Safety and efficacy of conservative management in acute severe pancreatitis

Introduction
Acute severe pancreatitis incidence observed in recent European studies varies between 20-70% cases per 100.000 populations, with mortality rate's range from 0.9 to 1.6/100.000 (1). Incidence is greater in women than in men, common age group being 40-60. 20-35% of patients with acute severe pancreatitis develop necrotizing pancreatitis. Mortality rate is about 2-20% and it varies with age being more frequently encountered in young (2). Most cases are secondary to gallstones or due to the alcohol abuse.
Acute severe pancreatitis is associated with one or more of the following features: more than one-third necrosis of pancreas, organ failure and local complications such as haemorrhage, abscess and pseudocyst. 10-15% of the patients with acute pancreatitis develop SIRS (systemic inflammatory immune syndrome), which leads to necrotic pancreatitis, MSOF (multiple systems organic failure) and death (3). Usually, half of deaths are occurring in within seven days after the pancreatitis onset.
The acute pancreatitis diagnosis is difficult to establish because of the local inflammatory process, which involves even the peripancreatic tissue. The abdominal X-ray (AXR), chest X-ray (CXR), Transabdominal Ultrasonography (AUS), pelvic and abdominal Computed Tomography (CT), Endoscopic Retrograde Cholangiopancreatography (ERCP), Magnetic Resonance Cholangiopancreatography (MRCP) and the Endoscopic Ultrasonography (EUS) represent imagistic investigations, useful in acute pancreatitis diagnosis (2, 3). The combination between serum amylase level, abdominal CT scan and transabdominal US established the diagnosis in 95% of the cases. There are different diagnosis scores for acute pancreatitis based on clinical criteria, radiology and laboratory findings. Laboratory parameters used in Ranson, Imrie and APACHE II scores represents indirect measurements for the massive inflammation and organic failure. Both Ranson and Imrie Criteria are simple to remember and helpful in surgical wards implying 48 hours to determine the severity of the acute pancreatitis (4) (Table 1).
Balthazar's prediction score for acute severe pancreatitis is based on CT-scan findings, a combination of peripancreatic inflammation and degree of pancreatic necrosis (4, 5). Atlanta Score determines the severity degree, making possible to establish a diagnosis methodology (5).
Balthazar and Ranson in 1985 developed a grading system for severity based on initial CT findings. The intravenous Contrast Enhanced Computed Tomography (CECT) has a sensitivity and positive predictive value close to 100% for detecting pancreatic necrosis between 4 and 10 days after the symptoms onset. Patients with score of 0 to 3 had 8% morbidity and 3% mortality, whereas those with a score of 7 to 10 had 92% morbidity and 17% mortality (5, 6). The surgical treatment is reserved to the acute pancreatitis local complications: pancreatic necrosis, infected pancreatic necrosis, pancreatic pseudocyst and abscess (6).
This study aims to asses opportunity of conservative treatment in acute severe pancreatitis.

Material and Methods
We performed a retrospective study (1998-2004) on 151 patients diagnosed with acute severe pancreatitis (Ranson ³ 3), assessing the efficacy of conservative versus surgical treatment for the patients outcome. The acute severe pancreatitis was defined according to the criteria described by the Atlanta International Symposium of Acute Pancreatitis (5). The group structure consists into 95 men and 56 females. The average group age was 59 + years old, maximum incidence being between 40-45 years old. Fourteen patients were admitted to the Intensive Care Unit (ICU) because of the severe clinical status. We determined for the group biological parameters significant for the suspected clinical diagnosis (serum amylase, glycaemia, plasmatic calcium, triglyceride, WCC-white count cells, ASAT, hematocrit and CRP-C reactive protein). In 2/3 of cases the serum amylase was four times the normal value and orientated the diagnosis. The imagistic assessment was made by transabdominal US and CT scan. The diagnosis was a combination of clinical, biochemical criteria and CT scan findings. The entire group study was tested under these criteria.
The conservative treatment was based on the initial assessment of the disease severity. The emergency conservative treatment was represented by fasting, gastrointestinal decompression, H2 receptor blocking agents, hydroelectrolitic support, symptomatic treatment, non-steroidian anti-inflammatory drugs, (NSAID), antibiotics and nutritional therapy. The importance of early initiation of antibiotics treatment is unclear. In our study, we used for the prophylaxis of necrosis infection imipenem 3g/day for 14 days for the entire study group. In several cases early surgery was required due to the patient's clinical status. Decompressive laparotomy was considered when a rapidly deterioration was present in the first day after admission.

