per day in the mild acute form and 0.5 ± 0.3 g per day in the severe form; P = 0.823). Octreotide was administered for a longer period of time in severe acute pancreatitis patients than in those with the mild acute form (13.6 ± 15.6 days in patients with severe acute pancreatitis versus 5.2 ± 3.6 days in patients with the mild acute form; P < 0.001). Somatostatin was used i.v. in 136 patients with acute pancreatitis (116 with mild acute pancreatitis (85.3%) and 20 with severe acute pancreatitis, 14.7%; P = 0.346) at a similar dosage in both forms of pancreatitis (5.6 ± 1.2 mg per day in patients with mild acute pancreatitis and 5.6 ± 1.1 mg per day in patients with the severe form; P = 0.898). Somatostatin treatment duration was significantly longer in severe acute pancreatitis patients than in those with mild acute pancreatitis (13.0 ± 15.7 days in patients with severe acute pancreatitis versus 4.8 ± 3.5 days in patients with the mild acute pancreatitis; P = 0.003). Antibiotics were used for the treatment of extrapancreatic infections and for the treatment of proven infection of pancreatic necrosis as well as for the prophylaxis against infection from pancreatic necrosis. Regarding the extrapancreatic infections, the antibiotics used are reported in Table 2; cephalosporin was the antibiotic principally used for these infections, followed by carbapenemens. Carbapenemens, glycopeptides and antifungal antibiotics were the antibiotics most frequently used in the treatment of proven infected pancreatic necrosis (Table 3). As is
Table 1 Type and frequency of analgesics administered to patients with mild acute pancreatitis and to those with severe acute pancreatitis Mild acute pancreatitis
Severe acute pancreatitis
No. patients
Frequency (%)
No. patients
Frequency (%)
NSAIDs Tramadol Opioids NSAIDs + tramadol NSAIDs + opioids Tramadolo + opioids NSAIDs + tramadol + opioids
412 183 16 63 14 5 7
89.8 84.7 50.0 75.9 63.6 38.5 46.7
47 33 16 20 8 8 8
10.2 15.3 50.0 24.1 36.4 61.5 53.3
Overall
700
83.3
140
16.7
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Table 2 Type and frequency of antibiotics administered for extrapancreatic infection in mild and severe acute pancreatitis Mild acute pancreatitis
Cephalosporins Beta-lactam antibiotics, penicillins Carbapenems Aminoglycosides Quinolones Glycopeptide antibiotics Fluconazole Antifungal antibiotics Sulfonamides Others
Severe acute pancreatitis
No. cases
Frequency (%)
No. cases
Frequency (%)
32 20 18 5 5 4 2 1 0 1
36.4 22.7 20.5 5.7 5.7 4.5 2.3 1.1 0.0 1.1
11 9 12 3 10 8 4 7 1 1
16.7 13.6 18.2 4.5 15.2 12.1 6.1 10.6 1.5 1.5
also shown in Table 3, carbapenems were the antibiotics most frequently used for the prophylaxis against infection from pancreatic necrosis (128 patients, 43.1%) followed by cephalosporin (78 patients, 25.3%) and by beta-lactam antibiotics (43 patients, 14.5%). 3.2. Nutritional support Nutritional support was used in 403 patients: 269/1006 (26.7%) with mild acute pancreatitis and 134/167 (80.2%) with severe acute pancreatitis. Three hundred and fifty-eight patients received parenteral nutritional support (88.8%): 250 (69.8%) with the mild acute form and 108 (30.2%) with the severe acute form) whereas only 19 of the 403 patients (4.7%) received enteral nutrition: 10 with the mild form and 9 with the severe form. Twenty-six patients (9 with the mild and 17 with the severe form of the disease) received both enteral and parenteral nutrition. The length of parenteral nutrition was significantly longer (P < 0.001) in severe acute pancreatitis patients than in those with the mild acute form (15.9 ± 14.3 days for patients with severe acute pancreatitis versus 6.0 ± 4.1 days for patients with mild acute form). In the same way, the length of enteral nutrition was significantly longer (P < 0.001) in patients with severe acute pancreatitis (22.0 ± 21.2 days) with respect to those having the mild form of the disease (6.9 ± 5.4 days).