Statistical Analysis
Statistical analysis was performed using SPSS for Windows 11.0.1 ® (SPSS, Chicago, IL, USA). Continuous variables were compared using the Mann Whitney U-test. Categorical data were compared using the Chi-square or Fisher Exact Test. Continuous data are expressed as mean (standard deviation) if the data were normally distributed or median (interquartile range) or if the distribution was not normal. Categorical data are reported as n (%). A p-value of less than 0.05 was considered statistically significant.

Results
We did an early assessment of the patient's status by history findings: alcohol abuse, billiary colic, medication, trauma, family history, autoimmune disease.
At admission time the patients were presenting sudden onset of epigastric pain that radiates to the back, which became severe and constant, vomiting (25%), high fever (10%), dehydration (25%) and epigastric tenderness (100%). After a while, tenderness and localized rigidity become generalized and the bowel sounds were becoming absent. Typical abdominal pain was present in 72% of patients; general status was altered in 42% of patients, local tenderness in 52% or diffuses in 27%. Cardio-vascular distress was present in 68% of cases, acute renal failure and jaundice being assessment signs that betrayed the poor prognosis from acute pancreatitis onset (Table 2 , Table 3 ). Biological elements specific for diagnosis were high WCC, high serum lipase and amylase and increased serum glucose.
Despite its unreliability for the positive diagnosis, the transabdominal US was helpful in confirming the suspicion of diagnosis. The US limitation is due to the fact that the gland was poorly visualised in 50% of cases because of the pancreas inflammatory state.
CECT has also been used to predict the severity of the acute pancreatitis. A follow-up made by serial CT scans also allowed us to determine when surgery was required (Table 4). The CT scan exam has its limitations; it cannot distinguish between sterile and infected necrosis and the controversy whether intravenous contrast can exacerbate the severity of acute pancreatitis.
The trend is towards delayed operation with the benefits of a better demarcation of necrotic tissue, well resuscitated and more stable patients (6, 7). Frequently, early surgery is performed when the patients are developing high intra-abdominal pressure (8 -10).
In fourteen patients the indication for emergency surgery was the abdominal compartment syndrome. Abdominal decompression was performed surgically through a midline laparotomy. The patients outcome was difficult, four developing MSOF, which did respond to treatment and died in within 24 h after surgery. The delayed healing of the ten early operated patients was accompanied by a long period of hospitalisation. After ten days post intervention, seven of them developed infected necrosis, necessiting surgical drainage and lavage, three patients healing by pancreatic fibrosis. Diagnosis of infected necrosis was made by US, CT guided aspiration of necrotic material and fluid collections around the pancreas in only 4 cases.
All patients that underwent early surgery had developed complication, pancreatic pseudocyst, suffering another surgical intervention for the pseudocyst drainage three months after acute inflammatory pancreatic process. From these patients, nine developed a pancreatic fistula that was treated conservatively six weeks with octreotide and NSAID`s.
From the entire group study, forty patients developed pancreatic necrosis, which in 20 cases became infected. Patients with infected necrosis significantly had more often rectal temperature greater than 38.5ºC (p = 0.001). Before operation (after maximum conservative treatment), four findings were significantly related to infection: rectal temperature greater than 38.5ºC, base excess greater than 4 mmol/L, hematocrit less than 35% (p = 0.0001) and paO2 less than 60 mm Hg (p = 0.001).
After two to three weeks of evolution, in thirteen patients with a CT index higher than three, was performed open necrosectomy with conventional tube drainage. These patients's evolution was delayed because of multiple germs infections and the diverse antimicrobial sensitivity. After bacteriology swabs have been taken by US, CT guided aspiration or from intraoperatory, the antibiotic therapy was adjusted (Table 5), the patient's evolution being prolonged but favourable.
From 151 patients diagnosed with acute severe pancreatitis, 104 underwent only conservative treatment with a complete remission of the inflammatory process and no chronic complications. Another 20 patients who developed localised necrosis were treated conservatively, no surgery was required, the outcome being represented by the inflammatory process remission accompanied by a well marked pancreatic fibrosis.