3.3. Endoscopic treatment Endoscopic retrograde cholangiopancreatography (ERCP) was carried out in 344 of the 1173 patients (29.3%). The mean interval between the onset of symptoms and ERCP was 6.7 ± 5.0 days and the mean interval between hospital admission and ERCP execution was 5.7 ± 5.0 days. Eighty-nine examinations (25.9%) were performed within 72 h from the onset of symptoms while, for the remaining patients, the procedure was performed within 72 h after hospital admission. Three hundred and twenty (93.0%) patients had biliary pancreatitis: 288 (90.0%) of them had mild acute pancreatitis and 32 (10.0%), had the severe form (P = 0.303) The reasons for carrying out ERCP in patients with biliary pancreatitis (more than one indication may be present in the same patient) were as follows: common bile duct stones in 289 patients (89.4%), jaundice in 153 (47.8%), clinical worsening of acute pancreatitis in 45 (14.1%) and cholangitis in 21 (6.6%). In the remaining 24 patients (4 with severe disease) the indications for the procedure were suspicion of common bile duct stones in 17 patients, deterioration of the disease in 4, disruption of the main pancreatic duct in 2 and suspicion of malignancy in 1. Common bile duct visualization was obtained in 305 patients (88.7%), and 295 patients underwent biliary sphinc-
Table 3 Type and frequency of antibiotics used for the treatment of proven pancreatic necrosis infection and for prophylaxis in preventing infection of pancreatic necrosis
Carbapenems Glycopeptide antibiotics Antifungal antibiotics Aminoglycosides Beta-lactam antibiotics, penicillins Cephalosporins Fluconazole Quinolones Others
Proven pancreatic necrosis infection (No. 56)
Prophylaxis against infection of pancreatic necrosis (No. 297)
No. cases
No. cases
16 11 7 4 3 3 3 2 2
Frequency (%) 31.4 21.6 13.7 7.8 5.9 5.9 5.9 3.9 3.9
More than one antibiotic was utilised on the same patient.
128 7 4 8 43 78 13 14 2
Frequency (%) 43.1 2.4 1.3 2.7 14.5 26.3 4.4 4.7 0.7
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terotomy (295/305, 96.7%). A standard sphincterotomy was performed in 242 of the 295 patients (82.0%) whereas precut sphincterotomy was performed in 53 patients (18.0%). Stones were found in 159 patients (53.9%) and in stones together with sludge in 154 patients (52.2%) of the 295 patients, respectively. The morbidity of the endoscopic procedure was 6.1% (11/344): nine bleeds, one retroperitoneal perforation and one acute cholecystitis. All these complications were treated conservatively. Mortality in the patients who underwent operative endoscopy was 1.7% (6 out of 344), and all the patients who died had severe pancreatitis. 3.4. Surgical treatment Of the 1173 patients observed in the study, 277 (23.7%) underwent surgery: 229 had mild pancreatitis and 48 had severe pancreatitis (19 had elective biliary surgery and 29 had pancreatic surgery). 3.4.1. Elective biliary surgery Of all the patients with mild acute biliary pancreatitis, 88 had previously been cholecystectomised. The gallbladder was reported as abnormal (due to lithiasis or inflammation) in 593 patients and it was removed in 212 of them (29.6%) (in 76% cases using a laparoscopic approach); in 80 out of 212 cases (71.5%), a pre-operative ERCP was associated. Seventeen patients underwent other surgical procedures for the treatment of biliary lithiasis (mainly, common bile duct exploration with stone removal and bilio-enteric anastomosis). The mean length of the hospital stay for patients undergoing cholecystectomy was 15 days (13.0 ± 6.3 days, range 3–44, for patients having the laparoscopic approach and 17.9 ± 8.8 days, range 6–50 days, for the remaining patients). In patients undergoing ERCP and surgery during the first admission (N = 66), the first was performed within 5.7 ± 5.3 days (range 0–36 days) and the latter within 10.4 ± 5.8 (range 2–36 days) respectively. In all but two patients (discharged with fluid collections) the course was uneventful. Cholecystectomy was performed in 165 (78%) cases during the same hospital observation for pancreatitis (15.4 ± 7.46 days on average after the onset of pancreatitis) and in the remaining 47 patients during a second admission (38.5 ± 42.7 days, range 10–260 days) after pancreatitis onset. Among the patients with severe biliary pancreatitis, 19 underwent elective cholecystectomy an average of 40 days after the onset of pancreatitis; in 47% of the cases this procedure was performed during second hospitalisation; no patient was hospitalised more than two times. there were two mortalities and 11 cases of long-term sequelae were observed (6 fluid collections, 4 pseudocysts, 1 fistula). 3.4.2. Pancreatic surgery In 29 cases of severe pancreatitis, pancreatic surgery was performed. Indications for surgery were: acute abdomen in
16 cases (55.1%: acute abdomen alone in 9 cases, combined with other indications in 7 cases), MOF in 10 cases (34.5%: MOF alone in 2 cases, combined with other indications in 8 cases), infected necrosis in 8 cases (27.6%: infected necrosis alone in 6 cases, combined with other indications in 2 cases) and sterile necrosis in 3 cases (10.3%: sterile necrosis alone in 2 cases, combined with other indications in 1 case). Surgery was performed 12.3 days on average after the onset of pancreatitis (range 0–64 days): in 19 cases (65.5%) before the 5th day, in 3 cases (10.3%) between the 6th and the 14th day and in 7 cases (24.1%) after the 14th day. In 26 cases (89%), a necrosectomy was carried out and, in the remaining 3 cases, simple drainage was carried out; in only 1 case was a laparostomy performed. Necrosectomy was associated with postoperative continuous lavage in 21 cases (72.4%). A feeding jejunostomy was added in only 11 cases (37.9%). In 14 cases (48%), postoperative complications occurred: 6 infections, 6 MOF, 4 pancreatic fistulas, 1 haemorrhage, 1 occlusion, 1 pseudocyst and 1 colic fistula. Mortality was 20.7% (6 cases) and 11 patients (37.9%) were discharged with sequelae (6 fluid collections, 4 pseudocysts, 4 fistulas).
4. Discussion In recent years, several therapeutic guidelines on acute pancreatitis have been released [4]. However, very few studies have been published which evaluate whether the suggestions of these guidelines have been extensively followed in clinical practise [5–9], and all of these papers showed a lack of compliance in following the guidelines. In 1999, the Italian Association for the Study of the Pancreas released a diagnostic and therapeutic algorithm on the diagnosis and treatment of acute pancreatitis [3]. Thus, in January 2000, a new multicentre study was planned which was aimed at a thorough analysis of the therapeutic methods, involving many Italian centres. The final results of the study concerning the therapeutic features of acute pancreatitis in Italy are reported in this paper. Many of the findings observed in the first ProInfAISP Study I [2] were confirmed, namely, the preponderance of mild pancreatitis (85.8%), the high percentage of biliary forms (69.3%) and the low rate of mortality (3.1%). The overall hospital stay was similar to that of our previous experience [2] and was similar to those reported in other countries [10,11]. Taking into consideration the basic treatment of acute pancreatitis, the present study demonstrates that patients with severe acute pancreatitis received a significantly higher amount of fluids than those with mild acute pancreatitis and that analgesics were also graded according to the severity of the pain. In fact, patients with mild acute pancreatitis received mainly NSAIDs and tramadol whereas patients with severe pancreatitis received a high percentage of opioids or an association of analgesics comprising NSAIDs, tramadol and opioids. There are no extensive studies on the pharma-
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cological control of pain in acute pancreatitis [12–15]; this is quite surprising due to the importance of this symptom. There is a lack of evidence about the different efficacy of various pharmacological substances in the different forms of acute pancreatitis, so studies comparing different schedules of pain-relieving drugs in patients with acute pancreatitis and utilising objective methods to evaluate pain decrease are welcome. Another open question in the treatment of acute pancreatitis is the efficacy of inhibiting gastric acid secretion; there are very few studies on this issue and the results are not conclusive [16,17]. However, in our observational study, gastric acid secretion inhibition is largely used in patients with acute pancreatitis and the finding that the duration of treatment with drugs inhibiting gastric acid secretion was significantly higher in patients with severe acute pancreatitis than in patients with the mild form is due to the fact that the hospital stay of patients which severe pancreatitis is significantly longer than that of those having the mild disease. One of the intriguing issues in acute pancreatitis is that of specific treatment for acute pancreatitis by using drugs such as those capable of reducing pancreatic secretion and those having antiprotease activity. Octreotide and somatostatin were prescribed by our clinician in only about 15% of patients. Why these drugs were administered is quite surprising because none of the available guidelines suggest their use in the early phases of acute pancreatitis. Regarding antiprotease therapy, it should be mentioned that among the various published guidelines only the Italian and Japanese ones recommend its use in acute pancreatitis [3,18]. In our present survey, gabexate mesilate was utilised in 70.8% of acute pancreatitis patients. Gabexate was utilised at a similar dosage in both forms of acute pancreatitis (mild and severe). However, the duration of drug administration