Discussion
Serum amylase rises within 2 to 12 hours from the symptoms onset, reaches the peak level in within 48 hours of the attack, returning to normal in 3-5 days (sensitivity of 80% with 88% specificity) (9). In patients with acute severe pancreatitis who develop a renal failure during the acute attack, the serum amylase could raise because kidneys clear 25% of serum amylase (9, 10). Plasmatic amylase >1000 in our study was considered diagnostic (11).
Serum CRP concentration represents an independent prognosis element (11) level greater than 210 mg/L, days 2-4, or plasmatic values higher than 120 mg/L at the first week's end can predict the pancreatitis evolution more than other criteria (11, 12). We could not asses the CRP evolution for the entire group because it was not tested for all patients at admission time.
Repeated CT scans were performed for in the second and in the third week of the pancreatitis evolution trying to assess a possible evolution to septic complications.
Infections occur in 30-40% of those who have over 30% necrosis of the pancreas and infectious complications account for about 80% of deaths from necrotising pancreatitis (13).
The pathogens frequently involved were Acinetobacter (35%), Staphylococcus spp. (24%), Enterococcus spp. (24%), Klebsiella pneumoniae (14%) and Pseudomonas spp. (11%), the likely source being the translocation of enteric organisms. Our patients did not receive selective digestive decontamination (14).
Imipenem, cefotaxime, piperacillin, ciprofloxacin and metronidazole are antibiotics with good pancreatic tissue penetrations (15). Prophylactic antibiotherapy is found to increase the incidence of fungal infection of pancreatic necrosis, which is associated with an increased mortality rate following surgery for infected necrosis (16). From the study group only one patient developed digestive fungal infection with Candida albicans.
In our study we did not observe that the antibiotic treatment significantly reduces the risk of developing infected pancreatic necrosis. High-risk patients for infected necrosis were those with a high Ranson score and an increased Computed Tomography Score Index (CTSI), confirmed by the ulterior evolution. All patients with CT index (Balthazar Score) higher than 3 developed infected necrosis under aggressive conservative treatment. These findings are sustained in a recent published double blind randomize study, which certifies no benefit prophylactic antibiotherapy in infected pancreatic necrosis (17, 18).
The conservatively treated group exhibited a better outcome when compared with the surgical treated patients. The emergency surgery was performed trying to improve the patient's outcome; it is not clear if surgical decompression in these patients is advantageous. Mortality was present and the morbidity significantly higher in the group exposed to early surgical treatment. The hospitalisation was longer for the surgical treated patients comparing with the conservative treated group.

Conclusion
The Balthazar Score, the pancreatic necrosis, the systemic status, the surgery of infected necrosis and the surgery timing are crucial factors for survival prognosis in patients with severe acute pancreatitis. In our study we observed that the patients who were operated later than three weeks after the pancreatitis onset had a better evolution. For patients with undergoing surgery timing had an important consequence regarding the outcome. Early surgical intervention often results in unnecessary procedures with an increase in the number of deaths. Whenever possible, prolonged observation allows selection of patients who are likely to benefit from delayed surgery or non operative treatment. The conservative treatment should be the first option in acute severe pancreatitis management.

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