was significantly shorter in patients having mild acute pancreatitis than in those with the severe form. This may be due to the fact that, in the Italian algorithm for treating acute pancreatitis it has been suggested that all patients with acute pancreatitis should be considered as having the severe form until prognostic assessment is made, thus gabexate mesilate is used in mild pancreatitis during the time necessary to obtain a precise diagnosis [3]. Furthermore, a new meta-analysis has recently been published on the use of antiproteases in acute pancreatitis showing that treatment with protease inhibitors does not significantly reduce mortality in patients with mild pancreatitis, but the drug may reduce mortality in patients with moderate to severe pancreatitis [19]. Two of the other open questions on the use of antiproteases in severe acute pancreatitis are treatment duration and the optimal dosage of the drug. In the present study, gabexate mesilate administration has a mean of 9.2 ± 7.8 days and this administration period is slightly higher than that usually suggested (7 days) [20,21]. Patients with severe pancreatitis received a mean of 1148 ± 387 mg per day of gabexate mesilate; this figure is higher than that suggested in a study in which a dosage
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of 900 mg/day of gabexate mesilate was demonstrated to be equally as effective as a dosage of 1500 mg/day [21]. Antibiotics have been used to cure both extrapancreatic infections which appeared during the course of acute pancreatitis and infected pancreatic necrosis and also as a prophylaxis in those patients who had pancreatic necrosis for the prevention of possible infection from the necrosis. In the treatment of extrapancreatic infections, the most used antibiotics were cephalosporins whereas carbapenemens, glycopeptides and antifungal antiobiotics were the most used antibiotics in the treatment of proven infected pancreatic necrosis. According to most of the guidelines published [1,3,18,22–27] and on the basis of the results of systematic reviews of randomised studies [28,29], carbapenems were also the antibiotics most frequently used in Italy for the prophylaxis against infection from pancreatic necrosis (43.1%), even if our clinicians use cephalosporins in 25.3% of the patients and beta-lactam antibiotics in 14.5% of the patients. Enteral feeding has been proven to decrease the inflammatory response and sepsis in severe acute pancreatitis patients [30,31]. However, in our country, enteral nutrition is used in a very low percentage of severe acute pancreatitis patients while parenteral nutrition is the preferred nutritional support. Three hundred and forty-four patients underwent ERCP; only 26% of the examinations were performed within 72 h from the onset of symptoms and this represents a clear deviation from the largely accepted guidelines [3,22]. Another lack of adherence to the international and national guidelines is that endoscopic sphincterotomy was performed in 90.0% of the patients with mild acute pancreatitis [3,22]. From a practical point of view, common bile duct visualization was obtained in about 90% of patients and biliary sphincterotomy was possible in 96.7% of the patients. The morbidity of the endoscopic procedure was 6.1% and all the complications were treated conservatively. Finally, the mortality rate in patients who underwent operative endoscopy was less than 2%. The role of cholecystectomy in mild biliary acute pancreatitis is aimed at preventing relapses [23,27,32,33]. In our series, only 29.6% of patients with biliary pancreatitis and in situ gallbladder underwent cholecystectomy. To partially explain this discrepancy from the international guidelines, it should be noted that some patients were initially observed in Medical Departments and then discharged. Some of them could have been operated on during subsequent hospitalisations and this data could have been missed. In any case, the rate of patients who did not undergo surgery remains too high. When cholecystectomy was performed, a laparoscopic approach was successfully accomplished in 76% of the patients with mild pancreatitis; this demonstrates that the recent pancreatitis did not modify the anatomy and allowed this mini invasive approach. In 39% of cases, an ERCP was performed before cholecystectomy; endoscopic treatment did not prolong the hospital stay, except for the small group of patients undergoing laparotomic cholecystectomy. A com-
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bined approach (ERCP plus laparoscopic cholecystectomy) seems to be the most logical and it was proven to be suitable in mild pancreatitis. The delay of 4 days between endoscopy and surgery appears to be slightly too long; it possibly reflects some challenges in planning surgical procedures and in transferring patients from medical to surgical departments. From our data, in 22% of cases, a cholecystectomy was performed during a second hospital admission, 38 days on average after the onset of pancreatitis. This finding, together with the high rate of non-operated patients, represents the main discrepancy between our series and the international guidelines on acute pancreatitis. However, in a recent report from the United Kingdom, non-compliance with the national guidelines was also reported, with only 30% of patients who had biliary acute pancreatitis undergoing surgery [5,33]. Among patients with severe biliary pancreatitis, cholecystectomy was delayed 40 days on the average and it was performed in about half of the cases during a second admission. In our opinion, this attitude is correct, because it is necessary to wait for the evolution of necrotic pancreatic areas. In this group of patients, the rate of change was the same as that obtained in patients with severe pancreatitis but without cholecystectomy. This procedure does not seem to affect the course of severe pancreatitis. In our series, 29 patients underwent pancreatic surgery for severe pancreatitis and it is difficult to draw firm conclusions from this small number of patients. We were surprised by the indications for surgery (acute abdomen in more than half of the cases) and by the timing of the surgery, since 34% of the patients underwent surgery on the same day they were admitted to hospital and 65% in the first 5 days after the onset of the pancreatitis. These data are difficult to understand. A very early surgical procedure is actually indicated only in the small group of patients with acute multiorgan failure not responding to intensive treatment. Necrosectomy is usually performed later, 2–3 weeks after the onset of the pancreatitis when infection from necrosis eventually occurs and when necrotic tissue is easily removed. Possibly, in our series, diagnostic uncertainties and mistakes are related, for the most part, to cases of early surgical intervention. In any case, the morbidity and mortality rates observed in patients with severe acute pancreatitis are similar to those usually reported in the literature [4] and in a previous Italian study [34]. We should, therefore, take into account some important points; only 29 patients of the 161 with necrotising pancreatitis were operated on and most of the necrotising pancreatitis patients were treated conservatively. It is possible that early and intensive medical treatment may have some beneficial influence on these results [35]. Furthermore, it is also possible that the so-called specific treatment with antiproteases may have been efficacious when carried out in the “therapeutic window” acting effectively on the early pathogenetic mechanisms of acute pancreatitis. Finally, appropriate antibiotic treatment may explain the low number of patients who required surgical treatment for the infection of pancreatic necrosis.
5. Conclusion Although compliance with the guidelines on investigation for severity stratification of acute pancreatitis was adequate, the results of this survey indicate a lack of compliance with the guidelines regarding the indications for interventional endoscopy and surgery. We believe that further efforts should be made by the scientific societies in releasing updated guidelines and their correct application should thus be stressed.
Practice points • The type of drugs capable of reducing abdominal pain were used correctly, i.e. NSAIDs or tramadol in patients with mild acute pancreatitis and opioids in patients with severe pancreatitis. • According to the Italian guidelines regarding the severity of the disease as well as the dosage (about 900 mg/day), antiproteases were used correctly. • The use of antibiotics in preventing infection in patients with necrotising pancreatitis should be modified (carbapenems were used in only fewer than 50% of the patients). • The use of enteral nutritional support should be increased in severe acute pancreatitis patients. • Stricter criteria should be used when deciding to perform ERCP in patients with acute pancreatitis. • More attention should be paid to performing a cholecystectomy in mild biliary pancreatitis in the same hospitalization period.
Research agenda • Although there was adequate compliance with the guidelines regarding the severity stratification of acute pancreatitis, the results of this survey indicate a lack of compliance with the guidelines regarding the indications for interventional endoscopy and surgery. • Even if scientific societies have endeavoured to emphasise guidelines and continue to stress their correct application, it seems that they are not followed correctly.
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Acknowledgements The study was supported by an unrestricted grant from Sanofi-Aventis, Milan, Italy. The authors thank E. Sarli of Centro Consulenze, Firenze, Italy for his technical and statistical support.
Appendix A. Members of the ProInf-AISP Study Group
Investigator
Centre
City
S. Agugiaro, L. Turri A. Bartoli, F. Barberini, G. Cavazoni F. Bartolo, D. Della Papa C. Bassi N. Bassi, M. Massani A. Benedetti, G. Macarri, L. Piergallini G. Briani, L. Bartolasi L. Brugnano G.M. Buonanno, C. Esposito A. Cardovana E. Cavina, M. Seccia, P. Lipollis, B. Musco, M. Barletta E. Chilovi, A. De Guelmi P. Chirletti, R. Caronna, S. Scozzafava, M. Cardi E. Cirino, A. Buffone E. Colangelo, V. Caracino F. Cortese A. Cosentini G. Costamagna, A. Tringali M. Curzio, S. Clivio, S. Segato A. D’Alessandro, V. Ambrosini B. D’Amborsio, C. Chiodo M. Dicillo, L. Reale, A. Grandolfo P. Fabbrucci, A. Bruscino, P. Mugnaini S. Ferrarese, I. Ugenti G.B. Forte, P. Rocco A. Franz`e, A. Bertel`e, G. Sereni D. Friedman, L.M. Mariani, F. Murelli V. Gai, C. Antro D. Garcea, A. Gardini, E. Lucci P.C. Giulianotti, F. Sbrana, T. Balestracci S.M. Giulini, A. Pellizzari, M. Ronconi, S. Cimaschi M. Grassini S. Lacitignola, L. Caliandro R. Mazzitelli, S.M. Costarella, A. Egidio P. Mello Teggia, E. Stefano, P. Cassini G. Modica, F. Lupo, G. Giraci F. Mosca, M. Del Chiaro G. Mosella, G. Benassai M. Nanni, A. D’Aristotile P. Negro A. Pirazzoli P.G. Rabitti C. Romano, G. Gerardi, B. Troianello D. Russello, A. Di Stefano, S. Avelli M. Salvai, N. Bellini P. Scalon C. Staudacher, D. Parolini M. Strazzabosco, S. Signorelli U. Tedeschi P.A. Testoni, E. Masci, A. Mariani E. Torelli, M.R. Garcea, V. Lombardi, L. Cecconi A. Valeri, L. Presenti, F. Alessio M. Ventrucci, S. Virz`ı, A. Cipolla
Ospedale S. Chiara Policlinico Monte Luce Ospedale S. Luca Policlinico G. B. Rossi Ospedale Regionale C`a Foncello Ospedale Torrette Ospedale Schio Ospedale Civile Azienda Ospedaliera Moscati Ospedale Fatebenefratelli Ospedale S. Chiara Ospedale Generale Regionale Ospedale Policlinico Umberto I Ospedale Vittorio Emanuele Il Ospedale Civile Ospedale S. Filippo Neri Ospedale Civile Policlinico A. Gemelli Ospedale di Circolo Ospedale S. Bortolo Az. Ospedaliera Ospedale S. Paolo Ospedale S. Maria Annunziata Policlinico Consorziale Ospedale Civile Ospedale Riuniti di Parma Ospedale San Martino Azienda Ospedaliera San Giovanni Battista Ospedale G.B. Morgagni Ospedale della Misericordia Ospedale Policlinico Presidi Ospedalieri Ospedale Civile Ospedali Riuniti Ospedale San Luigi Gonzaga Policlinico P. Giaccone Ospedale Cisanello Policlinico Universitario Federico Il Ospedale di Pescara Ospedale Policlinico Umberto I Ospedale dagli Infermi Azienda Ospedaliera Cardarelli Ospedale Ascalesi Ospedale Cannizzaro Ospedale Generala Regionale Ospedale Bassano del Grappa Ospedale San Raffaele Ospedale Riuniti Ospedale San Martino Ospedale San Raffaele Ospedale Del Ceppo Azienda Ospedaliera Careggi Ospedale di Bentivoglio
Trento Perugia Vallo Della Lucania Verona Treviso Ancona Schio Locri Avellino Milano Pisa Bolzano Roma Catania Pescara Roma Catanzaro Roma Varese Vicenza Cosenza Bari Firenza Bari Caserta Parma Genova Torino Forl`ı Grosseto Brescia Asti Martina Franca Reggio Calabria Orbassano Palermo Pisa Napoli Pescara Roma Rimini Napoli Napoli Catania Aosta Bassano dal Grappa Milano Bergamo Belluno Milano Pistoia Firenze Bentivoglio
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Conflict of interest statement None declared. [19]
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